discussing politics helps kids and the youth of today be more open minded and think for themselves based on what other people bring to the table

If young kids are our future, they should have the opportunity to understand what they will be doing in the future

Cuidado porque aquí puedes caer fácilmente en la trampa y comértelo con patatas.

purpose

purpose

comparible expirences of invasion is not as realivant to indigenous identity in Africa. does this mean that indigeneity means cultural similarity in Africa?

james clifford- As a historian rather than a traditional anthropologist, his work was sometimes viewed as focusing more on the text of anthropology (the writing) than the practice (the fieldwork). current problems in indigenous studies, museum studies, visual and performance studies, cultural studies, and cross-cultural translation. He grew up in New York City and was for thirty-three years Professor in the History of Consciousness Department at the University of California, Santa Cruz .

I thought this was quite interesting because I thought "" and '' simply did the same thing. I did not know '' initiated a different data type.

As I interpret this: There are many different ways to accomplish the same thing, so two algorithms that can perform the same tasks might be completely different from each other, with their own benefits and pitfalls.

Small typo in formula. Should be C6H4NO3- on the LHS and C6H4NO3H on the RHS

one thing I need to work on is making sure my main idea stays clear throughout the whole paper. I noticed that some of my paragraphs kind of drift away from my thesis, so I want to revise by making each paragraph connect more directly back to my main point about authentic voice and AI. I also want to add more detail in certain parts, especially in my personal story, so it feels more vivid and meaningful instead of rushed. another thing I need to fix is making my transitions smoother so the paper flows better from one idea to the next. I also plan to strengthen my evidence by making sure I clearly explain how it supports my argument instead of just including it. overall, I want to focus on making my writing clearer, more connected, and more reflective of my own voice.

noted

my favorite part about writing is seeing how much better it can get, like seeing the progression is satisfying

I feel like most people forget just how much we use our writing skills in such a wide varity of ways, lke the ones listed above

I like the refrigerator reference

one helpful experience I’ve had with peer feedback was when someone actually took the time to explain what was working in my writing and what wasn’t, instead of just saying “it’s good” or making small edits. they pointed out where my ideas were strong and where I could go deeper, which made it easier for me to improve my paper in a real way. a not helpful experience I’ve had was when someone barely gave any feedback and just wrote something really general that didn’t help me understand what to fix. it felt like they didn’t really read my work. what would have made that experience better is if they gave more specific comments, like asking questions or pointing out exact parts that were confusing or needed more detail.

one of my favorite parts, educating myself.

I feel like we'll see a lot of this in our AI essays.

I would probably start with something personal or relatable to draw the reader in, maybe something about how writing can feel different depending on the situation or how people connect more to real, emotional writing. I would also introduce my main idea about why authentic voice matters and how AI can’t fully replace that, especially when it comes to lived experience and emotion. I might briefly mention my example so the reader knows what to expect. for the conclusion, I would focus on the bigger message or “so what” of my paper. I would talk about why this matters not just for school, but for the future, especially with AI becoming more common in jobs and writing. I would also connect it back to my experience and explain why keeping human voice is important, not just for me but for other students and future generations.

noted

different problems cause for different solutions

a thesis is the reason being in front of the reader/audience. it gives an all around valid explanation for persweying or clarity

to where the point of its validation would be seen clearly by the audience/supporters readers as well. Whoever it may be one has to have a good start to support the writing in depth

when I write a paper, I usually just start by writing whatever comes to mind first instead of overthinking it. I don’t spend too much time planning in the beginning because I feel like that slows me down, so I just get my ideas out and see where it goes. once I have something written, I go back and read through it a couple times and start adjusting things like wording, structure, and flow. in the middle stage, I might add more details or examples if something feels too short or unclear. toward the end, I focus on making sure everything makes sense together and that my main point is clear. I usually reread it a few times to fix anything that sounds off and make sure it actually sounds okay.

Source Credibility: Although the author is a student, her paper uses unbiased language throughout. All of her sources are directly accredited and come from reputable organizations such as the NCAA, AP News, and UN Women.

Author Credibility: The author, Kai Jefferson, is a Communications student for UCLA. She writes for UCLA Center for the Study of Women, which is internationally recognized for its research on women, gender, and sexuality issues.

Female athletes influence society beyond sports, similar to male players.

Personal Connection: Athletes can encourage people to help in their communities.

Women athletes are becoming very popular.

Personal Connection: I have noticed an uptick in women's sports on TV in bars and in daily conversations.

Women are gaining equal recognition in the sectors they play for.

Personal Connection: I've noticed women's college basketball gaining more attention.

Main Idea: Women's sports are growing and gaining recognition despite it's challenges.

I noticed in the table that in 2015-2017, the percent of uninsured was around 10.5%. It then raised to 11.1 in 2018, 12.1 in 2019, then dipped again in 2020 at 11.1. I wonder what the cause of this was.

This is a great step for the U.S. because so many people have health issues that they cannot get sorted just because of expensive healthcare. This shows how Ways to get coverage nowadays have increased and more people are able to get help.

I feel like this rule is very unfair because health insurance alone is expensive, and those who cannot afford it would then have to be punished with more financial penalties. I think it was a good idea to remove this rule.

The main goal for healthcare has always been to make it universal yet still respective to countrywide cost. I feel like Obama’s idea of healthcare really made an impact on how healthcare is seen now due to large amounts of support.

Source Credibility: The sources included in this publication range from the United States Senate to ESPN and CBS News, which makes the main idea conveyed highly reputable. Additionally, the host of the site, American Public University, is an accredited online college.

Author Credibility: The author, Dr. Brittany Jacobs, holds a master’s degree in sports management and a doctorate in sports and exercise science, among other qualifications. These credentials, along with her involvement with USA Olympic and rugby teams, make her a very strong and credible author for this source.

Women are paid less despite success.

Personal Connection: It feels unfair that equal, or better performance doesn't mean equal pay.

Laws like Title IX helped increase girls' involvement in sports.

Personal Connection: Laws and regulations aid in making a huge difference in fairness.

Women were historically restricted from sports.

Personal Connection: I have learned through my research that women didn't have the same rights or opportunities in the past.

I think one important reason this spread so quickly is the design of Twitter. Features like retweets and hashtags make it very easy for information to spread to a large audience in a short time. Also, people may feel more motivated to participate because they want attention or to express strong opinions. This makes me think that platform design plays a big role in shaping online behavior.

I found this scenario very difficult because both options have good reasons. From a care ethics perspective, I feel that intervening might be better because it focuses on protecting your parent and taking responsibility for their well-being. However, I also think not intervening can respect their independence and dignity. This made me realize that ethical decisions are often not about right or wrong, but about balancing different values.

eLife Assessment

This important study examines the stability and compensatory plasticity in the retinotopic mapping in patients with congenital achromatopsia. It provides convincing evidence for a stable mapping of the visual field in V1, alongside changes of the readout from V1 into V3, which shows revised receptive field location and size. This paper would be of interest to scientists studying the visual system, brain plasticity, and development.

Reviewer #1 (Public review):

Summary:

This paper examines plasticity in early cortical (V1-V3) areas in an impressively large number of rod monochromats (individuals with achromatopia). The paper examines three things:

(1) Cortical thickness. It is now well established that early complete blindness leads to increases in cortical thickness. This paper shows increased thickness confined to the foveal projection zone within achromats. This paper replicates work by Molz (2022) and Lowndes (2021), but the detailed mapping of cortical thickness as a function of eccentricity and the inclusion of higher retinotopic areas is particularly elegant.

(2) Failure to show largescale reorganization of early visual areas using retinotopic mapping. This is a replication of a very recent study of Molz et al. but I believe, given anatomical variability, the larger n in this study, and how susceptible pRF findings are to small changes in procedure, this replication is also of interest.

(3) Connective field modelling, examining the connections between V3-V1. The paper finds changes in the pattern of connections, and smaller connective fields in individuals with achromatopsia than normally sighted controls, and suggests that these reflect compensatory plasticity, with V3 compensating for the lower resolution V1 signal in individuals with achromatopsia.

This is a carefully done study (both in terms of data collection and analysis) that is an impressive amount of work.

*Effects of eye-movements

The authors have carried out the eye-movement analyses I asked of them. Unfortunately, in 4 individuals they couldn't calibrate the eyetracker (it's impressive they managed in 10). I think this means that 4 of 13 (since a different participant was excluded from head motion) individuals weren't included in correlation analyses. Limiting the correlation analysis to individuals with better fixation has obvious issues. I'd recommend redoing (or additionally including) stats using non-parametric measures while classifying these 4 as having fixation instability of 3 (i.e. greater instability than the participant with the worst fixation who was successfully calibrated).

*Interpreting pRFs

The paper would be strengthened by a little more explicit clarity about what pRFs represent and how that affects their interpretation of their findings as plasticity vs. non-plasticity (I know the authors are aware of this, but I think it would be helpful for readers who are less experienced in pRFs). In the introduction it would be helpful to point out that pRFs represent the collective response of a large population of neurons, and as a result pRF estimates can vary depending on which population of neurons that stimulus drives.

For example, imagine for the sake of argument that rods only project to V1 neurons with larger receptive fields. If one measured pRFs in a control observer under phototopic vs. scotopic conditions one would see smaller pRFs in the photopic conditions. This wouldn't represent 'plasticity' - it would represent the fact that the firing neurons contributing to the pRF signal are a slightly different population because of a change in the stimulus content. This is of course exactly what you see in 2C. And indeed, the authors make this identical point ". In the non-selective condition, the smaller pRFs in controls are in line with the higher spatial resolution of the<br /> cone system, which is not active in the achromat group." But this point would be clearer if more of the conceptual underpinnings were made explicit in the introduction (or at this point in the paper).

Shifts in which population of neurons drive your pRFs can explain main of the more puzzling results in the paper without detracting from your main conclusions. For example, in 2D, I don't think it's differences in S/N driving your results (pRFs are at least theoretically meant to be robust to S/N). If smaller RFs 'drop out' under low luminance and these smaller RFs also tend to be more central, then one would expect the control results of 1D. And I think a similar argument might even be made for the smaller difference in the rod monochromats.

It would be possible to make the point of Figure 4B more simply if Figure 4B was replaced by additional Panels in Figure 2 simply showing V3 pRF sizes/eccentricity distributions. That would make the point that you don't see the same expansion in pRF sizes in V3 in a way that is just as clear, and is closer to the data.

*Interpreting cRFs

Similarly, I think the paper would be improved with more clarity about the underlying signal in CF modeling. Once again, I appreciate that the authors are familiar with this, but it will help the reader in interpretation. (And I do believe thinking carefully about this may alter your interpretations). CF receptive fields 'find' the region in V1 that best predict the V3 signal in a given voxel. In resting state this likely represents a combination of:

(1) visually driven signal - correlations that may or may not reflect connectivity but represent the fact that regions that represent the same region of visual space will be active at the same time.

(2) global bilaterally symmetrical signal consisting of enhanced correlations between iso-eccentric regions (Raemaekers et al., 2014), which may arise from vasculature that symmetrically stems from the posterior cerebral artery (Tong et al., 2013; Tong and Frederick, 2014).

(3) intrinsic neural fluctuations that are more strongly correlated between connected neurons. These are likely quite weak compared to the other contributions.

I think if you ignore 2, (which is not likely to differ between rod mono and controls) and model 1 and 3, you might well see shifts in CFs towards the boundary of the scotoma - essentially the CF's location will be biased towards the region of V1 that has stronger correlations - which = the region which has a visual signal.

I do find convincing the argument that you don't see the same shift in controls in the rod-selective condition. So I think the results of 4A are fine. But a little more clarity about 'what's under the hood' in CF modeling would be nice.

*Interpreting the relationship between pRFs and cRFs

So there's something here that confuses me. We are all agreed that V3 pRF sizes are similar across RM and control. V1 pRFs are larger in RM. It feels intuitive that smaller CFs would compensate but I can't make it make sense to myself when I think it through. Each pRF represents a combination of receptive field location scatter and bandwidth. You want to argue that eccentricity mapping looks pretty normal, so there's no reason to think increased rf scatter, and I can believe that (though I do think this assumption should be discussed explictly).

So far I think we agree.

But let's think about what drives a CF during visual stimulation ... Specifically lets think about 'the pRF of the CF' (the region of visual space represented by the cluster of voxels in the CF). If pRFs for individual voxels in V1 are big, then the pRF for the CF is also going to be large. But we know that pRFs for V3 are normal size. So, the V3 CF will 'find' a smaller number of voxels in V1, in order to try to find the 'correct sized' CF pRF. Note that this explanation is very similar to yours. But doesn't require ANY 'intrinsic' connectivity. It's really just assuming the whole thing is driven by the visual signal and the CF size is determined by the ratio of the pRF sizes in V3 vs. V1.

One possible solution would be to regress out the visual stimulus and redo this analysis based on the residuals.

Reviewer #3 (Public review):

Summary:

This study addresses a long-standing question in visual neuroscience concerning how the human visual system balances stability and plasticity when sensory input is altered from early in life. Using achromatopsia as a model of lifelong cone deprivation, the authors examine whether early visual cortex undergoes retinotopic reorganization to compensate for the absence of foveal cone input, or whether canonical retinotopic organization is largely preserved. By combining fMRI-based population receptive field (pRF) mapping with connective field (CF) modelling, the authors characterize changes across multiple hierarchical stages of visual processing.

The main findings indicate that primary visual cortex (V1) shows no systematic remapping of the foveal projection zone, whereas extrastriate cortex, particularly V3, exhibits altered patterns of sampling from V1. The authors interpret these results as evidence for hierarchical adaptation, whereby downstream readout mechanisms adjust to make more efficient use of degraded rod-mediated input while preserving early-stage retinotopic organization.

Strengths:

A major strength of this work is the use of silent substitution to generate rod-selective stimuli. This approach enables a principled comparison between achromats and typically sighted controls by isolating rod-driven responses in both groups. In doing so, the study overcomes a key limitation of prior work, where differences in cortical organization could often be confounded by differences in photoreceptor class rather than reflecting neural reorganization per se. The inclusion of a rod-driven baseline in controls provides an important reference for distinguishing long-term adaptation from transient or stimulus-driven effects.

Another notable strength is the integration of CF modelling alongside conventional pRF mapping. While pRF analyses alone suggest enlarged receptive fields in V1, consistent with reduced spatial resolution, the CF analysis offers a more mechanistic account by revealing changes in how V3 samples information from the V1 surface. This multi-level modelling approach moves beyond descriptive accounts of cortical map structure and provides a framework for interpreting how downstream areas may adjust their integration strategies under conditions of altered input.

Weaknesses:

Although the study is methodologically strong, the central claims regarding stability and compensatory plasticity require clearer conceptual framing and stronger empirical support. Stability is primarily defined as the absence of large-scale retinotopic remapping in V1, yet the presence of significantly enlarged V1 pRFs indicates substantial tuning-level plasticity at the input stage; distinguishing topographic stability from functional reorganization would therefore strengthen the interpretation. Moreover, the proposed compensatory mechanism raises a signal-processing concern, as reduced downstream sampling (smaller CFs in V3) cannot restore spatial information lost due to coarse upstream representations, and may instead limit integration. The mechanistic link between altered CF properties and normalization of extrastriate pRFs is not directly tested, as group differences are not shown to covary across individuals or visual field locations. Finally, the interpretation of these changes as compensatory implies functional benefit, yet no behavioral or performance measures are provided to establish that the observed reorganization preserves or enhances visual function, leaving open whether these effects reflect adaptive optimization or passive downstream consequences of altered input.

Author response:

The following is the authors’ response to the original reviews.

Public Reviews:

Reviewer #1 (Public review):

Summary:

This paper examines plasticity in early cortical (V1-V3) areas in an impressively large number of rod monochromats (individuals with achromatopia). The paper examines three things:

(1) Cortical thickness. It is now well established that early complete blindness leads to increases in cortical thickness. This paper shows increased thickness confined to the foveal projection zone within achromats. This paper replicates the work by Molz (2022) and Lowndes (2021), but the detailed mapping of cortical thickness as a function of eccentricity and the inclusion of higher visual areas is particularly elegant.

(2) Failure to show largescale reorganization of early visual areas using retinotopic mapping. This is a replication of a very recent study by Molz et al. but I believe, given anatomical variability (and the very large n in this study) and how susceptible pRF findings are to small changes in procedure, this replication is also of interest.

(3) Connective field modelling, examining the connections between V3-V1. The paper finds changes in the pattern of connections, and smaller connective fields in individuals with achromatopsia than normally sighted controls, and suggests that these reflect compensatory plasticity, with V3 compensating for the lower resolution V1 signal in individuals with achromatopsia.

Strengths:

This is a carefully done study (both in terms of data collection and analysis) that is an impressive amount of work. I have a number of methodological comments but I hope they will be considered as constructive engagement - this work is highly technical with a large number of factors to consider.

Weaknesses:

(1) Effects of eye-movements

I have some concerns with how the effects of eye-movements are being examined. There are two main reasons the authors give for excluding eye-movements as a factor in their results. Both explanations have limitations.

(a) The first is that R2 values are similar across groups in the foveal confluence. This is fine as far as it goes, but R2 values are going to be low in that region. So this shows that eyemovements don't affect coverage (the number of voxels that generate a reliable pRF), but doesn't show that eye-movements aren't impacting their other measures.

We agree with the reviewer that eye movements could affect pRF measures. We have now also included data for all participants where we were able to obtain eye tracking measures and directly tested this relationship. Relevant results are copied below.

Recap of results: 1) as expected gaze was less stable in achromats than controls, 2) achromats with more stable gaze did not show more activation in the scotoma projections zone, which we might have observed if fixation instability masks signals in this region 3) Gaze instability was not correlated with pRF size and eccentricity across V1 in achromats. We note that the relationship between nystagmus and visual sampling is complex - patients experience a stable image and may sample only during a specific phase of the eye movement. It is therefore not inherently clear if and how nystagmus affects pRF size.

Relevant Manuscript text incorporating these analyses is copied below.

To quantify eye movement, we used the following methods added to the manuscript:

“Fixation stability

Participants’ gaze was tracked throughout all pRF mapping runs. Collecting reliable gaze data from individuals with nystagmus is a challenge because out of the box calibration procedures mostly fail without stable fixation. To account for this, we implemented a post-hoc custom calibration procedure (Tailor et al., 2021). The eye-tracker was first precalibrated on a typically sighted individual. Then, before every other run, we collected gaze data from a 5-point fixation task (at fixation and above, below, left, and right of fixation at 5 eccentricity). This data allowed us to subsequently map the patient's recorded gaze coordinates to their precise locations on the screen. In 10 out of the 14 achromats we acquired reliable enough data to assess fixation stability.

Calibration data processing: We first removed the first 0.5 seconds for each fixation location to allow for fixation to arrive on the target. We then performed (a) blink removal, (b) filtered out time points with eye movement velocity outliers (±2SD), and (c) filtered out any positions >3SDs to the left or right of the mean fixation location, and >1SD above or below. We took the median of the remaining gaze measurements as an approximate fixation estimate. The resulting 5 median fixation locations were used to fit an affine transformation that remapped the recorded gaze positions into screen space. 

Quantifying fixation stability: after applying the transformation of the post-hoc calibration, data was filtered for blinks and extreme velocities (<2SD). For each functional run, fixation instability was measured as the standard deviation of gaze x-positions across 1second windows. Measures were then averaged across the two run repeats.”

We report the resulting new fixation data results as follows:

Results (coverage section):

“Another potential confound in our findings is fixation instability. In pRF mapping, which is usually conducted under photopic (cone-dominant) conditions, unstable fixation can cause a signal drop in the foveal projection zone. As expected due to nystagmus, the achromatopsia group showed higher fixation instability compared to controls (rodselective: t_(9.08)=-3.19, p=0.01; non-selective: t<sub<(9.41)</sub>=-4.88, p<0.001 degrees-offreedom corrected for unequal-variance; see Supplement Figure S2a). However, several lines of evidence suggest this instability cannot fully account for the lack of "filling in" in achromats. First, within the achromat group, we found no correlation between fixation stability and coverage (rod-selective: spearman-r₍₈₎ = -0.36, p=0.31; non-selective spearman-r₍₈₎=0.07,p=0.85); Individuals with more stable, control-like fixation did not show more signal inside the scotoma (see Supplement 2). Second, in adults with achromatopsia, typically with less severe nystagmus (Kohl et al., 1993), two recent studies also found absence of filling in (Anderson et al., 2024; Molz et al., 2023).

So, while we cannot fully exclude nystagmus masking foveal signals in the cortex of some patients, this converging evidence from structural and functional MRI measures across different studies and groups, strongly suggests that the deprived cortex does not substantially ‘fill in’ with peripheral rod inputs in achromatopsia.”

Results (pRF size + eccentricity):

“Larger pRFs indicate that neuronal populations in achromats’ V1 cortex, combine information across larger areas in visual space than in typically sighted controls. This could reflect true neural tuning differences as well as be driven by larger eye movement. However, fixation instability in achromats do not significantly correlate with pRF size in our sample (rod-selective: spearman-r₍₈₎ = -0.41, p=0.24; non-selective spearman-r₍₈₎=0.37,p=0.29)

It has been shown that fitting artefacts around scotoma edges, can give rise to similar outward eccentricity shifts (Binda et al., 2013). However, when accounting for fitting artefacts around the foveal scotoma edge by modelling the rod-free zone during pRF fitting, pRF size and eccentricity differences remain unchanged (see Supplement 3). Finally, we found no significant correlations between gaze stability and the eccentricity shift (rod-selective: spearman-r₍₈₎ = 0.58, p=0.08; non-selective spearman-r₍₈₎=0.09,p=0.8, Supplement 4D)

Together, these analyses reveal subtle differences in how V1 of achromats responds to rod signals outside the foveal zone, which are consistent with results from other studies (Molz et al. 2023, Anderson et al. 2024). While we found no direct evidence that these are being driven by confounding factors such as eye-movements or fitting artefacts, more work is needed to understand the underlying processes that give rise to these shifts.”

The following text has been added to Supplement 2

“As expected, achromats showed significant higher fixation instability compared to controls (as reported in the main text). We found no significant correlation between fixation instability and either coverage, pRF size, eccentricity in achromats. Results of Spearman R correlations in both rod- and non-selective conditions are reported in the figure. We note that the relationship between nystagmus and visual sampling is complex- patients experience a stable image and may sample only during specific eyemovement phases. It is therefore not fully clear if and how nystagmus should give rise to altered pRFs.”

(b) The authors don't see a clear relationship between coverage and fixation stability. This seems to rest on a few ad hoc examples. (What happens if one plots mean fixation deviation vs. coverage (and sets the individuals who could not be calibrated as the highest value of calibrated fixation deviation. Does a relationship then emerge?).

In any case, I wouldn't expect coverage to be particularly susceptible to eye-movements. If a voxel in the cortex entirely projects to the scotoma then it should be robustly silent. The effects of eye-movements will be to distort the size and eccentricity estimates of voxels that are not entirely silent.

There are many places in the paper where eye-movements might be playing an important role. 

Examples include the larger pRF sizes observed in achromats. Are those related to fixation instability?

We thank the reviewer for their comment. As detailed in our previous response, we have now extracted fixation instability data from additional patients and have expanded our discussion of its potential effects throughout the manuscript.

Given that fixation instability is expected to increase pRF size by a fixed amount, that would explain why ratios are close to 1 in V3 (Figure 4).

We agree with the reviewer’s point, that the ratio change on its own is not strong evidence of compensation, this analysis was meant to complement the CF result. The plot in Figure 4 is intended to reconcile the connective field (CF) and pRF results. Its purpose is to illustrate that even though larger pRFs in achromats might seem counterintuitive alongside their smaller V3 CF sizes, the pRF data do not contradict the CF findings but they are in fact consistent with one another. We also agree that there are alternative explanations for the differences in pRF size, such as fixation stability, and we have now added this point to the text.

Results (CF size):

“To understand how this finer cortical sampling in V3 (smaller connective fields) impacts visual processing, we consider its effect on population receptive fields (pRFs). In V1, pRF sizes in achromats were significantly larger than in controls for both stimulus conditions, indicating coarser spatial tuning at the cortical input stage (Figure 4C, left). By selectively sampling from a smaller area of the V1 surface (smaller CFs), V3 can effectively compensate for this coarser input. If so, this process should result in a relative normalisation of pRF size in V3 compared to V1 (Figure 4C, right).

To test this prediction, we plotted the ratio of pRF sizes between achromats and controls, where a value of 1 indicates parity between the groups (Figure 4B). As our compensatory connective field hypothesis predicts, the ratio was closer to 1 in V3 than in V1 across both stimulus conditions, confirming the pRF size difference was significantly reduced at the higher cortical stage. Together this shows converging evidence across the two models (pRF and CF) of hierarchical refinement as a possible compensatory mechanism, where V3's altered connectivity helps to normalize the processing of degraded sensory input from V1.”

Discussion:

“The hierarchical reorganisation observed in V3 is unlikely to be driven by fixation instability. Connective field (CF) estimates are robust to eye movements (Tangtartharakul et al., 2023), because they are anchored to V1 inputs rather than absolute screen position. Considered alone, the pRF results could alternatively be explained by eye movements introducing a fixed size offset that affects smaller V1 pRFs more strongly than those in V3. While we found no evidence for this relationship between pRF size and gaze measures in our patients, we cannot fully rule out the possibility. Nevertheless, the internal consistency between the CF and pRF measures provides a more parsimonious account; that sampling across the hierarchy accounts for coarser tuning at the input stage.”

(2) Topography

The claim of no change in topography is a little confusing given that you do see a change in eccentricity mapping in achromats. 

Either this result is real, in which case there *is* a change in topography, albeit subtle, or it's an artifact. 

Perhaps these results need a little bit of additional scrutiny. 

One reason for concern is that you see different functions relating eccentricity to V1 segments depending on the stimulus. That almost certainly reflects biases in the modelling, not reorganization - the curves of Figure 2D are exactly what Binda et al. predict. 

Another reason for concern is that I'm very surprised that you see so little effect of including/not including the scotoma - the differences seem more like what I'd expect from simply repeating the same code twice. (The quickest sanity check is just to increase the size of the estimated scotoma to be even bigger?).

We thank the reviewer for their comment. We have double-checked our scotoma modelling, confirming its correct implementation. The results of the scotoma modelling are not identical to the full one, just similar (see below).

Previous studies on “artificial scotomas” (such as the one reported by Binda et al.) have shown mixed results. While Binda and colleagues found that modelling artificial scotomas normalised pRF shifts, others found no effect (Haak et al. 2012, Prabhakaran et al. 2020). Notably, the rodfree zone in achromatopsia is considerably smaller (~0.5° radius) than most tested artificial scotomas. Moreover, it is unclear whether scotoma modelling is beneficial in clinical populations as artificial scotomas (screen-based masking) are not equivalent to retinal scotomas from inactive photoreceptors. A recent achromatopsia study (Anderson et al. 2024) also found no change in pRF estimates with scotoma modelling.

In our scotoma analyses, we found meaningful differences only in the non-selective condition in controls where cones in the rod-free zone are stimulated - which would be the main expected effect of this modelling exercise (see below). In all other conditions (rod-selective in controls, both conditions in achromats), only rods are stimulated, we found no difference in coverage, eccentricity or pRF size when modelling the scotoma likely because the foveal signal is weak/absent, and did not contribute much to pRF estimates in the unmasked analyses.

This means we cannot account for the eccentricity shift as an edge effect with this scotoma model – but we remain cautious about interpreting it as real. This is because first, as we mention in the paper, in the non-selective condition, which has a higher signal-to-noise ratio, the eccentricity estimates in achromats match those of the control group's rod system. Second, it is still possible that the observed shift is an artefact of modelling that was not accounted for by the approach of scotoma modelling.

Our claim of "no change in topography" specifically referred to the absence of "filling-in" as measured by cortical coverage - the percentage of activated tissue regardless of fitted parameters. However, to avoid confusing given the eccentricity and pRF size results we now rephrased our claim.

Abstract:

“Cortical input stages (V1) exhibited high stability, with input-deprived cortex showing no retinotopic remapping and exhibiting structural hallmarks of deprivation.”

Results (pRF eccentricity):

“It has been shown that fitting artefacts around scotoma edges, can give rise to similar outward eccentricity shifts (Binda et al., 2013). However, when accounting for fitting artefacts around the foveal scotoma edge by modelling the rod-free zone during pRF fitting, pRF size and eccentricity differences remain unchanged (see Supplement 3). Finally, we found no significant correlations between gaze stability and the eccentricity shift (rod-selective: spearman-r₍₈₎ = 0.58, p=0.08; non-selective spearman-r₍₈₎=0.09,p=0.8, Supplement 4D)

Together, these analyses reveal subtle differences in how V1 of achromats responds to rod signals outside the foveal zone, which are consistent with results from other studies (Molz et al. 2023, Anderson et al. 2024). While we found no direct evidence that these are being driven by confounding factors such as eye movements or fitting artefacts, more work is needed to understand the underlying processes that give rise to these shifts.”

To better illustrate the effect of scotoma modelling text has been added to Supplement 3:

“Studies on artificial scotomas, where part of the visual field is masked, suggest that pRF estimates of eccentricity and size can be biased by fitting scotoma-edge artefacts, and that these can be mitigated by modelling the scotoma in the pRF fitting procedure (e.g., Binda et al. 2013).

We therefore repeated the pRF modelling procedure with the rod-scotoma being modelled as a black oval mask (1.25°x0.9°) over the stimulus aperture model. As expected, a visible difference between the two models is only apparent in the nonselective condition in controls where the cones in the rod-free zone are being stimulated. In all the other conditions (rod-selective in controls, and both stimulation conditions in achromats) only the rods are stimulated, therefore the masked stimulus still matches the retinal activation, and no major differences can be observed. Performing the same statistical tests applied to the full model in the main text yields equivalent results of equivalent coverage in the rod-selective condition, with equivalent coverage across groups(t(47) = 0.78, p=0.43, BF10=0.31) and controls show a higher coverage in the non-selective stimulation condition compared to achromats (Mann U(52)=141, p<0.01; unequal variance, reverted to non-parametric).

This consistency in pRF properties when modelling the rod scotoma, is in line with previous results from scotoma modelling; While Binda and colleagues found that this normalised pRF shifts, others found no effect (Haak et al. 2012, Prabhakaran et al. 2020). Notably, the rod-free zone in achromatopsia is considerably smaller (~0.5° radius) than most tested artificial scotomas, and as artificial scotomas (screen-based masking) are not equivalent to retinal scotomas from inactive photoreceptors, it is unclear how artificial scotoma findings generalise to clinical populations. Our results are in line with a recent achromatopsia study (Anderson et al. 2024) which also found no change in pRF estimates with scotoma modelling.”

I'd also look at voxels that pass an R2>0.2 threshold for both the non-selective and selective stimulus. Are the pRF sizes the same for both stimuli? Are the eccentricity estimates? If not, that's another clear warning sign.

Comparable results were obtained when using higher R2 thresholds. These results are now included in Supplement 6.

(3) Connective field modelling

Let's imagine a voxel on the edge of the scotoma. It will tend to have a connective field that borders the scotoma, and will be reduced in size (since it will likely exclude the cortical region of V1 that is solely driven by resting state activity). This predicts your rod monochromat data. The interesting question is why this doesn't happen for controls. One possibility is that there is topdown 'predictive' activity that smooths out the border of the scotoma (there's some hint of that in the data), e.g., Masuda and Wandell.

One thing that concerns me is that the smaller connective fields don't make sense intuitively. When there is a visual stimulus, connective fields are predominantly driven by the visual signal. In achromats, there is a large swath of cortex (between 1-2.5 degrees) which shows relatively flat tuning as regards eccentricity. The curves for controls are much steeper, See Figure 2b. This predicts that visually driven connective fields should be larger for achromats. So, what's going on?

The reviewer raises interesting points about the interpretation of our connective field results. The possibility of differential top-down modulation between controls and achromats is intriguing, however it is not supported by the data, if top-down modulation is activating foveal V1 in controls then we shouldn’t see a drop in the amount of significant vertices sampling from the fovea in the rod-selective condition compared to the non-selective, but in fact we do see quite a large drop in the amount of significant vertices in that area in the rod-selective condition. Therefore, at the moment we do not think there is strong basis to assume our data could be explained by achromats lacking top-down predictive activity in the scotoma area that is present in controls.

Regarding the concern about smaller CFs seeming counterintuitive given the flat eccentricity tuning in achromats' V1: we believe there is not a straightforward prediction from pRF properties to CF sizes. The relationship between V1 pRF characteristics and V3 CF sampling is complex and not well-established in the literature, and the two can be decoupled to some degree. For instance, in our data, controls show flat V1 pRF sizes in the rod-selective condition (similar to achromats), yet their V3 CF sizes maintain the typical eccentricity-dependent increase seen in the non-selective condition. This suggests that CF size patterns don't simply mirror V1 pRF properties or visual stimuli responses.

Importantly, CF modelling fundamentally differs from pRF analysis in how it might be affected by scotomas. Unlike pRF analysis where a scotoma creates a "silent" region in visual space, in CF modelling the deprived cortex remains physically present and continues generating neural signals (albeit not visually-driven ones). If V3-V1 connectivity were anatomically fixed, V3 would continue sampling from deprived V1 regions even if they do not produce visual-driven signals. A change in this sampling pattern, as we see in our data, is therefore evidence for plasticity.

Our data support this interpretation. First, in achromats, the CF size pattern observed cannot be easily explained by scotoma-edge artefacts. V3 vertices sampling from the immediate vicinity of the scotoma (1°-3°) show CF sizes comparable to controls. The effect is only significant further away from the scotoma (4°-6°).

Second, to assess how the presence of a scotoma affects CF measure we can compare the two conditions in the controls, since the rod-selective condition has a scotoma present and the nonselective condition does not. For this purpose, we performed an additional analysis, quantifying on a vertex-by-vertex level the differences in CF fitted parameters between the two stimulation conditions across V1. See results below. In achromats there are no systematic shifts between the stimulation conditions, as expected as both are rod-driven. In controls, this analysis reveals only subtle shifts (~0.45° in the rod-selective condition). CF size has also changed slightly although not significantly different from that observed in achromats. These shifts are much smaller than the CF size and eccentricity differences between controls and achromats, so we consider it unlikely that our findings are driven by scotoma artefacts.

Author response image 1.

Results (CF size):

“The significant CF size differences are unlikely to be a model-fitting bias around a scotoma edge, as V3 vertices sampling from the immediate vicinity of the scotoma (1°3°) show CF sizes comparable to controls. The significant reduction in CF size occurs only further in the periphery (4°-6°), in regions that are primarily stimulus-driven.

To understand how this finer cortical sampling in V3 (smaller connective fields) impacts visual processing, we consider its effect on population receptive fields (pRFs). In V1, pRF sizes in achromats were significantly larger than in controls for both stimulus conditions, indicating coarser spatial tuning at the cortical input stage (Figure 4C, left). By selectively sampling from a smaller area of the V1 surface (smaller CFs), V3 can effectively compensate for this coarser input. If so, this process should result in a relative normalisation of pRF size in V3 compared to V1 (Figure 4C, right).

To test this prediction, we plotted the ratio of pRF sizes between achromats and controls, where a value of 1 indicates parity between the groups (Figure 4B). As our compensatory connective field hypothesis predicts, the ratio was closer to 1 in V3 than in V1 across both stimulus conditions, confirming the pRF size difference was significantly reduced at the higher cortical stage. Together this shows converging evidence across the two models (pRF and CF) of hierarchical refinement as a possible compensatory mechanism, where V3's altered connectivity helps to normalize the processing of degraded sensory input from V1.”

Discussion (added paragraph):

“The hierarchical reorganisation observed in V3 is unlikely to be driven by fixation instability. Connective field (CF) estimates are robust to eye movements (Tangtartharakul et al., 2023), because they are anchored to V1 inputs rather than absolute screen position. Considered alone, the pRF results could alternatively be explained by eye movements introducing a fixed size offset that affects smaller V1 pRFs more strongly than those in V3. While we found no evidence for this relationship between pRF size and gaze measures in our patients, we cannot fully rule out the possibility. Nevertheless, the internal consistency between the CF and pRF measures provides a more parsimonious account; that sampling across the hierarchy accounts for coarser tuning at the input stage.”

The beta parameter is not described (and I believe it can alter connective field sizes).

In Author response image 2, we plot the beta parameter of the pRF modelling in V1 with no R² filtering, error bars are 95% CIs:

Author response image 2.

The reviewer did not specify how beta might alter connective field sizes. We assume he meant that as in pRF mapping, the slope of activity from deprived to non-deprived cortex will artefactually create a CF model fit with smaller CF sizes. To test this, we calculated the slope of beta values between 0° and 3° in each participant in the rod-selective condition, as this range includes the scotoma and the area at the edge of the scotoma. We then used the slope as a covariate in an ANCOVA when comparing the CF sizes across groups in each sampled V1 segment. Accounting for the beta slope of V1 did not change the reported results. This analysis still shows smaller CF sizes in V3 in the rod-selective conditions between 4°-6° eccentricity – these differences remain significant (p<0.001 for 4°-5° and p<0.05 for 5°-6° when comparing achromats vs controls).

Similarly, it's possible to get very small connective fields, but there wasn't a minimum size described in the thresholding.

CF sizes were fit with a grid fit. Possible values were [0.5,1,2,3,4,5,7,10]. Therefore, the minimum size is 0.5. Filtering out the smallest connective field sizes does not change the results:

Author response image 3.

I might be missing something obvious, but I'm just deeply confused as to how the visual maps and the connectome maps can provide contradictory results given that the connectome maps are predominantly determined by the visual signal. Some intuition would be helpful.

We agree that this appears counterintuitive, and now added further clarification. The two models (pRF and CF) fundamentally differ in what they measure and how they relate to visual processing. V1 pRF sizes reflect the relationship between neural activity and visual stimuli - essentially how much of a visual stimulus drives a voxel's response - while V3 CF sizes reflect how V3 samples from the V1 cortical surface, indicating how many V1 voxels contribute to a V3 voxel's activity.

The measures constrain each other, as a V3 voxel's pRF size is expected to match the pooling of its connected V1 inputs. But they can be decoupled: A V3 voxel could sample from a small area of V1 cortex (a small CF in mm) that happens to represent a large area of visual space if those V1 voxels have large pRFs. The aim of Figure 4B is to clarify that the measures are consistent with one another even though they diverge in direction. In achromats, where V1 voxels have larger pRFs (coarser spatial resolution), V3 appears to compensate by sampling more selectively from V1 via smaller CF sizes. Theoretically, this should reduce the pRF size difference between controls and patients in V3, a prediction that our data supports.

Results (CF size):

“To understand how this finer cortical sampling in V3 (smaller connective fields) impacts visual processing, we consider its effect on population receptive fields (pRFs). In V1, pRF sizes in achromats were significantly larger than in controls for both stimulus conditions, indicating coarser spatial tuning at the cortical input stage (Figure 4C, left). By selectively sampling from a smaller area of the V1 surface (smaller CFs), V3 can effectively compensate for this coarser input. If so, this process should result in a relative normalisation of pRF size in V3 compared to V1 (Figure 4C, right).

To test this prediction, we plotted the ratio of pRF sizes between achromats and controls, where a value of 1 indicates parity between the groups (Figure 4B). As our compensatory connective field hypothesis predicts, the ratio was closer to 1 in V3 than in V1 across both stimulus conditions, confirming the pRF size difference was significantly reduced at the higher cortical stage. Together this shows converging evidence across the two models (pRF and CF) of hierarchical refinement as a possible compensatory mechanism, where V3's altered connectivity helps to normalize the processing of degraded sensory input from V1.”

Discussion (added paragraph):

“The hierarchical reorganisation observed in V3 is unlikely to be driven by fixation instability. Connective field (CF) estimates are robust to eye movements (Tangtartharakul et al., 2023), because they are anchored to V1 inputs rather than absolute screen position. Considered alone, the pRF results could alternatively be explained by eye movements introducing a fixed size offset that affects smaller V1 pRFs more strongly than those in V3. While we found no evidence for this relationship between pRF size and gaze measures in our patients, we cannot fully rule out the possibility. Nevertheless, the internal consistency between the CF and pRF measures provides a more parsimonious account; that sampling across the hierarchy accounts for coarser tuning at the input stage.”

Some analyses might also help provide the reader with insight. For example, doing analyses separately on V3 voxels that project entirely to scotoma regions, project entirely to stimulusdriven regions, and V3 voxels that project to 'mixed' regions.

We agree that it is important to plot the connective field dynamics across the scotoma region.

In Figure 4A we split the V3 vertices based on the V1 area they sample from. Therefore the 0°-1° would be considered as mainly sampling from the “scotoma” region and the higher the eccentricity is, the less “scotoma” it includes. The V3 vertices that have a significantly smaller CF size compared to controls are those sampling from mostly if not entirely stimulusdriven regions 4°-5° and 5°-6°. We are not sure how further binning the data by within, across and outside scotoma would be more informative.

However, in Author response image 4, we plot in more details the distribution of CF sizes sampling from a V1 segment clearly inside and clearly outside the scotoma. The top figure shows the CF size distribution of V3 vertices that sample from a V1 0°-1° segment, where V1 is deprived of input due to the rod scotoma. In achromats, there is a clear drop in vertices with a very small (0.5) CF size. The bottom figure shows the distribution of V3 vertices that sample from the V1 4°-5° segment which falls outside the scotoma and shows a significant difference in CF size across the groups. Here in achromats you can see a drop in larger V3 CF sizes sampling from the V1 region, and an increase in smaller ones (note that this further addresses a previous concern that connective field differences across groups are solely driven by very small CFs).

Author response image 4.

Following the reviewer’s comment we have added the following statement in the results section discussing CF size:

“The significant CF size differences are unlikely to be a model-fitting bias around a scotoma edge, as V3 vertices sampling from the immediate vicinity of the scotoma (1°3°) show CF sizes comparable to controls. The significant reduction in CF size occurs only further in the periphery (4°-6°), in regions that are primarily stimulus-driven.”

The finding that pRF sizes are larger in achromats by a constant factor as a function of eccentricity is what differences in eye-movements would predict. It would be worth examining the relationship between pRF sizes and fixation stability.

We found no relationship between fixation stability and pRF size in V1, although as we explain in response to an earlier point, this does not fully exclude the reviewers alterative explanation, which we now add to the discussion.

Discussion:

“The hierarchical reorganisation observed in V3 is unlikely to be driven by fixation instability. Connective field (CF) estimates are robust to eye movements (Tangtartharakul et al., 2023), because they are anchored to V1 inputs rather than absolute screen position. Considered alone, the pRF results could alternatively be explained by eye movements introducing a fixed size offset that affects smaller V1 pRFs more strongly than those in V3. While we found no evidence for this relationship between pRF size and gaze measures in our patients, we cannot fully rule out the possibility. Nevertheless, the internal consistency between the CF and pRF measures provides a more parsimonious account; that sampling across the hierarchy accounts for coarser tuning at the input stage.”

Reviewer #2 (Public review):

Summary:

The authors inspect the stability and compensatory plasticity in the retinotopic mapping in patients with congenital achromatopsia. They report an increased cortical thickness in central (eccentricities 0-2 deg) in V1 and the expansion of this effect to V2 (trend) and V3 in a cohort with an average age of adolescents.

In analyzing the receptive fields, they show that V1 had increased receptive field sizes in achromats, but there were no clear signs of reorganization filling in the rod-free area. In contrast, V3 showed an altered readout of V1 receptive fields. V3 of achromats oversampled the receptive fields bordering the rod-free zone, presumably to compensate and arrive at similar receptive fields as in the controls.

These findings support a retention of peripheral-V1 connectivity, but a reorganization of later hierarchical stages of the visual system to compensate for the loss, highlighting a balance between stability and compensation in different stages of the visual hierarchy.

Strengths:

The experiment is carefully analyzed, and the data convey a clear and interesting message about the capacities of plasticity. 

Weaknesses:

The existence of unstable fixation and nystagmus in the patient group is alluded to, but not quantified or modeled out in the analyses. The authors may want to address this possible confound with a quantitative approach.

We have responded to this in the “Recommendations for the authors” section of this reviewer, as they included a more detailed description of these points there.

Recommendations for the authors:

Reviewer #1 (Recommendations for the authors):

(1) I think the term rod monochromats should be included early in the paper since it's a more intuitive term to describe this population.

We agree with the reviewer that the term “rod monochromats” is more intuitive as it clarifies the retinal source of the disease but have chosen the term achromats for consistency with a wide literature of published work in this group, including our own and our close collaborators’. To clarify, in the first mention of the group as achromats in the introduction we have now added this term:

“Achromatopsia (also known as rod monochromacy) causes cone photoreceptors in the retina to be inactive from birth (Aboshiha et al., 2014).”

(2) The paper essentially contains two definitions of 'eccentricity'. One (atlas/segments) comes from the Benson atlas and the other (functional) comes from pRF mapping. It would be good to make this distinction terminology clearer earlier in the paper. It would also be good to use more consistent terminology. I assume 'sampled atlas V1 eccentricity' in 3A is the same as 'V1 segment' in 1A?

For consistency we have now referred to these as V1 segment and sampled V1 segment in the figures when describing the atlas-based definition, and eccentricity for the measured pRF-based eccentricity.

(3) The 'stability vs. plasticity' framing in the introduction could be tightened slightly.

We have made the following changes following the reviewer’s comment:

“In the visual domain, the focal point of the debate on plasticity and stability has hinged on the extent to which retinal input deprivation can drive local reorganisation in early visual cortex, for example, for deprived tissue to take on inputs from spared retinal locations (Adams et al., 2007; Baker et al., 2005, 2008; Baseler et al., 2002, 2011; Calford et al., 2005; Dilks et al., 2009; Dumoulin & Knapen, 2018; Ferreira et al., 2016; Goesaert et al., 2014; Haak et al., 2015; Molz et al., 2023; Ritter et al., 2019; Schumacher et al., 2008). In reality visual impairment is a more global phenomenon, affecting all levels of visual processing, with complex dynamics beyond constricted local retinocortical projection zones(Carvalho et al., 2019).”

(4) Figure 1A, define the x axis as degrees.

We have now added the ° sign to all the tick labels indicating Benson map eccentricity.

(5) Figure 2B, is there room for pictures of the silent substitution/standard stimulus

We have now added images in a Supplement 5 to avoid cluttering the main Figure 2B

(6) Figure 2

Panel A has a slightly weird organization. The reader is supposed to compare the square symbols to each other, and the circles to each other, why not organize the figure so they are adjacent in the graph (i.e. non selective control, non-selective achromat, selective control, selective achromat)? That also helps the reader orient that in the non-selective conditions you have almost complete pRF coverage. 

We have taken on the reviewer’s suggestion and changed the order.

In the inset, maybe use empty symbols? That's the traditional way to say that the square/circle applies to both red and black.

We prefer the current format.

Figure 2C - the symbols change to circles? Why not keep the symbols of A?

We have now changed the symbols of 2C&D.

I'd put the non-selective maps above the selective maps?

We appreciate the feedback but prefer to keep it as it is, as we feel the critical point is conveyed by the rod maps.

(7) 'We propose a new hierarchical model of neural adaptation'. These ideas are hardly new. There are also other models, that would explain your data (cumulative plasticity) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953572/

We thank the reviewer for the reference. We have now cited it in our discussion and removed the word “new” form the mentioned sentence.

“Therefore, there is theoretically broader scope for experience-dependent reweighting of inputs (Beyeler et al., 2017; Makin & Krakauer, 2023) and to optimise use of inputs that are still available, more reliable, or more relevant in the impaired system. Conversely, higher-order visual areas may appear more plastic simply because they integrate the cumulative effects of learning from multiple lower stages (Beyeler et al., 2017).”

We propose a hierarchical model of neural adaptation…” [deleted the word new]

(8) Line 508. No image of the stimulus is contained in the paper

Corrected

(9) Line 620. I believe the Figure is 1B, not 1C.

Corrected

(10) Figure 4A. CF Size - add mm2 to the axes.

Corrected

Reviewer #2 (Recommendations for the authors):

I am not an expert on pRF mapping, and as such, I am unsure how to relate to pRF mapping performed in patients with unstable fixation (not quantified, but referred to) and nystagmus, such as the achromatic population here. Since the majority of the results hinge on this analysis, I would appreciate more data about the differences between the groups. Supplement 2, which is meant to speak to this, shows only the data from 3 typical participants, and in itself is not evidence for "no correlation between stable fixation and enhanced foveal". Additionally, I'd appreciate a clear methods explanation of how the authors address these confounds; this is too important a concern to be left for the discussion section.

We agree with the reviewer that eye movements could affect pRF measures. We have now also included data for all participants where we were able to obtain eye tracking measures and directly tested this relationship. Relevant results are copied below.

Recap of results: 1) as expected gaze was less stable in achromats than controls, 2) achromats with more stable gaze did not show more activation in the scotoma projections zone, which we might have observed if fixation instability masks signals in this region 3) Gaze instability was not correlated with pRF size and eccentricity across V1 in achromats. We note that the relationship between nystagmus and visual sampling is complex - patients experience a stable image and may sample only during a specific phase of the eye movement. It is therefore not inherently clear if and how nystagmus affects pRF size.

Relevant Manuscript text incorporating these analyses is copied below.

To quantify eye movement, we used the following methods added to the manuscript:

“Fixation stability

Participants’ gaze was tracked throughout all pRF mapping runs. Collecting reliable gaze data from individuals with nystagmus is a challenge because out of the box calibration procedures mostly fail without stable fixation. To account for this, we implemented a post-hoc custom calibration procedure (Tailor et al., 2021). The eye-tracker was first precalibrated on a typically sighted individual. Then, before every other run, we collected gaze data from a 5-point fixation task (at fixation and above, below, left, and right of fixation at 5 eccentricity). This data allowed us to subsequently map the patient's recorded gaze coordinates to their precise locations on the screen. In 10 out of the 14 achromats we acquired reliable enough data to assess fixation stability.

Calibration data processing: We first removed the first 0.5 seconds for each fixation location to allow for fixation to arrive on the target. We then performed (a) blink removal, (b) filtered out time points with eye movement velocity outliers (±2SD), and (c) filtered out any positions >3SDs to the left or right of the mean fixation location, and >1SD above or below. We took the median of the remaining gaze measurements as an approximate fixation estimate. The resulting 5 median fixation locations were used to fit an affine transformation that remapped the recorded gaze positions into screen space.

Quantifying fixation stability: after applying the transformation of the post-hoc calibration, data was filtered for blinks and extreme velocities (<2SD). For each functional run, fixation instability was measured as the standard deviation of gaze x-positions across 1second windows. Measures when then averaged across the two run repeats.”

Results (coverage section):

“Another potential confound in our findings is fixation instability. In pRF mapping, which is usually conducted under photopic (cone-dominant) conditions, unstable fixation can cause a signal drop in the foveal projection zone. As expected due to nystagmus, the achromatopsia group showed higher fixation instability compared to controls (rodselective: t_(9.08)=-3.19, p=0.01; non-selective: t<sub<(9.41)</sub>=-4.88, p<0.001 degrees-offreedom corrected for unequal-variance; see Supplement Figure S2a). However, several lines of evidence suggest this instability cannot fully account for the lack of "filling in" in achromats. First, within the achromat group, we found no correlation between fixation stability and coverage (rod-selective: spearman-r₍₈₎ = -0.36, p=0.31; non-selective spearman-r₍₈₎=0.07,p=0.85); Individuals with more stable, control-like fixation did not show more signal inside the scotoma (see Supplement 2). Second, in adults with achromatopsia, typically with less severe nystagmus (Kohl et al., 1993), two recent studies also found absence of filling in (Anderson et al., 2024; Molz et al., 2023).

So, while we cannot fully exclude nystagmus masking foveal signals in the cortex of some patients, this converging evidence from structural and functional MRI measures across different studies and groups, strongly suggests that the deprived cortex does not substantially ‘fill in’ with peripheral rod inputs in achromatopsia.”

Results (pRF size + eccentricity):

“Larger pRFs indicate that neuronal populations in achromats’ V1 cortex, combine information across larger areas in visual space than in typically sighted controls. This could reflect true neural tuning differences as well as be driven by larger eye movement. However, fixation instability in achromats do not significantly correlate with pRF size in our sample (rod-selective: spearman-r₍₈₎ = -0.41, p=0.24; non-selective spearman-r₍₈₎=0.37,p=0.29)

It has been shown that fitting artefacts around scotoma edges, can give rise to similar outward eccentricity shifts (Binda et al., 2013). However, when accounting for fitting artefacts around the foveal scotoma edge by modelling the rod-free zone during pRF fitting, pRF size and eccentricity differences remain unchanged (see Supplement 3). Finally, we found no significant correlations between gaze stability and the eccentricity shift (rod-selective: spearman-r₍₈₎ = 0.58, p=0.08; non-selective spearman-r₍₈₎=0.09,p=0.8, Supplement 4D)

Together, these analyses reveal subtle differences in how V1 of achromats responds to rod signals outside the foveal zone, which are consistent with results from other studies (Molz et al. 2023, Anderson et al. 2024). While we found no direct evidence that these are being driven by confounding factors such as eye-movements or fitting artefacts, more work is needed to understand the underlying processes that give rise to these shifts.”

The following text has been added to Supplement 2

“As expected, achromats showed significant higher fixation instability compared to controls (as reported in the main text). We found no significant correlation between fixation instability and either coverage, pRF size, eccentricity in achromats. Results of Spearman R correlations in both rod- and non-selective conditions are reported in the figure. We note that the relationship between nystagmus and visual sampling is complex- patients experience a stable image and may sample only during specific eyemovement phases. It is therefore not fully clear if and how nystagmus should give rise to altered pRFs.”

The field connectivity analysis similarly seems to be used only on task data from the same design; if it was replicated from resting-state data, that would be a good way to show consistency which is independent of measures requiring fixation. 

We agree that resting-state data would be valuable; however, we did not collect such data in these individuals due to time limitations. Instead, we demonstrate the consistency and reliability of our results by replicating our findings across two different stimulation conditions (rod-selective and non-selective), which differ in luminance, contrast and signal amplitude in both groups and for controls also in the photoreceptors involved. The convergence of results across these distinct visual conditions strengthens our confidence in the reliability of the observed effects. Also, notably, CF estimates have been shown to be robust to large eye movements, and therefore also to differences in fixation stability across groups (Tangtartharakul et al., 2023).

The authors may want to contextualize their findings in relation to what reorganization exists in cases of late-onset loss of part of the visual field on one hand (stroke recovery), and in the case of complete blindness from early life on the other, as both speak to different levels of plasticity the visual system is capable of.

We thank the reviewer for their comment and have added a new paragraph discussing this topic.

Discussion:

“Our findings on hierarchical adaptation have broader implications for other visual disorders, depending on their timing and nature. For instance, a central scotoma acquired in adulthood, as in macular degeneration, may not trigger the same V3 sampling shifts (Haak et al., 2016), suggesting a sensitive window for this form of plasticity, after which connective fields remain more stable. This also raises questions about congenital blindness, where the absence of any driving input could lead to weakening or repurposing of hierarchical connections (Saccone et al., 2024). Moreover, principles may differ between a deprived but structurally intact cortex, as in retinal dystrophies, and a physically damaged cortex, as in stroke. In the latter, more extensive reorganisation may be required to sample effectively from surviving, and potentially disparate, regions of V1. Perceptual training effects in stroke rehabilitation may reflect such dynamics (Cavanaugh et al., 2025; Elshout et al., 2021).”

A more minor point: Can the authors clarify what the dark adaptation is used for, and provide the supplementary analysis showing that the duration difference for some of the participants didn't impact the results (stated but not shown).

The dark adaptation period before the rod-selective condition allowed rod photoreceptors to recover from bleaching caused by prior mesopic light exposure, ensuring optimal rod sensitivity under scotopic conditions. To verify that our 15-minute adaptation period was sufficient, we tested 10 control participants with an extended 45-minute adaptation period. As we found no differences in the resulting rod maps between standard and extended adaptation protocols, these participants were combined with the main control group for all analyses. Author response image 5 are the plots for the two dark adaptation periods.

Author response image 5.

I find Confucianism interesting because it focuses on relationships and responsibilities, not just individual actions. As someone who grew up in China, I feel this idea is very familiar, especially the importance of respecting family and maintaining harmony. I think this framework can help us better understand how people from different cultures might behave differently on social media.

While this overview of Confucianism has focused on the importance of personal virtue and social harmony, it does not take into account the tension that exists within the system, namely the potential conflict between individual moral judgment and hierarchical obedience. This can often lead to moral conflicts when the negative actions of the ruling party must be opposed. For example, if an unjust leader or parent is acting immorally, the Confucian principles of loyalty and respect may inhibit the individual from speaking out against them.

I want to add something about consequentialism. Our summary says it focuses on the results, but I think one problem is that it can ignore fairness. For example, if hurting one person makes many people happy, consequentialism might say it is okay. This feels wrong because it does not protect individuals. So, I think this framework is useful, but it can be dangerous if we only care about the outcome and not about justice or rights.

Source Credibility: The sources linked in the blog were directly linked to the Canadian Women's Foundation or Canadian Women & Sport, which are both nationally recognized foundations in Canada.

Women's sports doesn't get enough media attention in all sectors of the world.

Personal Connection: Most games on TV and social media are men's sports.

Supports the theory that minimal participation in girls sports is not cultural to the United States.

Personal Connection: I've seen many girls refuse to join school teams or drop out due to peer pressures.

Main Idea: Promotion of women's sports increases confidence, opportunities, and equality for girls and women.

Ethics helps us navigate our behavior on social media by providing us with principles such as honesty, respect, and responsibility, among others, to use when assessing what we share, post, and engage in on our social media platforms. Ethics also helps us look beyond our own interests and those of our friends and consider how our actions affect others and our society in general.

I found it incredibly fascinating to read about the protesters' ingenuity in using a donkey to protest without consequence. Drawing a comparison between bots and the donkey was particularly fascinating to explore. When I read the article, I discovered that the protesters came up with the idea in response to protests against their sultan being outlawed. It made me wonder: in a time of intense censorship and the defunding of public media/journalism, is it too far-fetched to think that we will see a rise in bots to protest without consequence?

1) What was the rationale for administering Clozapine prior to immunization? Was post-immunization administration of clozapine considered to assess its therapeutic efficacy? 2) Could this paradigm be adapted to a milder or more chronic model in which delayed clozapine administration would be feasible? 3) On what basis were the observed behavioral features interpreted as psychosis rather than catatonia?

for chapter 2: I often hear people say “social media is not real life,” but I don’t fully agree. I think social media is still part of real life because real people are behind the posts and conversations. For example, people share their opinions, emotions, and daily experiences online. However, I also think social media shows a “filtered” version of life, where people only show the best parts. So, social media is real, but it is not the complete picture of reality.

As a general observation, this textbook gives really seamless explanations for many complicated programming tasks. In my business minor, we learned some basic functions in R, but I found it really difficult to understand the specialized structure and syntax of the code beyond the basic level. Though Python similarly uses the English language, the code and syntax itself feel more straightforward and comprehensible. After some research, I learned that my experience comparing the two programs is common. Python is more widely used in large-scale environments due to being easier to learn. I wonder if this has any trade-offs as the code gets more complex.

On 2021-12-07 10:40:57, user S. von Jan wrote:

I feel that some of the assumption that go into the model calculation are overestimated, others are underestimated, and some important further information is not considered. I am referring specifically to v (vaccine uptake), s (susceptibility reduction) and b (relative increase in the recovery rate after a breakthrough infection).

The authors assume a vaccination rate of 65% for the period between 11.10 and 7.11. For the sake of transparency, I think it should be mentioned in the study that in Germany an underestimation of the vaccination rate of up to 5 percentage points is assumed (1), perhaps this should also be considered in the scenarios. Moreover, the recovered cases are not mentioned at all, do they not play a role for the model?

For s in the "upper bound" scenario, a 72% efficacy of the vaccination in Germany is assumed (2), this figure comes from the German Robert Koch Institute (RKI) and is calculated based on the vaccination breakthroughs in Germany, i.e., it only includes the number of symptomatic cases in Germany. The RKI writes on the estimated vaccine effectiveness: "The values listed here must therefore be interpreted with caution and serve primarily to classify vaccination breakthroughs and to provide an initial estimate of vaccine effectiveness" (3, own translation). The vaccine effectiveness estimated here refers to the effectiveness of vaccination against Covid 19 infections with clinical symptoms, not against infection in general. However, there are indications that infections are more often asymptomatic in vaccinated persons ("vaccinated participants were more likely to be completely asymptomatic, especially if they were 60 years or older"(4)), and vaccinated people in Germany must rarely participate in Covid 19 tests. The RKI points out that vaccination would considerably reduce transmission of the virus to other people but assumes that even asymptomatically infected vaccinated people can be infectious: "However, it must be assumed that people become PCR-positive after contact with SARS-CoV-2 despite vaccination and thereby are infectious and excrete viruses. In the process, these people can either develop symptoms of an illness (which is mostly rather mild) or no symptoms at all" (5, own translation). So is the effectiveness of vaccination against symptomatic infections in this setting relevant when it comes to the role of the vaccinated/unvaccinated to the infection incidence?

In the "lower efficacy" scenario, s is given as 50% to 60% based on an English study. This percentage corresponds to the data from another study, which estimates the effectiveness of the Biontech/Pfizer vaccination against infection as 53% after 4 months in the dominant delta variant (6). Would this number not be more plausible for the "upper bound" scenario? The "lower efficacy" scenario could then be calculated with an efficacy of 34%, for example, as suggested by another study on infection among household members (7).

If we consider b, "an average infectious period that is 2/3 as long as this of unvaccinated infecteds" is assumed. This figure seems reasonable based on the available information on the faster decline of the viral load in vaccinated persons. However, there are statements, for example by Prof. Christian Drosten in an interview with the newspaper “Die Zeit”, that make this effect seem less significant: "The viral load - and I mean the isolatable infectious viral load - is quite comparable in the first few days of infection. Then it drops faster in vaccinated people. The trouble is, this infection is transmitted right at the beginning. I'm convinced that we have little benefit from fully vaccinated adults who don't get boostered" (8, own translation). Moreover, there is another issue that is not mentioned in the paper at all, but which I think should be taken into account: Unvaccinated people in Germany have to test themselves much more frequently than vaccinated people (e.g., at the workplace) due to the 3G rules (9, this means vaccinated, recovered or tested). Children and adolescents have a testing frequency of 3 rapid tests a week (10). Even if the effectiveness of the rapid Covid 19 tests for asymptomatic infections should be 58% (i.e., only 58% of infected persons are correctly identified as positive) (11), a test rate of 2 to 3 tests per week would still reduce the duration during which an unvaccinated person is infectious and not in quarantine. This consideration is not included in the model calculation.

Overall, it appears that several central parameters were underestimated or overestimated in the model calculation: The vaccination rate is actually higher, the effectiveness of vaccination against infection is certainly lower than the figure given in the “upper bound” scenario, and the period in which infected persons infect others is shortened for unvaccinated persons by 3G regulations, since they have to go into quarantine if they test positive. As a result, the contribution of the unvaccinated to the infection incidence in Germany is likely to be strongly overestimated in the model calculation, especially in the “upper bound” scenario.

(1) https://www.rki.de/DE/Conte... <br /> (2) For adolescents, s is even estimated at 92%, without explicit data being available here.<br /> (3) https://www.rki.de/DE/Conte.... <br /> (4) https://www.thelancet.com/j...<br /> (5) https://www.rki.de/SharedDo... <br /> (6) https://www.thelancet.com/j... <br /> (7) https://www.thelancet.com/j... <br /> (8) https://www.zeit.de/2021/46... <br /> (9) https://www.bundesregierung... <br /> (10) https://taz.de/Schulen-in-d... <br /> (11) https://www.cochrane.de/de/... This overview work does not yet refer to the delta variant.

On 2020-05-30 07:55:21, user Irene Petersen wrote:

You seem to conflate the risk of getting exposed (and thereby infected) and the risk of dying with covid19. However, these risks may vary substantially and therefore we would need a two-step approach to obtain meaningful predictions. For example, age and ethnicity are strong predictors for exposure while diabetes and obesity are strong predictors of mortality once you are infected.

On 2020-06-23 13:30:40, user Ralph Hawkins wrote:

Analysis of the RECOVERY trial pre-print data, looking only at non-ventilated patients together, not stratified by oxygen use. There is NO DEMONSTRABLE TREATMENT BENEFIT.<br /> Dex treated 360/1780 (20.2%) vs standard care 787/3836 (21.6%) p=0.2427

On 2020-06-23 19:20:17, user addie wrote:

The article states that patients receiving mechanical ventilation were ten years younger than those not receiving respiratory support - this implies that ventilators were being rationed? Can the authors speak to this.

Thank you.

On 2020-06-25 15:01:25, user Kirielson wrote:

I think this paper is fine, my question I would have for the authors: Did you attempt to evaluate if the patient could relay back those risks to you through any metric? Finding a way to see if a patient understands it by evaluation may see how effective one is over the other while looking at their preferneces.

On 2020-06-26 16:13:44, user Veli VU wrote:

the authors do not detect SARS-CoV-2 in samples from 2019 March. Rather, they do detect IP2/IP4 resembling SARS-CoV-2. Whatever virus it is it does not have the E and N1/N2 of SARS-CoV-2. Fluctuations in qRT-PCRs even in 2020 samples -different sewers- are way too high to trust the reliability of the RT-PCRs. However, their approach is amazing. I hope they use a metagenomic approach to sequence to sewers rather than doing an RT-PCR assay, which doesn't look very rigorous.

On 2021-06-04 13:42:50, user fauxnombre1 wrote:

Help me understand. The cumulative dose is not a product of the duration of treatment? Patients receiving treatment longer have a better survival rate?

On 2021-06-10 20:23:12, user John Jay wrote:

Sorry if this was already mentioned, but is there a discussion of how the demographics (ie age, co-morbidities, status before care, etc.) varied between the group given 3,000mg HCQ + 1,000mg AZM and all other patients in the study?

On 2020-06-06 05:51:49, user Tim Lee wrote:

The possible relationship between A blood type and COVID-19 progressive respiratory failure.

Endemen et al (2020) found that progressive respiratory failure in COVID-19 is linked to hypercoagulability.21 This conclusion is supported by cohort studies that found hypercoagulability and a severe inflammatory state in COVID-19 patients 22,23 . Type A blood increases the risk for thromboembolic events.25 Viral infections activate the blood coagulation system.29

It may be that all factors that increase your risk for hypercoagulation increase the risk for progressive respiratory failure in COVID-19. One factor that has caught my attention is mercury. It is ubiquitous and known to cause hypercoagulation. (26-28) For more info please read my note on the topic https://www.qeios.com/read/...

1. Endeman H, Zee P van der, Genderen ME van, Akker JPC van den, Gommers D. Progressive respiratory failure in COVID-19: a hypothesis. Lancet Infect Dis. 2020;0(0). doi:10.1016/S1473-3099(20)30366-2

2. Panigada M, Bottino N, Tagliabue P, et al. Hypercoagulability of COVID-19 patients in Intensive Care Unit. A Report of Thromboelastography Findings and other Parameters of Hemostasis. J Thromb Haemost JTH. Published online April 17, 2020. doi:10.1111/jth.14850

3. Spiezia L, Boscolo A, Poletto F, et al. COVID-19-Related Severe Hypercoagulability in Patients Admitted to Intensive Care Unit for Acute Respiratory Failure. Thromb Haemost. Published online April 21, 2020. doi:10.1055/s-0040-1710018

4. Ellinghaus D, Degenhardt F, Bujanda L, et al. The ABO blood group locus and a chromosome 3 gene cluster associate with SARS-CoV-2 respiratory failure in an Italian-Spanish genome-wide association analysis. medRxiv. Published online June 2, 2020:2020.05.31.20114991. doi:10.1101/2020.05.31.20114991

5. Groot Hilde E., Villegas Sierra Laura E., Said M. Abdullah, Lipsic Erik, Karper Jacco C., van der Harst Pim. Genetically Determined ABO Blood Group and its Associations With Health and Disease. Arterioscler Thromb Vasc Biol. 2020;40(3):830-838. doi:10.1161/ATVBAHA.119.313658

6. Worowski K. The Hypercoagulability in Mercury Chloride Intoxicated Dogs. Thromb Haemost. 1968;19(1/2):236-241. doi:10.1055/s-0038-1651201

7. Lim K-M, Kim S, Noh J-Y, et al. Low-Level Mercury Can Enhance Procoagulant Activity of Erythrocytes: A New Contributing Factor for Mercury-Related Thrombotic Disease. Environ Health Perspect. 2010;118(7):928-935. doi:10.1289/ehp.0901473

8. Song Y. [Effects of chronic mercury poisoning on blood coagulation and fibrinolysis systems]. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi Zhonghua Laodong Weisheng Zhiyebing Zazhi Chin J Ind Hyg Occup Dis. 2005;23(6):405-407.

9. Antoniak S. The coagulation system in host defense. Res Pract Thromb Haemost. 2018;2(3):549-557. doi:10.1002/rth2.12109

On 2021-06-08 17:43:19, user Jan Zo wrote:

The article was published recently in Mol Cell Ped https://doi.org/10.1186/s40...

On 2020-04-10 15:16:29, user Guilherme Araujo Lima da Silva wrote:

Hi, Do you have the code available? Is it R, Python or Julia?

On 2020-06-09 16:22:37, user Sinai Immunol Review Project wrote:

Title <br /> Eosinopenia Phenotype in Patients with Coronavirus Disease 2019: A Multi-center Retrospective Study from Anhui, China

Keywords<br /> • Lymphopenia<br /> • Covid-19 severity<br /> Main Findings<br /> It was previously shown that more than 80% of severe COVID-19 cases presented eosinopenia, in a cohort of Wuhan [1]. In this preprint Cheng et al. aim to describe the clinical characteristics of COVID-19 patients with eosinopenia. In this retrospective and multicenter study, the COVID-19 patients were stratified in three groups: mild (n=5), moderate (n=46) and severe (n=8). All patients received inhalation of recombinant interferon and antiviral drugs, 50% of the eosinopenia patients received corticosteroids therapy compared to 13.8% of the non-eosinopenia patients according to the patients’ clinical presentation. The median age of eosinopenia patients was significantly higher than the non-eosinopenia ones (47 vs 36 years old) as well as body temperature (not significant). Eosinopenia patients had higher proportions of dyspnea, gastrointestinal symptoms, and comorbidities. Eosinopenia patients presented more common COVID-19 symptoms, such as cough, sputum, fatigue, than non-eosinopenia patients (33.3% vs 17.2%). Interestingly lymphocytes counts (median: 101 cells/ul) in eosinopenia patients were significantly less than in non-eosinopenia patients (median: 167 cells/ul, p<0.001). All patients within the severe group recovered and presented with similar numbers of eosinophils and lymphocytes compared with healthy individuals upon resolution of infection and symptoms. The results showed by Cheng et al. are similar to another study involving MERS-Cov [2], but is contradictory to the previous observation with infants infected with respiratory syncytial virus, where high amounts of eosinophils were found in the respiratory tract of patients [3].

Limitations<br /> The sample size of this study (n=59) is very narrow and could bias the observations described. The authors did not thoroughly measure potential confounding effects of or control for type of treatments, which were different across the patients. <br /> It is still unclear if SARS-COV-2 infection induces eosinopenia or eosinophilia in the respiratory tract, since all reports so far showed peripheral eosinophil counts. As eosinophils antiviral response to respiratory viral infections has been shown [4], it would be important have discussed if the high inflammatory response produced by eosinophils could contribute to the lung pathology during COVID-19, especially when vaccine candidates have been tested and could induce increased amounts of eosinophils.

Significance<br /> This study suggests that eosinophilia may be a clinical phenotype of COVID-19 that distinguishes eosinopenia patients from non-eosinopenia patients. The contribution of the present study is relevant and calls for experimental analysis to reveal the importance of eosinopenia in COVID-19.

Credit<br /> Reviewed by Alessandra Soares-Schanoski as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

1. Du, Y., et al., Clinical Features of 85 Fatal Cases of COVID-19 from Wuhan: A Retrospective Observational Study. Am J Respir Crit Care Med, 2020.
2. Hwang, S.M., et al., Clinical and Laboratory Findings of Middle East Respiratory Syndrome Coronavirus Infection. Jpn J Infect Dis, 2019. 72(3): p. 160-167.
3. Harrison, A.M., et al., Respiratory syncytical virus-induced chemokine expression in the lower airways: eosinophil recruitment and degranulation. Am J Respir Crit Care Med, 1999. 159(6): p. 1918-24.
4. Lindsley, A.W., J.T. Schwartz, and M.E. Rothenberg, Eosinophil responses during COVID-19 infections and coronavirus vaccination. J Allergy Clin Immunol, 2020.

On 2020-07-02 23:29:56, user Sergey wrote:

This pre-print does not have a Methods section- how did the medRxiv QC miss this?

On 2020-04-14 05:46:51, user Alexander wrote:

The same results: d-dimer>2500 (OR 6.9, 95% CI, 3.2-15.2), ferritin >2500 (OR 6.9, 95% CI, 3.2-15.2). Is it correct?

On 2020-07-12 14:20:35, user Knut M. Wittkowski wrote:

Herd immunity is not a "strategy", it's nature's way of dealing with influenza-like illnesses. Once the data is in, the models become obsolete. Herd immunity is already established in many places, including the northeast of the US (NYC) and most of Europe. Proof: There is no rebound in spite of widespread "reopening". QED

On 2021-01-28 19:31:33, user Maciek Boni wrote:

The public Github repo has been renamed: https://github.com/bonilab/...

On 2020-07-15 07:10:13, user Dr Ahmed Sayeed wrote:

Section Review comments and notes Abstract, title and references The study appears to be new and promising in the current scenario of COVID pandemic In the objectives, the authors have the aim to describe the bronchoscopic findings in COVID patients but in the method, they have forgotten to mention how the bronchoscopic findings will be studied What is the meaning of COVID19 patients? Is suspected covid19 or confirmed COVID 19 with Nasopharyngeal swab(PCR or serology or Nuclear acid amplification test) The references are recent and relevant with the inclusion of appropriate study

Introduction/background In introduction line 4, the term bronchial alveolar lavage would be more appropriate than bronchial culture The author uses the term culture repeatedly which excludes other methods like PCR, grams stain, KOH stain, AFB and would be advised to use the broader term to include other methods of detection of organisms The limitations of the study are not mentioned Methods The study subjects The age group of the patients should be mentioned and the site of covid infection? lung also needs to be mentioned The variables are defined and measured Yes the study appears to valid and reliable

Results My knowledge of statistics is very limited and it is difficult for me to comment

Discussion and Conclusions<br /> There is a grammatical error in line 2 and 5 of the discussion Suggest difficult to do suction In paragraph 3 of the discussion the reference 18 is written twice The reference in the discussion are not quoted in serial order The limitations of the study need to be explained more

Overall The study design was appropriate This study added the to the scarcity of the novel virus literature and it showed that more hospital acquired infections are common in patients with covid I did not find any major flaws in the article

full review:

Overall statement or summary of the article and its findings

The article needs some correction and rewriting with some of my suggestion<br /> Some more literature needs to be done and added to the discussion with some new references

Overall strengths of the article and what impact it might have in the respiratory field

The article appears to be promising and will definitely add to the literature of BAL in COVID which not frequently performed in fear of spreading the infection to the health care staff Culture and sensitivity will make a difference in the management of COVID ventilated patients

Specific comments on the weaknesses of the article and what could be done to improve it Major points in the article which need clarification, refinement, reanalysis, rewrites and/or additional information and suggestions for what could be done to improve the article.

More literature review<br /> More references need to be added<br /> Minor points like figures/tables not being mentioned in the text, a missing reference, typos, and other inconsistencies.

English and grammar

On 2020-05-01 04:18:35, user Dr. Anthony Burnetti wrote:

The proposed mechanism is blocking the import of accessory proteins into the nucleus that suppress the innate immune response. The dose needed to block viral replication in vitro is possibly higher than a dose that could have a positive impact on the immune response. It is still quite possible that the approved dose could have stronger effects in animals than in tissue culture.

On 2021-06-20 08:07:15, user Stephen Smith wrote:

note bottom-left panel in Fig1 needs replacing with the correct scatterplot; have tweeted the corrected sub-panel and will update PDF here shortly.

On 2020-04-16 23:17:24, user Samantha Grist wrote:

We appreciate the authors’ urgency in addressing SARS-CoV-2 decontamination for reuse of N95 filtering facepiece respirators (FFRs). In the spirit of that urgency and health impacts, we note two concerns with the current preprint that could (unintentionally) cause confusion: (1) likely mismatch between the wavelength range to which the reported UVA/B light meter is sensitive and the viral-killing UV-C wavelengths emitted by the LED High Power UV Germicidal Lamp, as highlighted by other commenters, and (2) omission of a direct comparison between the UV-C doses applied in this study and the minimally acceptable UV-C dose understood to be needed for efficacy (e.g., CDC Guidance).

We have contacted the authors Fischer and Munster via separate email suggesting that they:

1. Please check a potential mismatch between the UVGI light needed for viral inactivation and the UVA/B light meter used: The LED High Power UV Germicidal Lamp described in the Methods emits in the 260-285 nm range, as is appropriate to inactivate virus by damaging DNA and RNA. However, the UVA/B light meter (General Tools) mentioned in the Methods section is not suited to detect the virus-killing light from the LED High Power UV Germicidal Lamp. Further supporting the possibility of a sensor-source mismatch is the reported irradiance of 5 µW/cm^2, which is ~1000x lower than typically reported for effective N95 FFR decontamination [Lore et al., 2012 (1.6-2.2 mW/cm^2); Heimbuch & Harnish, 2019 (4.2-18 mW/cm^2), Mills et al., 2018 (17 mW/cm^2)].

Being designed for germicidal function, the LED High Power UV Germicidal Lamp would have significant output in the UV-C range and would not be expected to have significant output in the UVA/B range (280-400 nm). Put another way, the UVA/B light meter used would not be able to accurately assess the germicidal function of the LED High Power UV Germicidal Lamp, which stems from the UV-C light. It is the UV-C-specific dose that is relevant to viral inactivation, with UV-B (280-320 nm) dose providing significantly lower germicidal efficacy, and UV-A (320-400 nm) considered very minimally germicidal [Kowalski et al., 2009; Lytle and Sagripanti 2005; EPA].

1. Please clarify the total UV-C dose delivered in Figure 1, as the peer-reviewed literature points to UV-C dose of > 1.0 J/cm2 as the critical factor in N95 FFR viral inactivation treatment. Although UV-C dose governs viral inactivation, the preprint does not clearly state the germicidal UV-C dose delivered to the N95 coupons for the Figure 1 treatment times. While germicidal UV dose is the product of the UV-C irradiance and exposure time, comparison to the minimally acceptable UV-C dose of 1.0 J/cm^2 is needed. UV-C irradiance varies significantly both between and within systems, so treatment time is not an accurate characterization metric for understanding UV-C germicidal efficacy (especially when translating to a different dosing system); dose needs to be quantified directly with a NIST-traceable, calibrated radiometer matched to the germicidal wavelength range of the source. At the reported 5 µW/cm^2 irradiance, the total dose delivered during a 60 min treatment period is only 18 mJ/cm^2, greater than an order of magnitude lower than the effective 1.0 J/cm^2 UV-C dose reported in the literature for similar viruses [Lore et al., 2012; Heimbuch & Harnish, 2019, Mills et al., 2018] and current CDC guidelines for UVGI decontamination of N95s [CDC]. A UV-C dose of 1.0 J/cm^2 across all N95 FFR surfaces is understood from the literature as the minimum acceptable for N95 decontamination.

Without these clarifications we are concerned that this important study may be misconstrued by readers as indicating that either (i) very low UV-C doses are sufficient for N95 decontamination (the peer-reviewed evidence suggests that they are not), (ii) a certain UV exposure time is sufficient for N95 decontamination (dose, not time, is the critical factor) or (iii) that UV-A or UV-B are effective decontamination wavelength ranges (they are not). In the spirit of the authors’ study, our #1 concern is for the health of our heroic healthcare professionals. For additional detail from the peer-reviewed literature, please see the 2020 scientific consensus summaries on N95 FFR decontamination at: n95decon.org.

On 2020-05-02 21:19:54, user Javier Mancilla-Galindo wrote:

This study could have a great impact in policy making. However, even when the authors have acknowledged that serological studies will be of great importance in order to take any decisions, the authors have not commented on the impact that having non-neutralizing antibodies, especially for the persons undergoing asymptomatic or mild disease, could have on this model. Also, a sufficient and efficient cellular immune response would be granted for this model to hold true. A third factor which could affect this model is the ability of the virus to mutate into an antigenically different strain.

Even when the initial intention of the model was not to take into account these factors, it would be important to clarify that a 100% effective adaptive immune response is being assumed and that no viral antigenic variability is being considered. The authors could address what is known up to this date on these topics to strengthen the discussion and conclusions of this study and for successful publication.

On 2021-02-09 15:49:22, user Rhonda Witwer wrote:

Great study! What was the source of your Type 3 resistant starch? Different sources have been shown to have different effects, making it important to disclose the RS source.

On 2021-10-06 17:29:33, user Trevor Madge wrote:

Forgive me I may have misunderstood the paper, but is the dataset only including those who where "sick" with COVID19? Does it exclude all asymptomatic infections?

On 2019-11-09 20:30:28, user GuyguyKabundi Tshima wrote:

EVOLUTION OF THE EPIDEMIC IN THE PROVINCES OF NORTH KIVU AND ITURI AT 07 NOVEMBER 2019<br /> Friday, November 08, 2019<br /> • Since the beginning of the epidemic, the cumulative number of cases is 3,286, of which 3,168 are confirmed and 118 are probable. In total, there were 2,192 deaths (2074 confirmed and 118 probable) and 1064 people healed.<br /> • 560 suspected cases under investigation;<br /> • No new confirmed cases;<br /> • No new confirmed deaths have been recorded;<br /> • 1 person cured out of the CTE of Butembo;<br /> • No health worker is among the new confirmed cases. The cumulative number of confirmed / probable cases among health workers is 161 (5% of all confirmed / probable cases), including 41 deaths;

NEWS

End of tour of the general coordinator of the Ebola response in North Kivu and Ituri

• The Epidemic Response Coordinator for Ebola Virus Disease, Prof. Steve Ahuka Mundeke, was on mission from 05 to 07 November 2019 in a few areas affected by Ebola Virus Disease in North Kivu and Ituri, to inquire about the epidemiological and security evolution of the response. During this mission, he visited some sites of the response to Beni in North Kivu, including the Mangango camp where the vaccination of pygmies took place;

• In Ituri, Prof Ahuka traveled to Biakato Mines in Mandima, Mambasa Territory, where he first reinserted three of the four cured patients he had discharged well into the Mangina Ebola Treatment Center in the area. Mabalako health center in North Kivu. He also comforted the family of the retaliating agent and journalist, murdered on the night of Saturday, November 2, 2019 in Lwemba in Mambasa territory in Ituri;

• He also chaired the daily meeting on the activities of the response in the sub-coordination of Biakato Mines;

• On his way back, the general coordinator of the riposte went to the Mangina Subcommittee, where he chaired under the trees the morning meeting in Mangina. He also visited the Health Center "Case of Salvation" which collaborates with the response and to whom he handed over a large batch of mattresses in the presence of the WHO coordinator of Mangina's sub-coordination. He again visited the Mangango camp, where the pygmies who have joined the activities of the riposte live to help the response reach all the other pygmies;

• He closed his tour of North Kivu and Ituri with a visit to the Ebola Treatment Center in Beni.

VACCINATION

• Pygmy vaccination continues in Mabalako at Mangango camp, 19/19 vaccinated pygmies;<br /> • Continuation of vaccination in expanded ring, around 3 confirmed cases on 04/11/2019 and 2 cases confirmed on 05/11/2019 and the vaccination of the biker as contacts, in Beni in five (5) areas health care, including in Butsili, Ngongolio, Tamende, mandrandele and Kasabinyole;<br /> • Since vaccination began on August 8, 2018, 248,460 people have been vaccinated;<br /> • The only vaccine to be used in this outbreak is the rVSV-ZEBOV vaccine, manufactured by the pharmaceutical group Merck, following approval by the Ethics Committee in its decision of 20 May 2018.

MONITORING AT ENTRY POINTS

• Since the beginning of the epidemic, the total number of travelers checked (temperature rise) at the sanitary control points is 114,626,335 ;<br /> • To date, a total of 111 entry points (PoE) and sanitary control points (PoCs) have been set up in the provinces of North Kivu and Ituri to protect the country's major cities and prevent the spread of the epidemic in neighboring countries.

As a reminder, the recommendations of the MULTISECTORAL COMMITTEE OF THE RESPONSE TO EBOLA VIRUS DISEASE are as follows:

1. Follow basic hygiene practices, including regular hand washing with soap and water or ashes;
2. If an acquaintance from an epidemic area comes to visit you and is ill, do not touch her and call the North Kivu Civil Protection toll-free number;
3. If you are identified as a contact of an Ebola patient, agree to be vaccinated and followed for 21 days;
4. If a person dies because of Ebola, follow the instructions for safe and dignified burials. It is simply a funeral method that respects funerary customs and traditions while protecting the family and community from Ebola contamination.
5. For all health professionals, observe the hygiene measures in the health centers and declare any person with symptoms of # Ebola (fever, diarrhea, vomiting, fatigue, anorexia, bleeding).<br /> If all citizens respect these health measures recommended by the Secretariat, it is possible to quickly end this 10th epidemic.

On 2019-11-10 21:15:52, user GuyguyKabundi Tshima wrote:

EVOLUTION OF THE EPIDEMIC IN THE PROVINCES OF NORTH KIVU AND ITURI AT 08 NOVEMBER 2019<br /> Saturday, November 09, 2019<br /> • Since the beginning of the epidemic, the cumulative number of cases is 3,286, of which 3,168 are confirmed and 118 are probable. In total, there were 2,192 deaths (2074 confirmed and 118 probable) and 1064 people healed.<br /> • 501 suspected cases under investigation;

THE LIST OF NO:

• No new cases have been confirmed;<br /> • No new confirmed deaths have been recorded;<br /> • No cured person has emerged from CTEs;<br /> • No health worker is among the new confirmed cases. The cumulative number of confirmed / probable cases among health workers is 161 (5% of all confirmed / probable cases), including 41 deaths;

NEWS

NOTHING TO REPORT

VACCINATION<br /> • Since vaccination began on August 8, 2018, 249,290 people have been vaccinated;<br /> • The only vaccine to be used in this outbreak is the rVSV-ZEBOV vaccine, manufactured by the pharmaceutical group Merck, following approval by the Ethics Committee in its decision of 20 May 2018.

MONITORING AT ENTRY POINTS<br /> • Since the beginning of the epidemic, the total number of travelers checked (temperature measurement ) at the sanitary control points is 115.036.328 ;<br /> • To date, a total of 111 entry points (PoE) and sanitary control points (PoCs) have been set up in the provinces of North Kivu and Ituri to protect the country's major cities and prevent the spread of the epidemic in neighboring countries.

As a reminder, the recommendations of the MULTISECTORAL COMMITTEE OF THE RESPONSE TO EBOLA VIRUS DISEASE are as follows:

1. Follow basic hygiene practices, including regular hand washing with soap and water or ashes;
2. If an acquaintance from an epidemic area comes to visit you and is ill, do not touch her and call the North Kivu Civil Protection toll-free number;
3. If you are identified as a contact of an Ebola patient, agree to be vaccinated and followed for 21 days;
4. If a person dies because of Ebola, follow the instructions for safe and dignified burials. It is simply a funeral method that respects funerary customs and traditions while protecting the family and community from Ebola contamination.
5. For all health professionals, observe the hygiene measures in the health centers and declare any person with symptoms of # Ebola (fever, diarrhea, vomiting, fatigue, anorexia, bleeding).<br /> If all citizens respect these health measures recommended by the Secretariat, it is possible to quickly end this 10th epidemic.

On 2019-11-27 15:46:04, user Guyguy wrote:

EVOLUTION OF THE EPIDEMIC IN THE PROVINCES OF NORTH KIVU AND ITURI AS AT 25 NOVEMBER 2019<br /> Tuesday, November 26, 2019<br /> • Since the beginning of the epidemic, the cumulative number of cases is 3,304, of which 3,186 are confirmed and 118 are probable. In total, there were 2,199 deaths (2081 confirmed and 118 probable) and 1077 people cured.<br /> • 392 suspected cases under investigation;<br /> • 1 new case confirmed in North Kivu in Mabalako;<br /> • No new deaths among confirmed cases;<br /> • No cured person has emerged from CTEs;<br /> • No health worker is among the new confirmed cases. The cumulative number of confirmed / probable cases among health workers is 163 (5% of all confirmed / probable cases), including 41 deaths;

NEWS

NOTHING TO REPORT

VACCINATION

• Despite the tense situation of the city of Beni, a vaccination ring was opened around the confirmed case of 24 October 2019 in the Kanzulinzuli Health Area of the General Reference Hospital;<br /> • 724 people were vaccinated with the 2nd Ad26.ZEBOV / MVA-BN-Filo vaccine (Johnson & Johnson) in the two Health Zones of Karisimbi in Goma;<br /> • Since the start of vaccination on August 8, 2018 with the rVSV-ZEBOV vaccine, 255,215 people have been vaccinated;<br /> • Approved October 22, 2019 by the Ethics Committee of the School of Public Health of the University of Kinshasa and October 23, 2019 by the National Ethics Committee, the second vaccine, called Ad26.ZEBOV / MVA-BN -Filo, is produced by Janssen Pharmaceuticals for Johnson & Johnson;<br /> • This new vaccine is in addition to the first, the rVSV-ZEBOV, vaccine used until then (since August 08, 2018) in this epidemic manufactured by the pharmaceutical group Merck, after approval of the Ethics Committee on May 20, 2018. has recently been pre-qualified for registration.

MONITORING AT ENTRY POINTS

• Sanitary control activities are disrupted in the towns of Beni and Butembo in North Kivu province following demonstrations by the population which decries killings of civilians;<br /> • Since the beginning of the epidemic, the total number of travelers checked (temperature measurement ) at the sanitary control points is 120,825,670 ;<br /> • To date, a total of 109 entry points (PoE) and sanitary control points (PoCs) have been set up in the provinces of North Kivu and Ituri to protect the country's major cities and prevent the spread of the epidemic in neighboring countries.

As a reminder, the recommendations of the MULTISECTORAL COMMITTEE OF THE RESPONSE TO EBOLA VIRUS DISEASE are as follows:

1. Follow basic hygiene practices, including regular hand washing with soap and water or ashes;
2. If an acquaintance from an epidemic area comes to visit you and is ill, do not touch him/her and call the North Kivu Civil Protection toll-free number;
3. If you are identified as a contact of an Ebola patient, agree to be vaccinated and followed for 21 days;
4. If a person dies because of Ebola, follow the instructions for safe and dignified burials. It is simply a funeral method that respects funerary customs and traditions while protecting the family and community from Ebola contamination.
5. For all health professionals, observe the hygiene measures in the health centers and declare any person with symptoms of Ebola (fever, diarrhea, vomiting, fatigue, anorexia, bleeding).<br /> If all citizens respect these health measures recommended by the Secretariat, it is possible to quickly end this 10th epidemic.

On 2019-09-30 05:24:02, user Guyguy wrote:

EVOLUTION OF THE EPIDEMIC IN THE PROVINCES OF NORTH KIVU AND ITURI AS AT 25 SEPTEMBER 2019

The epidemiological situation of the Ebola Virus Disease dated September 25, 2019

Thursday, September 26, 2019

Since the beginning of the epidemic, the cumulative number of cases is 3,178, of which 3,066 confirmed and 112 probable. In total, there were 2,126 deaths (2014 confirmed and 112 probable) and 981 people healed.

• 483 suspected cases under investigation; <br /> • 3 new confirmed cases, including: <br /> • No cases in North Kivu; <br /> • 3 in Ituri, including 2 in Mandima and 1 in Mambasa; <br /> • 4 new confirmed deaths, including; <br /> • 1 community death in Ituri in Mandima; <br /> • 3 deaths of confirmed cases in North Kivu, including 2 in Katwa and 1 in Beni; <br /> • 1 person cured out of CTE in North Kivu in Butembo; <br /> • No health worker is among the new confirmed cases. The cumulative number of confirmed / probable cases among health workers is 160 (5% of all confirmed / probable cases), including 41 deaths. <br /> NEWS <br /> Six people from Mambasa cured of Ebola Virus Disease out of Komanda CTE in Ituri * <br /> • The Ebola Treatment Center (ETC) in Komanda, Ituri province, unloaded on Thursday, September 26, 2019, six people cured of Ebola Virus Disease, all from Mambasa; <br /> • For the director of the Komanda CTE, Claude Banga Lonema, this treatment center receives patients from the Nyakunde and Komanda health zones, as well as from Mambasa well before the construction of its CTE, which has become functional for almost a week; <br /> • For the director of the CTE of Komanda, Dr. Claude Banga Lonema, all these cures are the work of a whole team, including medical and paramedical staff, psychosocial teams, nutritionists and hygienists and guards, to whom he is grateful for all their efforts in this day-to-day treatment center, as well as dedication and their apostolate; <br /> • The coordinator ai of the Subcommittee on Response and Chief Medical Officer of the Komanda Health Zone, Dr. Faustin Singo Ngozo, said on this occasion that the success and success of Ebola Virus Disease is an asset for everyone in the response. This success must be shared, because if surveillance does not work, there will always be notification of deaths. The presence of cures at the Komanda CTE shows that epidemiological surveillance has been successful in detecting cases in a timely manner and has enabled the care physicians to have sufficient time to treat these patients. To this end, he recommended mutual support among all the teams in the response to push him out of the way to harm the epidemic, which he said has lasted too long, to continue working with the same momentum. He also asked the six healings to help the response in sensitizing everyone in his respective environment. Military healing, he said, is a resource that can educate his colleagues to end this epidemic; <br /> • Among the Mambasa healers who were discharged from the Komanda Treatment Center were an 8-year-old girl, a man in uniform, including the Armed Forces of the Democratic Republic of the Congo, and the village chief of Makoko II, a village in strong resistance. The latter two promised to raise awareness about Ebola Virus Disease in their respective communities; <br /> • This triumphal exit from the six healings of Mambasa, an area still showing resistance against EVD, was made in the presence of the few partners, namely the delegates of WHO and UNICEF: <br /> • Beginning with the prayer, this ceremony also ended with prayer and a family photo between the cures and the teams of the response in this ETC; <br /> • Immediately after, their exits from the CTE of Komanda, the cured were accompanied by the teams of the response to Mambasa, their respective health zone, where a festive atmosphere awaited them; <br /> • The Komanda CTE is located in the Mangiva Health Area, precisely in Makayanga village in the health zone of Komanda, 100 km from the Mambasa health zone.

As a reminder, the recommendations of the MULTISECTORAL COMMITTEE OF THE RESPONSE TO EBOLA VIRUS DISEASE are as follows:

1. Follow basic hygiene practices, including regular hand washing with soap and water or ashes;
2. If an acquaintance from an epidemic area comes to visit you and is ill, do not touch her and call the North Kivu Civil Protection toll-free number;
3. If you are identified as a contact of an Ebola patient, agree to be vaccinated and followed for 21 days;
4. If a person dies because of Ebola, follow the instructions for safe and dignified burials. It is simply a funeral method that respects funerary customs and traditions while protecting the family and community from Ebola contamination.
5. For all health professionals, observe the hygiene measures in the health centers and declare any person with symptoms of # Ebola (fever, diarrhea, vomiting, fatigue, anorexia, bleeding). <br /> If all citizens respect these health measures recommended by the Secretariat, it is possible to quickly end this 10th epidemic.

VACCINATION <br /> • Expanded ring vaccination around 2 confirmed cases in the Mataba Health Area in Kalunguta, North Kivu. In addition, two other vaccination rings, in the same health zone, are waiting to be opened in Lisasa and Kabasha Health Zones; <br /> • Since the beginning of vaccination on August 8, 2018, 228,430 people have been vaccinated; <br /> • The only vaccine to be used in this outbreak is the rVSV-ZEBOV vaccine, manufactured by the pharmaceutical group Merck, following approval by the Ethics Committee in its decision of 20 May 2018.

MONITORING AT ENTRY POINTS <br /> • Since the beginning of the epidemic, the total number of travelers checked (temperature rise) at the sanitary control points is 98,818,462; <br /> • To date, a total of 111 entry points (PoE) and sanitary control points (PoCs) have been set up in the provinces of North Kivu and Ituri to protect the country's major cities and prevent the spread of the epidemic in neighboring countries.

LEXICON <br /> • A community death is any death that occurs outside a #Ebola Treatment Center. <br /> • A probable case is a death for which it was not possible to obtain biological samples for confirmation in the laboratory but where the investigations revealed an epidemiological link with a confirmed or probable case.

On 2019-10-02 02:06:42, user Guyguy wrote:

EVOLUTION OF THE EPIDEMIC IN THE PROVINCES OF NORTH KIVU AND ITURI AS AT 29 SEPTEMBER 2019<br /> The epidemiological situation of the Ebola Virus Disease dated September 29, 2019<br /> Monday, September 30, 2019

• Since the beginning of the epidemic, the cumulative number of cases is 3,191, of which 3,077 are confirmed and 114 are probable. In total, there were 2,133 deaths (2019 confirmed and 114 probable) and 991 people healed . <br /> • 346 suspected cases under investigation; <br /> • 3 new confirmed cases, including: <br /> • 1 in North Kivu in Kalunguta; <br /> • 2 in Ituri, including 1 in Mambasa and 1 in Mandima; <br /> • 4 new confirmed deaths in Ituri, including: <br /> • 1 community death in Ituri 1 in Mandima; <br /> • 3 confirmed deaths in CTEs in Ituri, including 2 in Mambasa and 1 Komanda; <br /> • No health worker is among the new confirmed cases. The cumulative number of confirmed / probable cases among health workers is 160 (5% of all confirmed / probable cases), including 41 deaths.

Synthesis of epidemiological data at week 39 (from 23 to 29/09/019)

• Number of probable new cases: 3 <br /> • Number of new confirmed cases: 20 <br /> • Number of new healings: 16 <br /> • Number of new deaths: 12 <br /> • Community: 4 <br /> • Confirmed deaths: 8

NEWS

Local providers of 17 silent and hard-to-reach health areas in Mambasa in Ituri sensitized on EVD

• One hundred and two local providers of 17 silent and hard-to-reach health areas in the Mambasa Ebola Virus Disease Response (EVD) sub-coordination were sensitized from 29 to 30 September 2019 in women's ward in Mambasa in Ituri province on this disease;

• This took place during a briefing day for the purpose of helping to stop the transmission of Ebola Virus Disease in this sub-coordination in order to prevent its spread to other health zones. , DRC provinces and neighboring countries;

• This day also had the objective of setting up a functional alert system in the community and in the health structures of the target health areas and a communication system allowing a rapid response in case of notification of a validated alert. , a new confirmed or probable case and accelerate ownership of the response by communities, their leaders and local health system actors;

• These local providers were trained on EVD basics, early definitions / detections of cases and actions to be taken, as well as escalation of alerts, risk communication and community engagement. They were also trained on dignified and safe burial (DHS), active case finding, community-level monitoring tools and reporting system, risk communication and community engagement;

• Awareness Day was opened by Mambasa Territory Administrator Mr. Idriss Koma Kukodila in the presence of the Deputy General Coordinator for Ebola Response to the Epidemic, Dr. Justus Nsio Mbeta, the Physician the coordination of the Mambasa Health Zone, representing the Mambasa sub-coordinator of the response and the field coordinators of WHO and UNICEF;

• The sub-coordination of the Mambasa response includes 3 health zones, including Mambasa, Lolwa and Mandima, and 28 health areas, including 6 hot spots reporting cases within 14 days. These include Binase, Lolwa, Mambasa, Salama, Mandima and Some;

• The 17 health areas are: Banana, Tabala, Bandishende, Makoko II, Epulu, Salate, Molokai, Bukulani, Akokora, Pede, Bakaiko Kenya, Nduye, Bongupanda, Malembi, Bahaka, Lolwa and Some. These are health areas that do not report EVD alerts and are areas of difficult access and insecurity.

VACCINATION

• Since vaccination began on August 8, 2018, 230,489 people have been vaccinated;

• The only vaccine to be used in this outbreak is the rVSV-ZEBOV vaccine, manufactured by the pharmaceutical group Merck, following approval by the Ethics Committee in its decision of 20 May 2018.

MONITORING AT ENTRY POINTS

• Since the beginning of the epidemic, the total number of travelers checked (temperature measurement) at the sanitary control points is 100,607,920;

• To date, a total of 111 entry points (PoE) and sanitary control points (PoCs) have been set up in the provinces of North Kivu and Ituri to protect the country's major cities and prevent the spread of the epidemic in neighboring countries.

As a reminder, the recommendations of the MULTISECTORAL COMMITTEE OF THE RESPONSE TO EBOLA VIRUS DISEASE are as follows:

1. Follow basic hygiene practices, including regular hand washing with soap and water or ashes;
2. If an acquaintance from an epidemic area comes to visit you and is ill, do not touch her and call the North Kivu Civil Protection toll-free number;
3. If you are identified as a contact of an Ebola patient, agree to be vaccinated and followed for 21 days;
4. If a person dies because of Ebola, follow the instructions for safe and dignified burials. It is simply a funeral method that respects funerary customs and traditions while protecting the family and community from Ebola contamination.
5. For all health professionals, observe the hygiene measures in the health centers and declare any person with symptoms of # Ebola (fever, diarrhea, vomiting, fatigue, anorexia, bleeding). <br /> If all citizens respect these health measures recommended by the Secretariat, it is possible to quickly end this 10th epidemic.

On 2019-10-10 12:58:07, user GuyguyKabundi Tshima wrote:

EPIDEMIOLOGICAL SITUATION

EVOLUTION OF THE EPIDEMIC IN THE PROVINCES OF NORTH KIVU AND ITURI AT OCTOBER 07, 2019<br /> Tuesday, October 08, 2019<br /> Since the beginning of the epidemic, the cumulative number of cases is 3,206, of which 3,092 are confirmed and 114 are probable. In total, there were 2,143 deaths (2029 confirmed and 114 probable) and 1006 people healed.<br /> 443 suspected cases under investigation;<br /> 1 new case confirmed at CTE in Ituri in Mandima;<br /> 1 new confirmed death in North Kivu in Mabalako;<br /> 10 people were cured from the CTE, including 7 in Ituri in Komanda and 3 in North Kivu, including Beni, 1 in Katwa and 1 in Mabalako;<br /> No health workers are among the newly confirmed cases. The cumulative number of confirmed / probable cases among health workers is 161 (5% of all confirmed / probable cases), including 41 deaths.

No more confirmed cases of EVD at Butembo CTE<br /> - The Butembo Ebola Treatment Center (CTE) in North Kivu no longer has a confirmed case of Ebola Virus Disease;<br /> - The last two confirmed cases supported in this CTE have been released since Sunday, October 07, 2019 and have been reintegrated this Tuesday, October 08, 2019 in their respective communities by the teams of the response to the Virus Disease #Ebola of the psychosocial care. These cases are respectively health zones of Biena and Kayna;<br /> - Miss Ornella Bwira Zawadi, psychosocial supervisor at Butembo CTC, explains the psychosocial care at the Treatment Center. The Butembo CTE uses 17 psychologists subdivided into four blocks of tasks. These are triage supervisors, suspected cases, confirmed cases and accompanying village;<br /> - In the triage center, the psychologist ensures the awareness of newly admitted CTE cases. These new cases are normally 72 hours in the ETC and are taken on the 1st and the last day;<br /> - From the first day, the psychologist announces the result to the patients, its clinical evolution and its state. The patient who is positive is moved from the suspect's room to the confirmed block, while the patient who is negative until the third day remains in the suspected cases;<br /> - When the person is confirmed Ebola case, the psychologist is responsible for announcing his result, to make him aware of its evolution and life at the CTE. He asks him questions about his career in order to facilitate the follow-up of contacts;<br /> - It also monitors the confirmed case daily and ensures the relay between the patient and his family;<br /> - The accompanying person allows the good collaboration between the other CTE provider teams with the patient. It transmits various information of the patient, as well as its evolution to the other teams of the CTE;<br /> - Thereafter, intervenes the reintegration of suspected or confirmed cases cured and removed from the CTE. The psychiatrist accompanies him in his community. He educates his community and his family, explaining that the person who has been cured of Ebola is not dangerous and can not infect anyone else with the Ebola Virus Disease;<br /> - This Tuesday, October 08, 2019, Butembo CTE also released non Ebola people who were admitted to CTE as suspected cases.

VACCINATION

• A vaccination ring was opened around the confirmed case of 06 October 2019 in the Oicha health zone in Tenambo, North Kivu;
• Continuation of vaccination around the last case of 04 October 2019 in Andindulu village in the Lolwa health zone in Ituri;
• Continuation of the vaccination of newly recruited front-line staff in the Reference Hospitals of Katwa and Kyondo Health Zones;
• Launch of Local Polio Immunization Days integrated with vitamin A supplementation and mebendazole deworming in 17 ZS of Butembo Antenna, most of which are Ebola virus-infected areas;
• Since vaccination began on 8 August 2018, 235,389 people have been vaccinated;
• The only vaccine to be used in this outbreak is the rVSV-ZEBOV vaccine, manufactured by the pharmaceutical group Merck, following approval by the Ethics Committee in its decision of 20 May 2018.

MONITORING AT ENTRY POINTS

• Since the beginning of the epidemic, the total number of travelers checked (temperature rise) at the sanitary control points is 103,567,829 ;
• To date, a total of 111 entry points (PoE) and sanitary control points (PoCs) have been set up in the provinces of North Kivu and Ituri to protect the country's major cities and prevent the spread of the epidemic in neighboring countries.

As a reminder, the recommendations of the MULTISECTORAL COMMITTEE OF THE RESPONSE TO EBOLA VIRUS DISEASE are as follows:

1. Follow basic hygiene practices, including regular hand washing with soap and water or ashes;
2. If an acquaintance from an epidemic area comes to visit you and is ill, do not touch her and call the North Kivu Civil Protection toll-free number;
3. If you are identified as a contact of an Ebola patient, agree to be vaccinated and followed for 21 days;
4. If a person dies because of Ebola, follow the instructions for safe and dignified burials. It is simply a funeral method that respects funerary customs and traditions while protecting the family and community from Ebola contamination.
5. For all health professionals, observe the hygiene measures in the health centers and declare any person with symptoms of # Ebola (fever, diarrhea, vomiting, fatigue, anorexia, bleeding).<br /> If all citizens respect these health measures recommended by the Secretariat, it is possible to quickly end this 10th epidemic.

On 2019-10-16 12:34:53, user GuyguyKabundi Tshima wrote:

EVOLUTION OF THE EPIDEMIC IN THE PROVINCES OF NORTH KIVU AND ITURI AS OF OCTOBER 10, 2019<br /> Friday, October 11, 2019<br /> Since the beginning of the epidemic, the cumulative number of cases is 3,210, of which 3,096 confirmed and 114 probable. In total, there were 2,146 deaths (2032 confirmed and 114 probable) and 1028 people healed.<br /> 422 suspected cases under investigation;<br /> 2 new case confirmed at CTE in Ituri in Mandima;<br /> 2 new confirmed deaths, including 1 in North Kivu in Mabalako and 1 in Ituri in Mandima;<br /> 1 person healed out of CTE in Ituri in Mambasa;<br /> No health workers are among the newly confirmed cases. The cumulative number of confirmed / probable cases among health workers is 161 (5% of all confirmed / probable cases), including 41 deaths.

NEWS

President Félix-Antoine Tshisekedi Tshilombo submits to sanitary control for the prevention of #Ebola Virus Disease at Beni Airport<br /> - The Head of State, Coordinator of the Multisectoral Committee for the Ebola Virus Epidemic Response (CMRE), President Félix-Antoine Tshisekedi Tshilombo and his delegation were welcomed on Thursday, October 10, 2019 by the monitoring team at the entry points / sanitary control at Mavivi Airport in Beni, North Kivu Province. President Tshisekedi and his team have gone through all stages of health control at this point of entry to prevent Ebola Virus Disease;<br /> - The Ebola Virus Epidemic Response Coordination Team and a few members of the CMRE Technical Secretariat have been staying in Mambasa, Ituri province since Wednesday. It is in this part of the Democratic Republic of Congo that the last confirmed cases of #Ebola Virus Disease are concentrated;<br /> - This team, made up of the different experts in Ebola Virus Disease, has moved closer to Mambasa to coordinate closely the activities of the response;<br /> - Since they have been there, several activities have taken place, among which the release of 5 cured people from the ETC and a big meeting with all the partners of the response present in this sub-coordination. This meeting stems from the orientations to end the epidemic in this part of the DRC.

VACCINATION

• The symbolic vaccination of the local chief resisting the vaccination of Butama in the health zone of Mambasa in Ituri. Also in Ituri, continued immunization around two confirmed cases from 07 and 08 August 2019 in Biakato mine in Mandima with low participation due to community reluctance;
• Immunization of front-line staff continued in the Kyondo and Kayna Reference Hospitals in North Kivu;
• Continuation of Local Polio Vaccination Days integrated with Vitamin A supplementation and Mebendazole deworming in 17 health zones at the Butembo antenna in North Kivu;
• Since vaccination began on August 8, 2018, 236,772 people have been vaccinated;

MONITORING AT ENTRY POINTS

• Since the beginning of the epidemic, the total number of travelers checked (temperature measurement ) at the sanitary control points is 104,765,252 ;
• To date, a total of 111 entry points (PoE) and sanitary control points (PoCs) have been set up in the provinces of North Kivu and Ituri to protect the country's major cities and prevent the spread of the epidemic in neighboring countries.

As a reminder, the recommendations of the MULTISECTORAL COMMITTEE OF THE RESPONSE TO EBOLA VIRUS DISEASE are as follows:

1. Follow basic hygiene practices, including regular hand washing with soap and water or ashes;
2. If an acquaintance from an epidemic area comes to visit you and is ill, do not touch her and call the North Kivu Civil Protection toll-free number;
3. If you are identified as a contact of an Ebola patient, agree to be vaccinated and followed for 21 days;
4. If a person dies because of Ebola, follow the instructions for safe and dignified burials. It is simply a funeral method that respects funerary customs and traditions while protecting the family and community from Ebola contamination.
5. For all health professionals, observe the hygiene measures in the health centers and declare any person with symptoms of # Ebola (fever, diarrhea, vomiting, fatigue, anorexia, bleeding).<br /> If all citizens respect these health measures recommended by the Secretariat, it is possible to quickly end this 10th epidemic.

On 2019-11-13 01:31:13, user Guyguy wrote:

EVOLUTION OF THE EPIDEMIC IN THE PROVINCES OF NORTH KIVU AND ITURI AT NOVEMBER 11, 2019

Tuesday, November 12, 2019<br /> • Since the beginning of the epidemic, the cumulative number of cases is 3,287, of which 3,169 confirmed and 118 probable. In total, there were 2,193 deaths (2075 confirmed and 118 probable) and 1067 people cured.<br /> • 545 suspected cases under investigation;<br /> • No new confirmed cases;<br /> • No new deaths of confirmed cases have been recorded;<br /> • No cured person has emerged from ETCs;<br /> • No health worker is among the new confirmed cases. The cumulative number of confirmed / probable cases among health workers is 161 (5% of all confirmed / probable cases), including 41 deaths;

NEWS

Organization of a press conference in Goma on the introduction of the second Ebola vaccine in the Democratic Republic of Congo

• The coordination of the epidemic response to Ebola Virus Disease organized this Tuesday, November 12, 2019, jointly with the International Non-governmental Organization Médecins Sans Frontières of France (MSF / France), a press conference on introduction of the second Ebola vaccine, Johnson & Johnson, at the Karibu Hotel in Goma, capital of North Kivu Province;<br /> • During this press conference, the coordinator of the response, Prof. Steve Ahuka Mundeke, announced that vaccination with this second vaccine will start on Thursday, November 14, 2019 in two health areas of Karisimbi in Goma, including Majengo and Kahembe. The beginning of the vaccination will thus precede the official launch of the introduction of this vaccine which will intervene in the days to come;<br /> • This vaccine will be administered intramuscularly in two doses with an interval of 56 days. It targets adults and children over twelve months old. It has a strong immune response and its dose has the advantage of increasing this response by making it more sustainable in order to protect populations against a possible Ebola outbreak, according to a member of the consortium that took care of the study of this vaccine, Dr Hugo Kavunga, project manager INRB, member of the consortium;<br /> • Everyone is eligible for this vaccine, including children over the age of one, even pregnant and lactating women. In addition, for women of childbearing age, they will be offered a pregnancy test. Those who do not want it, will always be vaccinated. Pregnant women will be followed, said Vaccine Project Coordinator at MSF / France, Dr Véronique Urbaniak;<br /> • The choice of vaccination site was made after several studies and it is in order to protect the population against possible epidemics that Majengo and Kahembe were selected;<br /> • The vaccine is called Ad26.Zebov / MVA-BN-Filo. It is of Belgian-American origin and is named Johnson and Johnson. It has already been used in Sierra Leone in West Africa, Uganda and soon Rwanda. This second vaccine complements the first in-use vaccine in belt strategy and has already saved more than 3,000 people to date;<br /> • In addition to the speakers, two other members of the consortium took part in the press conference, including the London Shool Project Investigator Dr. Dan Baush and the Epicenter's Immunization Coordinator Marie Burton.

VACCINATION

• Preparation of the launch of the 2nd Ebola vaccine, J & J in Kahembe and Majengo Health Areas in Karisimbi, Goma, North Kivu;<br /> • 37 participants, including 4 high-risk contacts, 6 contacts, 7 CPs and 20 front-line staff, were vaccinated from the confirmed case of 09 November 2019 in the Bingo Health Area in Mabalako, North Kivu;<br /> • Since vaccination began on August 8, 2018, 250,622 people have been vaccinated;<br /> • The only vaccine to be used in this outbreak is the rVSV-ZEBOV vaccine, manufactured by the pharmaceutical group Merck, following approval by the Ethics Committee in its decision of 20 May 2018.

MONITORING AT ENTRY POINTS

• Disruption of activities at PoC VIRENDI (SC BUTEMBO) following clashes between FARDC soldiers and incivists not otherwise identified.<br /> • Since the beginning of the epidemic, the total number of travelers checked (temperature rise) at the sanitary control points is 116,184,525 ;<br /> • To date, a total of 111 entry points (PoE) and sanitary control points (PoCs) have been set up in the provinces of North Kivu and Ituri to protect the country's major cities and prevent the spread of the epidemic in neighboring countries.

As a reminder, the recommendations of the MULTISECTORAL COMMITTEE OF THE RESPONSE TO EBOLA VIRUS DISEASE are as follows:

1. Follow basic hygiene practices, including regular hand washing with soap and water or ashes;
2. If an acquaintance from an epidemic area comes to visit you and is ill, do not touch her and call the North Kivu Civil Protection toll-free number;
3. If you are identified as a contact of an Ebola patient, agree to be vaccinated and followed for 21 days;
4. If a person dies because of Ebola, follow the instructions for safe and dignified burials. It is simply a funeral method that respects funerary customs and traditions while protecting the family and community from Ebola contamination.
5. For all health professionals, observe the hygiene measures in the health centers and declare any person with symptoms of # Ebola (fever, diarrhea, vomiting, fatigue, anorexia, bleeding).<br /> If all citizens respect these health measures recommended by the Secretariat, it is possible to quickly end this 10th epidemic

On 2020-04-18 16:52:45, user novictim wrote:

Also worth considering is the timeline for treatment. HCQ proposed mode of action is not just its anit-inflammatory properties but its ability to act as a zinc ionophore. Zinc ions then interfere in viral replication. So you have to use Hydroxychloroquine early in the infection to see the maximum benefit. If you give it after lung epithelium and T-cells are already compromised, the benefit is less significant.<br /> I look forward to the trial results involving prophylaxis with HCQ and the use of it at the first signs of COVID-19.

On 2020-05-08 13:34:09, user Sinai Immunol Review Project wrote:

Title: <br /> Homologous protein domains in SARS-CoV-2 and measles, mumps and rubella viruses:<br /> preliminary evidence that MMR vaccine might provide protection against COVID-19<br /> The main findings of the article: <br /> This work aimed to determine whether measles, mumps and rubella (MMR) vaccination might provide protection against COVID-19. The authors examined: 1) sequence homologies between SARS-CoV2 and measles, mumps and rubella viruses; 2) correlations between MMR vaccination coverage, rubella antibody titers, and COVID-19 case fatality in European countries. <br /> Sequences of measles, mumps and rubella virus, which are component of MMR vaccine, were aligned to SARS-CoV-2 to identify homologous domains at the amino acid level. The Macro domain of rubella virus p150, a protease) aligned with SARS-CoV-2 Macro domain of non-structural protein 3 (NSP3), also a protease, at 29 % amino acids identity, suggest similarity in protein folding. Residues conserved in both strains include surface-expressed residues and residues required for ADP-ribose binding, and ADP-ribose 1” phosphatase (ADRP) enzymatic activity. Although the Macro domains are within a cytoplasmic non-structural protein, the authors speculate that they could contribute to vaccine antigenicity if released upon cell lysis. Measles and mumps, both paramyxoviruses, showed structural homology between their F proteins and SARS-CoV-2 spike protein. Both F proteins and spike proteins are responsible for fusion of viral and cellular membrane. The sequence identity was 20 % over a 369-amino acid region and surface-exposed residues were well conserved.<br /> The examination of historic vaccination schedules or recommendations for MMR vaccination in Italy, Spain and Germany revealed that populations who are currently in the age group of 40-49 years old in Germany, 30-39 years old in Spain, and 20-29 years old in Italy were vaccinated. However, the rubella vaccine was introduced for pre-adolescent girls and campaigns for women in child bearing age were conducted early 1970s to 90s in each countries. The latter might cover the women who are currently in the age group of 59-69 years old. If MMR is indeed protected for COVID-19 fatality, the above analysis would suggest that older populations and males are both more likely to die from Covid-19, and less likely to be seropositive for rubella specific immunity. <br /> On the other hand, analysis of anti-rubella IgG titers in moderate and severe COVID-19 patients showed increased levels of rubella IgG in severe patients. To argue that the increase in rubella antibodies in severe COVID-19 was not due to a generalized increased antibody response, the authors mentioned that there was no increase in varicella zoster virus antibody titers in a small subset of patients analyzed. While increase of anti-rubella IgM was not clearly observed in both severe and mild patients, anti-rubella IgG antibody titers were increased in patients who had been admitted for a period of less than 7 days. The authors suggest that IgG titers trend with disease burden on the basis of the shared homology between SARS-CoV2 and rubella virus.<br /> Critical analysis of the study: <br /> This study demonstrated shared homologies between SARS-CoV2 and MMR viruses that could support the hypothesis that previous MMR vaccination protects against fatality in COVID-19 patients. The authors suggested that older populations and males were less likely to be seropositive for rubella and this might be related to their higher mortality rate. On the other hand, they found that anti-rubella IgG was higher in severe patients than mild patients with COVID-19. Since there was no information about the demographics of severe and mild patients, especially the percentage of male patients and average age to analyze the relationship between severity and MMR vaccination history, the data appears inconclusive. Because of the homology in spike protein of SARS-CoV-2 and F protein of paramyxoviruses, which are important for virus entry in the host cells, measuring cross-reactive anti-measles and anti-mumps antibody titers may provide more information on whether MMR vaccination has the potential to protect against COVID-19. <br /> The importance and implications for the current epidemics<br /> The homology search for conserved domains among different virus strains and vaccine antigens may provide helpful information to develop vaccine antigens that elicit cross-reactive immunity to several viruses. While it is not clear at present if MMR vaccination reduces or not the severity of COVID-19, given the high coverage of MMR vaccination and the potential for vaccines to modulate innate immunity, this question deserves further investigation.

On 2021-07-12 23:16:53, user TheSailor wrote:

Did I miss the part where it was confirmed that all were fully vaccinated?

On 2020-05-11 01:41:57, user Sinai Immunol Review Project wrote:

Main findings<br /> The need for improved cellular profiling of host immune responses seen in COVID-19 has required the use of high-throughput technologies that can detail the immune landscape of these patients at high granularity. To fulfill that need, Chua et al. performed 3’ single-cell RNA sequencing (scRNAseq) on nasopharyngeal (or pooled nasopharyngeal/pharyngeal swabs) (NS), bronchiolar protected specimen brush (PSB), and broncheoalveolar lavage (BAL) samples from 14 COVID-19 patients with moderate (n=5) and critical (n=9, all admitted to the ICU; n=2 deaths) disease, according to WHO criteria. Four patients (n=2 with moderate COVID-19; n=2 with critical disease, n=1 on short-term non-invasive ventilation and n=1 on long-term invasive ventilation), were sampled longitudinally up to four times at various time points post symptom onset. In addition, multiple samples from all three respiratory sites (NS, PSB, BAL) were collected from two ICU patients on long-term mechanical ventilation, one of whom died a few days after the sampling procedure. Moreover, three SARS-CoV-2 negative controls, one patient diagnosed with Influenza B as well as two volunteers described as “supposedly healthy”, were included in this study with a total of n=17 donors and n=29 samples.

Clustering analysis of cells isolated from NS samples identified all major epithelial cell types, including basal, scretory, ciliated, and FOXN4+ cells as well as ionocytes; of particular note, a subset of basal cells was found to have a positive IFN? transcriptional signature, suggesting prior activation of these cells by the host immune system, likely in response to viral injury. In addition to airway epithelial cells, 6 immune cell types were identified and further subdivided into a total of 12 different subsets. These included macrophages (moMacs, nrMacs), DCs (moDCs, pDCs), mast cells, neutrophils, CD8 T (CTLs, lytic T cells), B, and NKT cells; however, seemingly neither NK nor CD4 T cells were detected and the Treg population lacked canonical expression of FoxP3, so it is unclear whether this population is truly represented.

Interestingly, secretory and ciliated cells in COVID-19 patients were shown to have upregulated ACE2 and coexpression with at least one S-priming protease indicative of viral infection; ACE2 expression on respiratory target cells increased by 2-3 fold in COVID-19 patients, compared to healthy controls. Notably, ciliated cells were mostly ACE2+/TMRPSS+, while secretory and FOXN4+ cells were predominantly ACE2+/TMRPSS+/FURIN+; accordingly, secretory and ciliated cells contained the highest number of SARS-CoV-2 infected cells. However, viral transcripts were generally low 10 days post symptom onset (as would be expected based on reduced viral shedding in later stages of COVID-19). Similarly, the authors report very low counts of immune cell-associated viral transcripts that are likely accounted for by the results of phagocytosis or surface binding. However, direct infection of macrophages by SARS-CoV-2 has previously been reported 1,2. Here, it is possible that these differences could be due to the different clinical stages and non-standardized gene annotation.

Pseudotime mapping of the obtained airway epithelial data suggested a direct differentiation trajectory from basal to ciliated cells (in contrast to the classical pathway from basal cells via secretory cells to terminally differentiated ciliated cells), driven by interferon stimulated genes (ISGs). Moreover, computational interaction analysis between these ACE2+ secretory/ciliated cells and CD8 CTLs indicated that upregulation of ACE2 receptor expression on airway epithelial cells might be induced by IFN?, derived from these lymphocytes. However, while IFN-mediated ACE2 upregulation in response to viral infections may generally be considered a protective component of the antiviral host response, the mechanism proposed here may be particularly harmful in the context of critical COVID-19, rendering these patients more susceptible to SARS-CoV-2 infection.

Moreover, direct comparisons between moderate and critical COVID-19 patient samples revealed fewer tissue-resident macs and monocyte-derived dendritic cells but increased frequencies of non-resident macs and neutrophils in critically ill COVID-19 patients. Notably, neutrophil infiltration in COVID-19 samples was significantly greater than in those obtained from healthy controls and the Influenza B patient. In addition, patients with moderate disease and those on short-term non-invasive ventilation had similar gene expression profiles (each n=1),; whereas, critical patients on long-term ventilation expressed substantially higher levels of pro-inflammatory and chemoattractant genes including TNF, IL1B, CXCL5, CCL2, and CCL3. However, no data on potentially decreasing gene expression levels related to convalescence were obtained. Generally, these profiles support findings of activated, inflammatory macrophages and CTLs with upregulated markers of cytotoxicity in critically ill COVID-19 patients. These inflammatory macrophages and CTLs may further contribute to pathology via apoptosis suggested by high CASP3 levels in airway epithelial cells. Interestingly, the CCL5/CCR5 axis was enriched among CTLs in PSB and BAL samples obtained from moderate COVID-19 patients; recently, a disruption of that axis using leronlimab was reported to induce restoration of the CD8 T cell count in critically ill COVID-19 patients 3.

Lastly, in critically ill COVID-19 patients, non-resident macrophages were found to have higher expression levels of genes involved in extravasation processes such as ITGAM, ITGAX and others. Conversely, endothelial cells were shown to express VEGFA and ICAM1, which are typical markers of macrophage/immune cell recruitment. This finding supports the notion that circulating inflammatory monocytes interact with dysfunctional endothelium to infiltrate damaged tissues. Of note, in the patient with influenza B, cellular patterns and expression levels of these extravasation markers were profoundly different from critically ill COVID-19.

Importantly, the aforementioned immune cell subsets were found equally in all three respiratory site samples obtained from two multiple-sample ICU donors, and there were no differences, with regards to upper vs. lower respiratory tract epithelial ACE2 expression. However, viral loads were higher in BAL samples as compared to NS samples, and lower respiratory tract macrophages showed overall greater pro-inflammatory potential, corresponding to higher CASP3 levels found in PSB and BAL samples. In general, the interactions between host airway epithelial and immune cells described in this preprint likely contribute to viral clearance in mild and moderate disease but might be excessive in critical cases and may therefore contribute to the observed COVID-19 immunopathology. Based on these findings and the discussed immune cell profiles above, the authors suggest the use of immunomodulatory therapies targeting chemokines and chemokine receptors, such as blockade of CCR1 by itself or in combination with CCR5, to treat COVID-19 associated hyperinflammation.

Limitations<br /> Technical<br /> In addition to the small sample size, it is unclear whether samples were collected at similar time points throughout the disease course of each patient, even with time since diagnosis normalized across patients. While sampling dates in relation to symptom onset are listed, it remains somewhat unclear what kind of samples were routinely obtained per patient at given time points (with the exception of the two patients with multiple sampling). Moreover, it would have been of particular interest (and technically feasible) to collect additional swabs from the convalescent ICU patient to generate a kinetic profile of chemokine gene expression levels, with respect to disease severity as well as onset of recovery. Again, with an n=1, the number of cases per longitudinal/multiple sampling subgroup is very limited, and, in addition to the variable sampling dates, overall time passed since symptom onset as well as disease symptoms and potential treatment (e.g. invasive vs non-invasive ventilation, ECMO therapy…) across all clinical subgroups, makes a comparative analysis rather difficult.

It is important to note that a lack of standardized gene annotation across different studies contributes to a significant degree of variability in characterizations of immune landscapes found in COVID-19 patients. As a result, inter-study comparisons are difficult to perform. For instance, an analysis of single-cell RNA sequencing performed on bronchoalveolar lavage samples by Bost et al. identified lymphoid populations that were not found in the present study. These include several enriched subtypes of CD4+ T cells and NK cells, among others. Ultimately, these transcriptomic descriptions will still need to be furthered with additional follow-up studies, including proteomic analysis, to move beyond speculation and towards substantive hypotheses.

Biological<br /> One additional limitation involved the use of the influenza B patient. Given that the patient suffered a rather mild form of the disease (no ICU admission or mechanical ventilation required, patient was discharged from hospital after 4 days) as opposed to the to authors’ assessment as a severe case, this patient may have served as an acceptable positive control for mild and some moderate COVID-19 patients. However, this approach should still be viewed cautiously, since the potential differences of pulmonary epithelial and immune cell pathologies induced by influenza compared to critical COVID-19 patients are still unclear. Moreover, it seems that one of the presumably healthy controls was recovering from a viral infection. Since it is unclear how a recent mild viral infection might have changed the respiratory cellular compartment and immune cell phenotype, this donor should have been excluded or not used as a healthy reference control.

Significance<br /> In general, this is a well-conducted study and provides a number of corroborative and interesting findings that contribute to our understanding of immune and non-immune cell heterogeneity in COVID-19 pathogenesis. Importantly, observations on ACE2 and ACE2 coexpression in airway epithelial cells generally corroborate previous reports. In addition, direct differentiation of IFN?+ basal cells to ACE2-expressing ciliated cells, as suggested by trajectory analysis, is a very interesting hypothesis, which, if confirmed, might contribute to progression of disease severity. The findings described in this preprint further suggest an important role for chemokines and chemokine receptors on immune cells, most notably macrophages and CTLs, which is highly relevant.

This review was undertaken by Matthew D. Park and Verena van der Heide as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn school of medicine, Mount Sinai.

References<br /> 1. Chen, Y. et al. The Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Directly Decimates Human Spleens and Lymph Nodes. Infectious Diseases (except HIV/AIDS) (2020) doi:10.1101/2020.03.27.20045427.<br /> 2. Bost, P. et al. Host-viral infection maps reveal signatures of severe COVID-19 patients. Cell (2020) doi:10.1016/j.cell.2020.05.006.<br /> 3. Patterson, B. K. et al. Disruption of the CCL5/RANTES-CCR5 Pathway Restores Immune Homeostasis and Reduces Plasma Viral Load in Critical COVID-19. medRxiv (2020).

On 2020-05-13 08:14:17, user Erwan Gueguen wrote:

The methodology used raises several questions:

• Why were 6 patients with a negative PCR included in a study on Sars CoV2, which means we don't even know if they have the disease? They should have been excluded from the study.

• In Figure 1 describing the flowchart of the studied population, Patients were divided into 2 groups. A HCQ + AZI group (n = 45), and an "other regimen" group (n = 87). It is very strange to find in this "other regimen" group patients who have not all undergone the same treatment. For example, there are 9 patients who also took HCQ+AZ but for a shorter period of time before transfer to ICU or death, 14 patients who took lopinavir/ritonavir, and even 28 patients who took AZI alone. This group is therefore not a control group since patients who have taken the same drugs are in the two groups being compared.

• Following the description of these 2 groups, we discover figure 2 which compares not these 2 groups but 3 groups. The "other regimens" group was divided into 2 groups AZI (n=26) and SOC (n=61) (SOC = standard of care which includes no targeted therapy, or lopinavir/ritonavir or treatment received <48h until unfavorable outcome (transfer to ICU or death). Why 2 patients were removed from the AZI group? (figure 1 n=28, but n=26 in figure 2). Figures suggest that 2 patients from the AZI group were placed in the SOC group. This could change the statistical analysis of the data. It is essential that the authors clarify this point because the results are not publishable as they stand.

• finally, table 1 shows 2 groups. Statistics are made on 2 groups but actually also on 3 groups for the therapeutic data (see table 2).

Conclusion: The study suffers from numerous methodological biases that make it difficult to interpret the data. The groups are not equivalent and the control group is made up of an agglomeration of patients who have undergone different treatments including HCQ+AZI treatment. It seems to me indispensable that the authors clarify the points raised before a submission to a peer-reviewed journal.

On 2020-03-21 14:55:55, user Alex Müller wrote:

Looking at supplementary Table 1, most of the controls had viral load qualitatively detected or the PCR was not done !!!! . Only 4 out of 16 controls had a proper measure of the viral load !!!! This is insane !

https://twitter.com/gaetanb...

On 2020-03-20 14:58:48, user David C. Norris, MD wrote:

1. The pink-highlighted NEG measures in Supplementary Table 1 (see image below) would seem to be false negatives (FN), as they are followed by positive results on subsequent days. A reanalysis with these FN's imputed as POS seems indicated.

https://twitter.com/davidcn...

1. How comparable are the outside-institution RT PCR results with those from the treated group? How fragile are the apparently positive results from this study, to plausible systematic between-institution differences in test sensitivity?

On 2020-03-21 16:42:23, user Nick wrote:

I attempted to reproduce Tables 2 and 3 (R code included at the end of the post), and obtained these results:<br /> `Table 2, Day 3: reported p=0.005, calculated p=0.0136<br /> Table 2, Day 4: reported p=0.04, calculated p=0.0780<br /> Table 2, Day 5: reported p=0.006, calculated p=0.0148<br /> Table 2, Day 6: reported p=0.001, calculated p=0.0019

Table 3, Day 3: reported p=0.002, calculated p=0.0019<br /> Table 3, Day 4: reported p=0.05, calculated p=0.0429<br /> Table 3, Day 5: reported p=0.002, calculated p=0.0025<br /> Table 3, Day 6: reported p<0.001, calculated p=0.0005`

That is, Table 3 was more or less reproduced, but Table 2 wasn't; most of my p values are around twice the ones in the preprint.

Of the 8 tests, 5 produced warnings because chisq.test() doesn't like cell values of 0 or 1. Using fisher.test() from the "stats" package got rid of the warnings and caused some of the Table 2 p values to move towards the ones in the preprint, but only one (Day 6) got close. It isn't clear to me why one would use Fisher's Exact Test here --- my understanding is that it is not sufficient to invoke per-cell numbers of less than 6, as many authors seem to do, but I don't have a reference to hand for that.

Code:<br /> `t2.d3 <- chisq.test(matrix(c(10, 10, 1, 15), ncol=2))<br /> cat("Table 2, Day 3: reported p=0.005, calculated p=", sprintf("%.4f", t2.d3$p.value), "\n", sep="")

t2.d4 <- chisq.test(matrix(c(12, 8, 4, 12), ncol=2))<br /> cat("Table 2, Day 4: reported p=0.04, calculated p=", sprintf("%.4f", t2.d4$p.value), "\n", sep="")

t2.d5 <- chisq.test(matrix(c(13, 7, 3, 13), ncol=2))<br /> cat("Table 2, Day 5: reported p=0.006, calculated p=", sprintf("%.4f", t2.d5$p.value), "\n", sep="")

t2.d6 <- chisq.test(matrix(c(14, 6, 2, 14), ncol=2))<br /> cat("Table 2, Day 6: reported p=0.001, calculated p=", sprintf("%.4f", t2.d6$p.value), "\n", sep="")

t3.d3 <- chisq.test(matrix(c(1, 15, 5, 9, 5, 1), ncol=3))<br /> cat("Table 3, Day 3: reported p=0.002, calculated p=", sprintf("%.4f", t3.d3$p.value), "\n", sep="")

t3.d4 <- chisq.test(matrix(c(4, 12, 7, 7, 5, 1), ncol=3))<br /> cat("Table 3, Day 4: reported p=0.05, calculated p=", sprintf("%.4f", t3.d4$p.value), "\n", sep="")

t3.d5 <- chisq.test(matrix(c(3, 13, 7, 7, 6, 0), ncol=3))<br /> cat("Table 3, Day 5: reported p=0.002, calculated p=", sprintf("%.4f", t3.d5$p.value), "\n", sep="")

t3.d6 <- chisq.test(matrix(c(2, 14, 8, 6, 6, 0), ncol=3))<br /> cat("Table 3, Day 6: reported p<0.001, calculated p=", sprintf("%.4f", t3.d6$p.value), "\n", sep="")`

On 2020-03-21 18:05:24, user Joanna Haas wrote:

1) There were 26 patients treated with hydroxychloroquine. Of these 6 are excluded because they did not continue the full 10 day course of treatment; 3 were transferred to ICU, one died, one discontinued due to adverse reaction (nausea) and one left hospital early.

Thus among the 26 patients started on with hydroxychloroquine, 15% (4/26) went to ICU or died vs. 0/15 of the controls, a difference that may be due to chance. However the baseline characteristics of the 6 patients who deteriorated rapidly are not presented in Supplementary Table 1. The analysis of outcomes of the treated group are based on the remaining 20 treated patients.

Among the 36 patients presented in S Table I the treated group is significantly older and more have lower respiratory tract disease at baseline (30% vs 12.5%).

What is the impact of treatment on clinical course? Among the 20 patients who received hydroxychloroquine, six were given azithromycin "to prevent clinical infection". Since 5 of 6 had negative swabs at day 3, it is possible that clinical and viral status diverge.

While it is to be hoped that hydroxychoroquine with or without azythromycin will be of use in treating patients infected with SARS CoV2, the data presented in this manuscript, which is focused on viral shedding, are limited. Clinical outcome and safety data are needed. An intention to treat analysis needs to be included for the clinical outcomes.

On 2020-03-21 20:58:27, user Sinai Immunol Review Project wrote:

This study was a single-arm, open label clinical trial with 600 mg hydroxychloroquine (HCQ) in the treatment arm (n = 20). Patients who refused participation or patients from another center not treated with HCQ were included as negative controls (n = 16). Among the patients in the treatment arm, 6 received concomitant azithromycin to prevent superimposed bacterial infection. The primary endpoint was respiratory viral loads on day 6 post enrollment, measured by nasopharyngeal swab followed by real-time reverse transcription-PCR.

HCQ alone was able to significantly reduce viral loads by day 6 (n = 8/14, 57.1% complete clearance, p < 0.001); azithromycin appears to be synergistic with HCQ, as 6/6 patients receiving combined treatment had complete viral clearance (p < 0.001).

Chloroquine is thought to inhibit viral infection, including SARS-Cov-2, by increasing pH within endosomes and lysosomes, altering the biochemical conditions required for viral fusion1,2. However, chloroquine also has immuno-modulatory effects that I think may play a role. Chloroquine has been shown to increase CTLA-4 expression at the cell surface by decreasing its degradation in the endo-lysosome pathway; AP-1 traffics the cytoplasmic tail of CTLA-4 to lysosomes, but in conditions of increased pH, the protein machinery required for degradation is less functional3. As such, more CTLA-4 remains in endosomes and is trafficked back to the cell surface. It is possible that this may also contribute to patient recovery via reduction of cytokine storm, in addition to the direct anti-viral effects of HCQ.

Despite what is outlined above, this study has a number of limitations that must be considered. First, there were originally n = 26 patients in the treatment arm, with 6 lost to follow up for the following reasons: 3 transferred to ICU, 1 discharge, 1 self-discontinued treatment d/t side effects, and 1 patient expired. Total length of clinical follow up was 14 days, but the data beyond day 6 post-inclusion are not shown.

Strikingly, in supplementary table 1, results of the real-time RT-PCR are listed for the control and treatment arms from D0 – D6. However, the data are not reported in a standard way, with a mix of broadly positive or negative result delineation with Ct (cycle threshold) values, the standard output of real time PCR. It is impossible to compare what is defined as a positive value between the patients in the control and treatment arms without a standardized threshold for a positive test. Further, the starting viral loads reported at D0 in the groups receiving HCQ or HCQ + azithromycin were significantly different (ct of 25.3 vs 26.8 respectively), which could explain in part the differences observed in the response to treatment between 2 groups. Finally, patients in the control arm from outside the primary medical center in this study (Marseille) did not actually have samples tested by PCR daily. Instead, positive test results from every other day were extrapolated to mean positive results on the day before and after testing as well (Table 2, footnote a).

Taken together, the results of this study suggest that HCQ represents a promising treatment avenue for COVID-19 patients. However, the limited size of the trial, and the way in which the results were reported does not allow for other medical centers to extrapolate a positive or negative result in the treatment of their own patients with HCQ +/- azithromycin. Further larger randomized clinical trials will be required to ascertain the efficacy of HCQ +/- azithromycin in the treatment of COVID-19.

References

1. Wang, M. et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research vol. 30 269–271 (2020).
2. Thomé, R., Lopes, S. C. P., Costa, F. T. M. & Verinaud, L. Chloroquine: Modes of action of an undervalued drug. Immunol. Lett. 153, 50–57 (2013).
3. Lo, B. et al. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science (80-. ). 349, 436–440 (2015).

On 2021-07-24 06:42:21, user itellu3times wrote:

Need to compare with background - what is the vaccination rate for Houston, during the period of the study? This may completely dominate the purported findings.

On 2020-03-21 23:09:04, user Moevi wrote:

Do we have any information regarding the patient ethnicity?

Indeed, the authors have chosen to use a study published in 2015 looking at ABO distribution among the Han population in Wuhan (unfortunately i was not able to find this study). However, if my understanding of the ABO group system is correct the distribution of ABO antigen may vary a lot depending on the ethnicity.

On 2020-04-23 15:54:21, user MacS wrote:

Didn't notice this was discussed already so adding to the fray. It's well known and accepted Type O blood is also less susceptible to Malaria ( https://www.sciencedaily.co... "https://www.sciencedaily.com/releases/2015/03/150309124113.htm)") And for what it is worth, we know the Malaria drug has decent favorable results. I don't see the WHO drawing on this correlation in their study of COVID19 although they are or should have the goods on the blood type difference with Malaria and should be taking all of this into consideration in countries in Africa that have now acquired a larger group of Type 'O' blood (herd immunity?)

On 2020-05-14 16:32:24, user Anita Bandrowski wrote:

"Hi, we're trying to improve preprints using automated screening tools. Here's some stuff that our tools found. If we're right then you might want to look at your text, but if we're not then we'd love it if you could take a moment to reply and let us know so we can improve the way our tools work. Have a nice day. Specifically, your paper (DOI:10.1101/2020.02.15.20023457); was checked for the presence of transparency criteria such as blinding, which may not be relevant to all papers, as well as research resources such as statistical software tools, cell lines, and open data.

We did not detect information on sex as a biological variable, which is particularly important given known sex differences in COVID-19 (Wenham et al, 2020).

We also screened for some additional NIH & journal rigor guidelines:<br /> IACUC/IRB: not detected ; randomization of experimental groups: not detected ; reduction of experimental bias by blinding: not detected ; analysis of sample size by power calculation: not detected .

We found that you used the following key resources: cell lines (1) . We recommend using RRIDs so that others can tell exactly what research resources you used. You can look up RRIDs at rrid.site

We did not find a statement about open data. We also did not find a statement about open code. Researchers are encouraged to share open data when possible (see Nature blog).

More specific comments and a list of suggested RRIDs can be found by opening the Hypothes.is window on this manuscript, direct link https://hyp.is/d1D3uI-sEeqy...<br /> References cited: https://tinyurl.com/y7fpsvzy"

On 2020-10-13 21:45:00, user Isaque Silva wrote:

The author was a past consultant of two companies that manufacturers hydroxychloroquine and yet consider himself enable, in a competing interest statement, to make such conclusion?? You must be kidding me.

On 2020-03-24 23:10:14, user Godfree Roberts wrote:

JANUARY 1 seems awfully late, if we are to believe multiple health officials:

Coronavirus may have been in Italy for weeks before it was detected. Test results worry experts as new cases emerge in Nigeria, Mexico and New Zealand Lorenzo TondoLast modified on Wed 18 Mar 2020 10.57 GMT. The Guardian

"The new coronavirus may have circulated in northern Italy for weeks before it was detected, seriously complicating efforts to track and control its rapid spread across Europe. The claim follows laboratory tests that isolated a strain of the virus from an Italian patient, which showed genetic differences compared with the original strain isolated in China and two Chinese tourists who became sick in Rome." https://www.theguardian.com...

NEXT ITEM: Massimo Galli, professor of infectious diseases at the University of Milan and director of infectious diseases at the Luigi Sacco hospital in Milan, said preliminary evidence suggested the virus could have been spreading below the radar in the quarantined areas.

“I can’t absolutely confirm any safe estimate of the time of the circulation of the virus in Italy, but … some first evidence suggest that the circulation of the virus is not so recent in Italy,” he said, amid suggestions the virus may have been present since mid-January.

The beginnings of the outbreak, which has now infected more than 821 people in the country and has spread from Italy across Europe, were probably seeded at least two or three weeks before the first detection and possibly before flights between Italy and China were suspended at the end of January, say experts.

The findings will be deeply concerning for health officials across Europe who have so far concentrated their containment efforts on identifying individuals returning from high risk areas for the virus, including Italy, and people with symptoms as well as those who have come in contact with them.The new claim emerged as the World Health Organization warned that the outbreak was getting bigger and could soon appear in almost every country. The impact risk was now very high at a global level, it said.“The scenario of the coronavirus reaching multiple countries, if not all countries around the world, is something we have been looking at and warning against since quite a while,” a spokesman said.symptoms.https://www.scmp.com/news/china/sci...

On 2020-03-25 03:16:39, user Sinai Immunol Review Project wrote:

Main findings: Antibodies specific to SARS-CoV-2 S protein, the S1 subunit and the RBD (receptor-binding domain) were detected in all SARS-CoV-2 patient sera by 13 to 21 days post onset of disease. Antibodies specific to SARS-CoV N protein (90% similarity to SARS-CoV-2) were able to neutralize SARS-CoV-2 by PRNT (plaque reduction neutralizing test). SARS-CoV-2 serum cross-reacted with SARS-CoV S and S1 proteins, and to a lower extent with MERS-CoV S protein, but not with the MERS-CoV S1 protein, consistent with an analysis of genetic similarity. No reactivity to SARS-CoV-2 antigens was observed in serum from patients with ubiquitous human CoV infections (common cold) or to non-CoV viral respiratory infections.

Analysis: Authors describe development of a serological ELISA based assay for the detection of neutralizing antibodies towards regions of the spike and nucleocapsid domains of the SARS-CoV-2 virus. Serum samples were obtained from PCR-confirmed COVID-19 patients. Negative control samples include a cohort of patients with confirmed recent exposure to non-CoV infections (i.e. adenovirus, bocavirus, enterovirus, influenza, RSV, CMV, EBV) as well as a cohort of patients with confirmed infections with ubiquitous human CoV infe<br /> ctions known to cause the common cold. The study also included serum from patients with previous MERS-CoV and SARS-CoV zoonotic infections. This impressive patient cohort allowed the authors to determine the sensitivity and specificity of the development of their in-house ELISA assay. Of note, seroconversion was observed as early as 13 days following COVID-19 onset but the authors were not clear how disease onset was determined.

Importance: Validated serological tests are urgently needed to map the full spread of SARS-CoV-2 in the population and to determine the kinetics of the antibody response to SARS-CoV-2. Furthermore, clinical trials are ongoing using plasma from patients who have recovered from SARS-CoV-2 as a therapeutic option. An assay such as the one described in this study could be used to screen for strong antibody responses in recovered patients. Furthermore, the assay could be used to screen health care workers for antibody responses to SARS-CoV-2 as personal protective equipment continues to dwindle. The challenge going forward will be to standardize and scale-up the various in-house ELISA’s being developed in independent laboratories across the world.

On 2021-04-12 19:59:24, user Rui Seabra wrote:

The article was published at: http://dx.doi.org/10.3389/f...

On 2020-03-31 18:56:14, user Igor H. wrote:

I would suggest verifying the calculations. Data for Colorado do not fit.<br /> Here is the comparison of actual reported hospitalizations and your prediction for 3/18-3/29:

First column after date are actual hospitalizations (not new per day but all covid hospitalized patients on the day) reported by Colorado Dept of Public Health - https://covid19.colorado.go... - and the right column is your predicted "allbed_mean" which is supposed to be “Mean covid beds needed by day” (I assume that you mean number of beds needed on the particular date, not a cumulative number from the beginning – patients get discharged or die)

3/18/2020 26 158<br /> 3/19/2020 38 186<br /> 3/20/2020 44 268<br /> 3/21/2020 49 323<br /> 3/22/2020 58 455<br /> 3/23/2020 72 573<br /> 3/24/2020 84 716<br /> 3/25/2020 148 882<br /> 3/26/2020 184 1069<br /> 3/27/2020 239 1294<br /> 3/28/2020 274 1542<br /> 3/29/2020 326 1841

When I look closely, Allbed_mean on the day is the sum of (admis_mean) from the beginning to that day.

This is how you project ***new*** admissions (admis_mean) for the same time period:

69<br /> 28<br /> 88<br /> 56<br /> 137<br /> 124<br /> 149<br /> 178<br /> 209<br /> 242<br /> 278<br /> 317

This is also hugely overestimated and the numbers more resemble TOTAL number of hospitalized patients on the day.

Also, spotcheck for New York State does not match. See attache https://uploads.disquscdn.c... d images (prediction and actual reported number this morning)<br /> https://uploads.disquscdn.c...

It appears that (Allbed_mean) is only correct if 100% of cases need hospitalization, which is not the case in the US (it was the case in China). So, actual number of beds needed seems to be 20% of the predicted number, which much more closely corresponds with reported data.

Igor Huzicka

On 2021-05-15 22:46:36, user sam wrote:

Here is the journal article

https://royalsocietypublish...

On 2020-04-23 17:35:06, user Hugh DeWitter wrote:

PCR test the autopsy lung tissue for M.genitalium DNA. <br /> See @hughdewitter on Twitter for studies in support.

PCR your patients' first void urine, before issuing antibiotics, as a predictor of severe Covid-19. Mgen resistance to macrolides and FQNs seen at 100 and 90%, steals iron (FUR), subclinical, never found by culture, and a retroactive study found that as far back as 1974 it was found in 25% of lungs of a random cohort. Before PCR it tested out as M.pneumoniae, genetically a nearly identical pathogen. Now we only PCR for M.pneumoniae.

Mycoplasma Genitalium thrives in the lung subclinically, especially paired with smoking, pollution, or robust old biofilms. Find that Zn abates symptoms, no one under 14 gets severe disease, vertical transmission, 40pct of infected convert to chronic subclinical carriers after an azithro course, hemolytic anemia from FUR iron theft, adheres to erythrocytes, deposits antigen on erythrocytes, more male carriers/fatalities, sickle cell vulnerability, no increased risk for HIV+ patients (recent antibiotic courses), migrates through tissue, migrates hematogenously, 35 different Mgen isolates, samples vulnerable to dessication, refrigeration causes 27pct PCR false negatives. See the study compilation posted on Twitter @hughdewitter.

On 2020-04-24 11:52:01, user ??? wrote:

Hello, my name is Eunno An, lived in incheon, korea.<br /> Would you mind sharing the dataset of pneumonia and COVID 19 ct image?<br /> The purpose is building a neural network classifying normal, pneumonia, COVID19.<br /> Apparently, non-commercial! It is Only study purpose.<br /> Thank you!

On 2020-04-24 14:40:59, user Tomas Hull wrote:

"New York antibody study estimates 13.9% of residents have had the coronavirus, Gov. Cuomo says"<br /> When false negatives were to be included - those who have undetectable levels of antibodies, mainly young population - it could mean that 30%, or more people in NY already have the antibodies...

The study as well as Dr. John Ioannidis, Dr. Jay Bhattacharya, who have gone public with these findings, stand vindicated.

https://www.cnbc.com/2020/0...

Will herd immunity be achieved by the end of summer, or earlier, as predicted by another brilliant scientist, Dr, Wittkowski? It remains to be seen...

https://www.medrxiv.org/con...

On 2020-05-05 14:08:15, user buzzbree wrote:

Beyond the seroprevelance conclusions of the study which are widely discussed, another very important issue that needs to be clarified by the authors is if the study fully adhered to Good Clinical Practice (GCP) standards. It is highly concerning that in the rush to publish the study- the authors may have not done so, and there is never an acceptable reason to do this- nor would an IRB agree.

To be fully compliant with GCP the Stanford IRB really needed to be informed of the the email Jay Bhattacharya's wife (https://www.buzzfeednews.co... sent to potential subjects. The email had several erroneous statements- that the test was FDA approved (Its not) and they would know if they were now immune from COVID-19 and would know that they were <br /> free from getting sick and could no longer spread the virus. These statements could have impacted subject safety by encouraging riskier behavior (i.e. ignoring social distancing) from the study subjects if they believed that the test was FDA approved and a positive result was <br /> definitive proof of protective immunity.

In the Buzzfeed article Dr. Bhattacharya has stated that he did not know about the email or <br /> approve of it, but he still had an ethical duty to report it to the IRB when he found out. There is only one line in manuscript stating that IRB approved the study- how the IRB addressed this email should be expounded upon in final manuscript given these new issues that have come to light. If the email was kept from the IRB, and instead the authors just capped enrollment from certain areas I do not see how that is compliant with GCP. These issues as they pertain to subject safety are not discussed in the manuscript- and they really should be.

Relevant GCP sections:

"3.3.8 Specifying that the<br /> investigator should promptly report to the IRB/IEC:(b) Changes <br /> increasing the risk to subjects and/or affecting significantly the <br /> conduct of the trial (see 4.10.2).

4.10.2 The investigator should <br /> promptly provide written reports to the sponsor, the IRB/IEC (see 3.3.8)<br /> and, where applicable, the institution on any changes significantly <br /> affecting the conduct of the trial, and/or increasing the risk to <br /> subjects.2 2

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Reply

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On 2020-04-24 17:27:51, user dak wrote:

How do you know that this is the virus and not RNA fragments produced in fighting the infections? If it was a whole virus, would you not expect the N1-N3 PCR amplicons to parallel each other? You could argue about the stability of RNA in waste water under conditions X, if that is known for this specific RNA fragment and the conditions X expected.

On 2020-04-24 23:54:28, user Gunnar V Gunnarsson wrote:

The conclution that HC causes higher risk of death is basically wrong due to a huge sampling bias. The problem lies in the fact that once people went on ventilators they where given HC or HC+AZ. This re-categorised the patients by increasing the number of high risk patients in the HC and HC+AZ groups making the No HC an invalid control group.

Before ventilation the statistics was like this: (Table 4 in paper)

HC: 90 - 9 (10.0%) deaths - 69 (76.6%) recover - 12 (13.3%) onto ventilation HC+AZ: 101 - 11 (10.9%) deaths - 83 (82.2%) recover - 7 (06.9%) onto ventilation No HC: 177 - 15 ( 8.4%) deaths - 137 (77.4%) recover - 25 (14.1%) onto ventilation

We see that death-rate is about the same for all groups but HC+AZ seams to have the highest recovery rate but it might not be statistically significant.

Now once people hit ventilation the re-categorisation occurs. More patients where given HC and HC+AZ which moved them from the No HC group to the HC or HC+AZ group. These groups therefore have a much higher % of ventilation patients because they where given the drugs after they hit ventilation.

The following data can be derived from the paper but is not presented:<br /> Once people hit ventilation we have the following results.

HC: 19 - 18 (95%) deaths - 1 (11%) recover HC+AZ: 19 - 14 (73%) deaths - 5 (27%) recover No HC: 6 - 3 (50%) deaths - 3 (50%) recover

If you compare these 2 tables, you see that 25 patient with No HC reach ventilation. Once they reach ventilation, 19 of these where give HC or HC+AZ, thereby moved from the No HC group to the other two. 79.5% of all patients reaching ventilation died so arguably 14 patients that died where moved from the No HC group to the other 2 groups only once they reach the much higher risk state.

Here are the number of people per group that got ventilation:

HC: 97 - 19 (19.6%) got ventilation HC+AZ: 113 - 19 (16.8%) got ventilation No HC: 158 - 6 ( 3.4%) got ventilation

So the conclusion that HC causes more death is basically wrong. All it shows is that people that need ventilation are more likely to die.

On 2020-04-29 16:09:10, user Serge Rdo wrote:

the response is i this article

https://www.mediterranee-in...

On 2020-04-25 22:57:46, user wbgrant wrote:

An additional article that supports the model study and should also be cited<br /> Prevalence and genetic diversity analysis of human coronaviruses among cross-border children.

Liu P, Shi L, Zhang W, He J, Liu C, Zhao C, Kong SK, Loo JFC, Gu D, Hu L.

Virol J. 2017 Nov 22;14(1):230. doi: 10.1186/s12985-017-0896-0.

On 2020-04-26 15:15:14, user Retelska wrote:

That's interesting and surely useful. it would be interesting to see a plot normalised by the number of infected persons, I don't know if you have this data. So I guess we would see that with flu 5% of seventy-years old or is hospitalized, whereas with covid, in addition to younger age, the proportion might be bigger. Also, about figure 1: Veterans group is certainly quite old. In Corea, hospitalized are very young, I suppose that much more young people were infected. I heard that infection spreads mostly between young, mobile people.

On 2020-04-27 10:23:45, user Gareth Gerrard wrote:

Hello - can I ask a question? For the data in Fig 1a, you performed a Mann-Whitney U test to show significance between the two methods. However, do these data include multiple paired samples? If so, since the data sets are not independent, would a Wilcoxon test have been more appropriate?

On 2020-05-02 16:22:01, user Eugene Chan wrote:

nice work, did you look at lower levels of virus? On average, how much virus (virus per mL) is in the sample

On 2020-04-29 14:04:12, user JWL36 wrote:

Would someone mind posting the link to the GIthub source code when they find it?

On 2020-04-29 19:07:05, user Sinai Immunol Review Project wrote:

Keywords: SARS-CoV-2, ACE-2, Renin-angiotensin system, Hypertension

Main findings: The authors analyzed clinical data obtained from COVID-19 patients and categorized them based on the antihypertensive drugs they were taking. They then investigated its association with morbidity and mortality of pneumonic COVID-19 patients. ARBs were found to be associated with a reduced risk of pneumonia morbidity in a total of 70,346 patients in three studies. They found that in the elderly (age>65) group of COVID-19 patients with hypertension comorbidity, the risk of severe disease was significantly lower in patients who were on ARB anti-hypertensive drugs prior to hospitalization compared to patients who took no drugs. Also, through their meta-analysis of the literature, the authors reported that ARB anti-hypertensive drugs were associated with a decreased risk of severe disease in elderly COVID-19 patients.

Critical Analyses:<br /> 1. Retrospective study with large potential for confounder bias. <br /> 2. Their inference that ARB is better than other anti-hypertensive drugs is based on literature met-analysis.<br /> 3. P-values could not be computed for some subsets because of very low/no patients in these categories(ref to table-1;ACEI, thiazide and BB)

Relevance: Anti-hypertensive ARB drugs taken by COVID-19 patients prior to entering the hospital may be associated with improved morbidity and mortality of pneumonia in elderly COVID-19 patients although confounders may bias results.

Reviewed by Divya Jha, PhD and edited by Robert Samstein, MD PhD, as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

On 2020-04-30 13:53:43, user Alan Beard wrote:

Could the authors clarify about Smoking status please . Is it <br /> Current Smoker only OR <br /> Current and Former Smokers(which would include current Vapers)

On 2020-04-30 23:50:07, user stephen zhang wrote:

https://doi.org/10.1016/j.b...

Link to the published version

On 2020-05-01 17:34:20, user Leonid Schneider wrote:

The IRB approval TJ-C20200113 is connected to this clinical trial:<br /> http://www.chictr.org.cn/sh...<br /> "A randomized, open-label, blank-controlled, multicenter trial for Shuang-Huang-Lian oral solution in the treatment of ovel coronavirus pneumonia (COVID-19)"

It is about Traditional Chinese Medicine (TCM) and never mentions chloroquine or other drugs in the preprint, which in turn never mentions TCM. The registered trial had only 400 patients. The study above had 568 patients.

On 2020-05-02 13:08:43, user Theo Sanderson wrote:

"the later the fixed-duration quarantine is introduced, the smaller is the resulting final number of deaths at the end of the outbreak."

It might be worth amending this sentence as it clearly cannot be strictly true (ad absurdum argument: a quarantine just before the last death of the epidemic would have negligible effect)

More generally, considering the literature on the practicality of timing interventions, such as https://arxiv.org/abs/2004.... might be helpful, and a brief discussion of the fact that the choices outlined here are not the only ones, and that some countries have managed to suppress the epidemic without population quarantine might add to the preprint.

On 2020-05-03 01:22:06, user tom wrote:

Very fine work here addressing the pressing need for credible validation of a high-quality antibody test. One question that I have is whether the 2018-19 sera were confirmed to have a representative prevalence of common cold coronavirus antibodies. It would also be nice to see a serosurvey that follows up on its indicated positives with a good ELISA or even neutralization assay.

Since the authors did not go into much interpretation, here are some back of envelope thoughts:

Boise has a 228k population * 1.79% seroprevalence = 4080 estimated exposures.

Ada County (in which Boise lies) has a 392k population, has had 663 recorded cases to date = 0.17% cumulative incidence, and has 17 recorded deaths = 2.6% CFR.

As the rest of Ada County's incidence should lag Boise metro a good bit due to the ex-metro's lower population density and thus lower average Rt, Boise should account for more than its pro rata share of the county's covid burden. Let's say Boise accounts for 100 more than its 386 pro rata share of the county's 663 cases, and 3 more than its 10 pro rata share of the county's 17 deaths. 13 deaths out of Boise's 4080 serologically estimated exposures = 0.32% IFR. (That's about 8x lower than Ada County's CFR, which is roughly in line with the 10x differential between the cumulative reported case incidence and the detected seroprevalence). This is about half the estimated IFR using NYC's reported deaths and the recent serological survey there.

Any IFR estimate presently inferrable from these data is provisional and likely to increase though, because while Idaho's new cases have been squelched long enough for essentially all past and current infections to have developed antibodies, it's quite likely that more deaths will occur among the currently active cases. I'd guess >25% more based on the histogram of reported case dates, so IFR likely >0.40%.

Of course with only 13 deaths, any such IFR estimates are subject to a wide confidence bracket, and very sensitive to the accuracy in counting of deaths.

On 2020-05-04 00:32:57, user Lynn wrote:

I did not notice any specific outcome related to the asthma patients. Did I miss something?

On 2020-05-04 11:11:16, user Will Jones wrote:

What was the median number of days between admission and death?

On 2020-05-05 09:18:09, user ??? wrote:

You may be interested in my paper "Growth Mechanism of Coronavirus ( How to Stop Spreading of COVID-19)" that predicts at temperatures above 25°C Coronavirus should have difficulty in replication because its outer cover melts and its RNA core decays at temperatures above 25°C. For instance, it explains why people catch cold more often in cold winter than in hot summer. You can read the paper in OCN.

On 2020-05-05 09:46:46, user ??? wrote:

You can read the paper in OSF preprints.

On 2020-05-05 19:12:27, user Nancy Lapid wrote:

This is not the first case of placental SARS-CoV-2 infection. An earlier case was reported in JAMA April 30. "This case of miscarriage during the second trimester of pregnancy in a woman with COVID-19 appears related to placental infection with SARS-CoV-2, supported by virological findings in the placenta." https://jamanetwork.com/jou...

On 2020-05-07 13:34:42, user Heather Lipkind wrote:

Hoping this sparks more research. We have localized it within the placenta to the syncytiotrophoblast. Much to learn about SARS-CoV-2.

On 2020-05-07 14:01:03, user Dr Gareth Davies (Gruff) wrote:

Please note: the current version on medRxiv is an intial draft. A newer draft is being submitted soon with some important improvements and clarifications so we request everyone to please hold off on critiquing until the final draft is preprint submission is approved so that we don't waste time responding to issues that have already been addressed since draft 1.0. Many thanks!

On 2020-05-09 21:31:00, user Gennadi Glinsky wrote:

In agreement with this study, recent genomics-guided tracing of the SARS-CoV-2 targets in human cells identified Vitamin D as one of the top 3 potential COVID-19 mitigation agents <br /> https://doi.org/10.26434/ch...

On 2020-05-13 10:37:19, user Keith baker wrote:

PCOS females in ageing would be a interesting sub group. The genetics of AR and ACE2 play a role in their conditions when excess testosterone, gives rise to risk factors DBII, obesity and specifically male like adipose patterns, on torso and heart.

On 2020-05-17 19:04:29, user Shreyans Pagariya wrote:

For more detailed predictions on when COVID-19 could end in each state of India using the same model described in the article, take a look at https://covid19quarantine.i...

On 2020-04-03 21:10:45, user Marconi Neves wrote:

Good article. We need to know how to test the quality of masks and other personal protective equipament.

On 2020-06-25 22:40:27, user Greg Green wrote:

Mr. Cohen,

Great read. to be clear, what is your best estimate, in terms of percentage, of the number of false positives for current mass testing?

On 2020-06-26 22:11:48, user Hilda Bastian wrote:

It's excellent that this trial was done, but the preprint is overly positive: given it's not clear that anyone either working in, or exercising in the gym, was infected, it's not possible to know if the hygiene and social distancing measures worked.

There have been clusters of outbreaks related to gyms (for example in Japan and South Korea), and this needs to be discussed. Given that infected gym employees have been shown to have been the source of clusters, it's problematic that all employees weren't tested and considered more here.

This trial report is missing key methodological information, such as the method of randomization. At one point, the authors refer to the trial's protocol, but do not provide a reference for it. (That level of detail on methodological issues isn't included in the ClinicalTrials.gov entry for the trial.)

I think it's unfortunate that this was a non-inferiority trial, given the known risk of gym clusters. The bar was set too low for this trial. There was too much missing data on testing - nearly 20% of participants and nearly 10% of employees. The authors argue that disease is more critical than infection, but the risk of seeding clusters is a critical concern in gym re-opening.

On 2020-06-28 05:19:24, user David Perkins wrote:

This study is so flawed that it should be immediately withdrawn, and the study designers reeducated on how to run a study. The flaw is that it doesn't test for the following: "If workers or users at a gym have covid-19, can procedures be put in place at the gym to greatly reduce (or even eliminate) the spread of the disease to other workers or users at the gym?" (Said another way "Is is safe to go to a gym and work out?") To run such a study without the consent of the workers or users would be unethical (or most likely, illegal). Instead, a study was set up to see who knows what? Was it that the equipment or the building doesn't spread the disease? I am completely shocked that this study was carried out and that it had coverage in the NYTimes and other national publications. Because using people that are carriers of Covid-19 is unethical, a better experiment would be to use a non-lethal disease such as the common cold (or the flu) and try to determine which procedures at gyms minimizes its transmission.<br /> Again, this study did not determine if it was safe to use a gym. It showed nothing!

On 2020-06-28 02:19:40, user LB wrote:

I appreciate the difficult circumstances under which this study was conducted, but would like some clarification, because there are some discrepancies in the data. The text states that "All patients who needed supplemental oxygen therapy in the control group also required further ICU support." However, the table shows only 8 of the 16 requiring ICU support. This section, "Among 9 patients given DMB within the first week of onset of symptoms, only one patient required oxygen therapy. This patient was one of the two cases which deteriorated within 24 hours of DMB initiation." seems to indicate that two patients in the DMB group required ICU care, but only one is listed in the table.

On 2020-06-29 01:07:28, user Dr. D. Miyazawa MD wrote:

This is the revised second edition.

Our hypothesis in this study is that face mask-wearing rates may be a significant factor for COVID-19 mortality, that obesity and old age are currently identified as the most relatively-independent factors for COVID-19 mortality, and that these three factors may be strong enough to "predict" mortality using means including Lasso regression to a considerable extent.To show the independence or causality of each factor, a multiple regression with a number of factors added to exclude confounding would be necessary, but that was not the goal of this study. Other studies aiming to identify predictors, or to show the independence of the factors of interest, for the difference among countries have done multiple regression analyses with a number of factors, but since the mechanism is currently largely unknown, the selection of factors other than the factors of interest would be close to random, making it of little significance to prove the true independence of the factors of interest.

On 2020-04-11 01:07:55, user Moi wrote:

Some stats about the situation in Germany and Chile (JHU numbers used):<br /> Delay \Psi around 13 (DE) and 14 (CL), resp, with quite small SD.<br /> Death rate \theta around 0,05 for both countries, constant since several weeks, far lower than your 14%

These are of course only the visible cases, not quite your concern.

Anyway, the numbers are different for different countries. Why?

And not speaking about asians, who seem to have basically overcome it.

On 2020-07-02 17:21:31, user Felice Bruno wrote:

what is the dosing protocol for Ivermectin used in the study ?

On 2020-07-04 10:45:14, user MathaHi wrote:

Confusing Terminology: on page 12: "We believe that the analysis in our study shows conclusively that COVID-19 epidemics grow according to the Gompertz Function and not the Sigmoid Function". I think the authors intended to set off the Gompertz Functions against Logistic Functions that are used when assuming that the rate of infection remains proportional to the product of the already infected population and the amount of still susceptible individuals. Logistic Functions as well as Gompertz Functions are both considered as special cases of Sigmoid Functions. Same issue at page 21 and 22.

Furthermore, assuming that the rate of infection is proportional to the currently infectious population instead of the already infected population might partially explain why it is decreasing faster than with the logistic SI model, as infected individuals become Resistant. For those viral epidemiologists that require more explanation: heterogeneity in both individual and collective susceptibility does the rest.

On 2019-06-28 18:46:32, user hkahn wrote:

Congratulations on an ambitious study design. It would be great to have also a comparative cohort sampled from the general adult population, but that would be very costly. Perhaps you could attempt parallel analyses from the EPIC population cohorts in Germany.

ANTHROPOMETRY:<br /> I didn't find many details, but surely the standing waist circumference (WC by the WHO protocol) will be included. I urge BeLOVE to consider adding the supine sagittal abdominal diameter (SAD) to the phenotyping assessments. The SAD has been quickly, reliably measured by a portable sliding-beam caliper (http://www.cdc.gov/nchs/dat... "http://www.cdc.gov/nchs/data/nhanes/nhanes_13_14/2013_Anthropometry.pdf)"). Studies in Sweden, Finland, India, Taiwan, Brazil, USA have demonstrated that SAD can serve to estimate the amount of visceral (intra-abdominal) adipose tissue. The supine SAD usually performs better than WC to identify dysglycemia, dyslipidemia, transaminase elevations, and hypertension. Since your participants will be supine for portions of the CRU assessment, you could inexpensively add the caliper measurement at that time.

Your SAD values by the low-cost caliper could be compared with the more costly dimensions and VAT area (or volume) estimates extracted from your supine abdominal imaging.

Population-based normative values for adult SAD are now available from Finland (Health 2000 Study) and from NHANES (2011-2016) in the USA. They confirm that SAD increases with age and tends to be larger for men than women.

The indicator SAD/height ratio (SADHtR) yields values that are nearly identical for men and women; thus, SADHtR can be evaluated as a risk estimator for men and women (just as the BMI purports to serve for men and women equally). Population norms for SADHtR are available from Finland and the USA. From the initial 4 years of NHANES we have demonstrated that SADHtR is superior to WHtR (and much superior to BMI) for identifying adults with insulin resistance (HOMA-IR), hypertriglyceridemia, and increased values of Tg/HDLc or the TyG index (https://www.ncbi.nlm.nih.go... "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003239/)").

I hope these thoughts will contribute to the success of the BeLOVE Study.

On 2019-07-16 21:33:06, user David Ludwig wrote:

One correction and one clarification:

1. There are two errors (slight underestimates) in the upper bounds of the effect sizes in the abstract. The relevant sentence should read: “Estimated energy requirement was higher in the Low vs High group by models involving ITT (ranging from 181 [CI 8-353] to 246 [64-427] kcal/d; P<=0.04) and PP (ranging from 245 [43-446] to 323 [122-525] kcal/d; P<=0.02).” The data in Table 2 are correct.

2. The full database will be publicly posted upon final publication of the manuscript in a peer-review journal.

On 2019-07-19 16:09:15, user Guyguy wrote:

EVOLUTION OF THE EBOLA EPIDEMIC IN THE PROVINCES OF NORTH KIVU AND ITURI

Thursday, July 18, 2019

The epidemiological situation of the Ebola Virus Disease dated 17 July 2019:

Since the beginning of the epidemic, the cumulative number of cases is 2,532, 2,438 confirmed and 94 probable. In total, there were 1,705 deaths (1,611 confirmed and 94 probable) and 718 people cured.<br /> 402 suspected cases under investigation;<br /> 10 new confirmed cases, including 4 in Beni, 2 in Butembo, 2 in Mandima, 1 in Vuhovi and 1 in Mutwanga;<br /> 7 new confirmed case deaths:<br /> 4 community deaths, 2 in Beni, 1 in Mandima and 1 in Vuhovi;<br /> 3 ETC deaths including 1 in Beni, 1 in Katwa and 1 in Mabalako;<br /> 1 person healed out of Ebola Treatment Center (ETC) Butembo.

NEWS

Cross-border collaboration<br /> Uganda's health authorities have launched investigations to find the contacts of a patient who died at the ETC in Beni on July 15, 2019, who had spent a day in Kasese district in Uganda a few days earlier. The patient is a Beni shopkeeper who went to the Mpondwe market in Kasese on Thursday, July 11 before returning to Beni on Friday, July 12. She was a regular at the Kasese market where she bought her goods, including fish.<br /> To enter Uganda, she did not go through a formal entry point where there was a health check, which did not allow health teams to detect her. However, after her admission to the ETC of Beni, she informed the medical teams of her trip to Kasese and the teams then alerted the Ugandan authorities. During her visit to the market, she would have vomited four times, increasing the risk of contamination of people who had been in direct contact with her. So, the Ugandan Ministry of Health and WHO launched the investigation in Kasese to identify all contacts and vaccinate them.

Point of entry surveillance<br /> From now on, the Port of Entry Monitoring Team will operate 24 hours a day at Goma International Airport. This surveillance began this Thursday, July 18, 2019.<br /> Port of Entry monitoring teams work night and day to find contacts from confirmed cases traveling in the area. It was the teams at the OPRP Health Checkpoint in the Nyragongo Health Zone who intercepted two bikers who had transported the deceased pastor and his mother. The two bikers were then directed to the vaccination teams to protect themselves against the disease. In general, when contacts from affected areas attempt to travel to Goma or Bunia and are intercepted at a checkpoint, they are usually returned to their original health zone to complete their 21-day follow-up period.

Minister of Health on mission in Eastern DRC<br /> The Minister of Health, Dr. Oly Ilunga Kalenga arrived in Goma this Thursday, July 18, 2019. He spent the day on the ground to meet the different teams responsible for protecting the city against the virus. He began his visit through the Great Northern Control Point, called the OPRP, located in the Nyragongo Health Zone where the pastor from Butembo passed. In the same health zone, he also visited the new Ebola treatment center (ETC) still under construction. This ETC, built by Médecins Sans Frontières (MSF), will have a capacity of 60 beds.<br /> Its mission will continue throughout North Kivu and Ituri to ensure the proper conduct of the response.

Press Conference in Goma: Minister of Health reassured people<br /> The coordination of the response held a press conference on Thursday in Goma following the WHO statement on the public health emergency of international concern.<br /> The Minister of Health reassured the population that the response teams and health staff in Goma City had been preparing for the arrival of sick people from areas affected by the epidemic. . Thus the person was very quickly identified and isolated, he said, adding that all the people who were in contact with this case were found and vaccinated. He took the opportunity to congratulate the health center nurse Afia Himbi who had quickly recognized this case and promised to meet him during his stay in Goma.<br /> He called on caregivers to remain vigilant and attentive. To the population, he recommended the respect of the measures of hygiene, the call of the green number if a relative is sick, the agreement to be vaccinated and to be followed during 21 days when one is identified like contact and the respect for safe and dignified burials.<br /> During this press conference, Dr. Oly Ilunga also referred to the statement of the international expert committee on the public health emergency. For the Minister of Health, the DRC welcomed this statement, noting that for the DRC, the epidemic is a public health emergency with a risk of regional spread since its declaration in August 2018. "It is in this spirit coordinating the response has worked with international partners, such as WHO, UNICEF and others, "he said.<br /> He also pointed out that this declaration is of greater importance for the neighboring countries of the DRC. He reassured his foreign counterparts of the intensification of surveillance in the DRC. He recalled that WHO has advised against closing borders and restricting international movements of the population. He hopes that this declaration will not have too much impact on the lives of the population.

THE RESPONSE TO THE OUTBREAK

165,907 Vaccinated persons<br /> The only vaccine to be used in this outbreak is the rVSV-ZEBOV vaccine, manufactured by the pharmaceutical group Merck, following approval by the Ethics Committee in its decision of 19 May 2018.

76 001 290<br /> Controlled people<br /> 80 entry points (PoE) and operational health checkpoints (PoC)

137 Contaminated health workers<br /> One health worker, vaccinated, is one of the new confirmed cases of Mandima.<br /> The cumulative number of confirmed / probable cases among health workers is 137 (5% of all confirmed / probable cases), including 41 deaths.

On 2019-07-21 06:26:16, user Guyguy wrote:

ENGLISH

OFFICIAL PRESS RELEASE RELATED TO THE EPIDEMIC OF EBOLA VIRUS DISEASE IN EASTERN DRC

1. The Democratic Republic of the Congo takes note of the statement by the World Health Organization (WHO) that the current epidemic is a public health emergency of international concern and endorses the recommendations of the WHO Director-General not to impose travel and trade restrictions and stigmatization of populations already in need of assistance.

2. The Democratic Republic of the Congo reiterates its strong commitment to continue the response to the Ebola virus epidemic and to strengthen cross-border control and control of major internal roads to ensure that no cases are omitted or escapes from the surveillance teams.

3. The response to the Ebola Virus Disease outbreak is now under the direct supervision of His Excellency the President of the Republic. To this end, it was decided to entrust the responsibility of the Technical Secretariat of the Multisectoral Committee to a team of experts under the direction of Professor Jean Jacques MUYEMBE TAMFUM.

4. This team of experts is responsible for coordinating all the activities for implementing the Ebola response strategy. The Technical Secretariat is in charge of putting in place all the innovative measures that are urgent and indispensable for the rapid control of the epidemic.

5. His Excellency the President of the Republic reassures the Congolese people and the neighboring countries that the measures currently taken in connection with the response to the Ebola Virus Disease in the DRC are likely to eradicate this epidemic.

Kinshasa, July 20th, 2019.

Source: Office of the President of the Democratic Republic of the Congo

********************************<br /> FRENCH

COMMUNIQUE OFFICIEL EN RAPPORT AVEC L'EPIDEMIE DE LA MALADIE A VIRUS EBOLA A L'EST DE LA RDC

1. La République Démocratique du Congo prend acte de la déclaration de l'Organisation Mondiale de la Santé (OMS) faisant de l'épidémie actuelle une urgence de santé publique de portée internationale et fait siennes les recommandations du Directeur Général de l'OMS de ne pas imposer des restrictions des voyages et de commerce ainsi que la stigmatisation des populations se trouvant déjà dans le besoin d'une assistance.

2. La République Démocratique du Congo réitère son ferme engagement à poursuivre la riposte à l'épidémie de la Maladie à virus Ebola et à renforcer le contrôle transfrontalier et celui des principales routes internes afin de veiller à ce qu'aucun cas ne soit omis ou n'échappe aux équipes de surveillance.

3. La conduite de la riposte à l'épidémie de la Maladie à virus Ebola se fait désormais sous la supervision directe de Son Excellence Monsieur le Président de la République. A cet effet, il est décidé de confier la responsabilité du Secrétariat Technique du Comité Multisectoriel à une équipe d'experts, sous la direction du Professeur Jean Jacques MUYEMBE TAMFUM.

4. Cette équipe d'experts a pour mission d'assurer la coordination de l'ensemble des activités de mise en oeuvre de la stratégie de riposte à la Maladie à virus Ebola. Le Secrétariat Technique est chargé de mettre en place toutes les mesures innovantes urgentes et indispensables au contrôle rapide de l'épidémie.

5. Son Excellence Monsieur le Président de la République rassure les populations congolaises et les pays voisins que les mesures actuellement prises en rapport avec la riposte à la Maladie à virus Ebola en RDC sont de nature à éradiquer cette épidémie.

Fait à Kinshasa, le 20 juillet 2019.

Source: Cabinet du Président de la République Démocratique du Congo

On 2019-11-08 19:03:54, user Rachel Couban wrote:

looking forward to reviewing the definition :)

On 2020-02-03 16:29:21, user Sarah wrote:

Hi, I'm not sure why you use the study 3 (Read et al.2020) estimate at 3.8. Their estimate is 3.11 (95%CI, 2.39-4.13). Is it an error?

On 2020-02-10 07:08:01, user ScientistCN wrote:

Only 1099 patients were analyzed, how can we get the significant figure to 0.01%?

On 2020-02-15 21:55:51, user Nate wrote:

It does need to be pointed out that this is Pre-Print at this point in time. It still needs to go through peer-review, etc., to be published.

That said, if this research is borne out/validated then this is pretty problematic news. The Chinese Government gave an R0 value of 2.6-2.9 or something like that, and also has publicly said the mortality rate is similar to the 2006 SARS outbreak (which had a lower R0 of something like 1.9 or something (possibly lower) ultimately. Assuming these figures are more accurate, If the Chinese Government is either not finding or hiding the number of cases but not the number of deaths, it actually may be good news, as the mortality rate would be considerably lower. However if they are wrong about or lying about both figures and it is both more contagious and more deadly, this could be a pretty serious epidemic/pandemic. If they, for instance are underestimating or underreporting the mortality rate by about .5 deaths per 1000 (I believe that’s the metric I’ve seen), the mortality rate would be roughly that of the 1918 Spanish Flu. Now, we are far better at treating symptoms now and preventing person to person spread of disease as we were in 1918, as well as developing vaccines. We have a lot of developed treatments that could be effective in minimizing symptoms or fighting the disease as well, even short of a currently viable cure/particularly effective treatment.<br /> However, that R0 value, if anywhere close to on target is pretty alarming. Even if the actual value is halfway between China’s figures and this study’s figures, and even if it were merely as deadly as SARS was.

Still, this isn’t an official figure yet. This isn’t even published, we don’t know how much other research will validate this number or contest it. So don’t panic based on a pre-print article. This probably has more value being available for other researchers, whom seeing other people’s figures, or methodology could benefit in their own research or methodology, and public heath officials who need to try to assess what a worst case scenario may look like. If these figures are accurate, they would be alarming. Even somebody who can read statistics and the language correctly in shouldn’t simply take something like this as fact, until it gets through peer review, other experts evaluate it once it’s published, and other figures start to align with their findings. I engaged in speculation, as it is really concerning should these figures be correct, and an interesting conversation to engage in. However, I am not credentialed in epidemiology, public health, or medicine. You should listen to experts and public health officials, over then speculation of somebody like myself. I am discussing the implications of this if true, not rendering an expert opinion.