On 2020-05-05 17:25:01, user Hannah Sally wrote:

Are all patients included in the study, patients whom were admitted because of COVID-19 or does this cohort also include patients whom were admitted to hospital for other reasons but concurrently were diagnosed in hospital with COVID-19? I may have missed something, but not sure if this is clear in the methods. This could impact the overall hospital admission mortality statistic.

On 2020-05-06 15:16:10, user Sinai Immunol Review Project wrote:

Summary: Using peripheral blood samples collected from 8 COVID-19 patients with moderate to severe acute respiratory distress syndrome (ARDS), the authors showed that COVID-19 patients exhibit lower CD3+ T cell counts as well as increased CD4:CD8 ratio. In addition to population analysis, PBMCs were stimulated with three pools of either overlapping peptides of SARS-CoV-2 spike (S) protein or HLA Class II or I predicted epitopes covering all viral proteins except S designed to activate CD4 and CD8 T cells, respectively. While stimulation of PBMCs with all three peptide pools led to detection and activation of SARS-CoV-2 specific CD4 and CD8 T cells, spike (S) peptide pool elicited the strongest response, indicating that the S surface glycoprotein is a strong inducer of both CD4 and CD8 T-cell responses. Phenotyping of activated T cells (CD4+CD69+CD137+ or CD8+CD69+CD137+) showed that the majority of activated CD4 T cells were central memory T-cells (CD45RA- and CCR7+) while activated CD8 T cells were mostly effector memory T cells (CCR7-) and terminally differentiated effector T cells. Cytokine analysis of cell culture supernatants from PBMCs stimulated by S-peptide pool led to a strong production of Th1 cytokines IFN?, TNF? and IL-2. Lastly, the authors profiled the kinetics of both humoral and cell-mediated response in four different time points using ELISA of virus-specific serum IgG and quantifying expression of cell surface markers induced by S peptide pool activation. Throughout the patients’ stay at the ICU, both levels of virus-specific IgG antibodies and frequencies of virus-specific CD4 cells increased significantly over time.

Limitations: A couple of additional assays done in parallel could have further strengthened the paper’s findings. Simultaneous profiling of cytokines from PBMCs could have easily answered whether these T cells which are capable of producing Th1 cytokines upon activation are indeed producing them in patients. Furthermore, it would have been informative to have added a couple of functional exhaustion markers (i.e. PD-1, Tim-3, etc.) and compare their expression between pre- and post-activation by S peptide pool—thereby addressing the effect of functional exhaustion in T cells reported in severe COVID-19 patients. Follow-up studies investigating which epitopes out of the S protein peptide pool elicited the most potent T-cell response would have yielded informative results for possible vaccine design efforts against the spike protein. Lastly, comparing the quality of virus specific T cells immunity between patients in ICU (the focus of the study) and patients with mild /moderate disease would have been very informative.

Significance of the finding: For the most part, the study design has been well established to answer the following questions: a) are there T cells reactive to spike (and other HLA-reactive) protein of SARS-CoV2 even in cases of COVID-19 with moderate to severe ARDS (which has been characterized with lymphopenia)? b) what are the phenotype and cytokine profile of CD4 and CD8 T cells upon activation? Answering these questions do advance the field’s understanding of T cell response to COVID-19 and add to much-needed effort to devise a vaccine against SARS-CoV2. Building on this article’s findings, perhaps future studies could perform mechanistic assays the function of T cells from COVID-19 patients in the context of systemic inflammation (i.e. adding IL-1, IL-6, TNF? in the culture media) as well as correlating epitope-specific immune response of patients with their clinical severity.

Review by Chang Moon as part of a project by students, postdocs and faculty at the<br /> Immunology Institute of the Icahn school of medicine, Mount Sinai.

On 2020-05-07 03:35:17, user Mazyar Javid wrote:

I left a comment for the first version expressing my astonishment on how<br /> many seem to be obsessed with tearing this study apart and discrediting its<br /> findings altogether. I agree that the study has limitations (as a scientist and<br /> a peer reviewer, I am yet to see a “perfect” study). Nonetheless, the authors<br /> have made substantial attempts to address the limitations reasonably and adjust<br /> their results accordingly.

Since the publication of the original report, we have seen results of multiple<br /> serologic studies that have largely corroborated these findings: Studies in<br /> less affected areas (e.g. Czech Republic) which indicated very low prevalence<br /> of seropositiveness (effectively undermining the notion that most of positives<br /> in these studies are false positives, otherwise we would have seen similar<br /> relatively high prevalence of “positives” there too), to studies in heavily<br /> affected areas such as NYC which show higher prevalence but smaller ratio of<br /> seropositives to confirmed cases (due to higher frequency of testing).

The implications, that the IFR is significantly lower than what is publicly<br /> portrayed, and that in many areas, the prevalence is possibly much higher than<br /> can be practically managed with containment strategies, requiring other mitigation<br /> strategies with focus on vulnerable populations are enormous, yet I rarely see<br /> anyone among our decision makers taking any of these data into consideration<br /> despite all the claims that decisions are driven by nothing but “data”.

Somehow this reminds of Plato’s Allegory of the Cave: We saw the projections<br /> and took them as the reality, until one dared to escape and saw what really<br /> lied outside and came back to inform us of the findings, yet we, mesmerized by<br /> the shadows, could not believe it and rushed to chastise the messenger. So is our story, preferring model projections over actual data and getting upset when the latter does not support the former...

On 2020-05-07 12:01:23, user Alex Cranberg wrote:

The authors’ conclusion about being far from herd immunity is based on the questionable assumption that the population is homogeneous. If population has variation in susceptibility herd immunity may be close or even reached. https://www.medrxiv.org/con...

On 2020-05-07 14:55:07, user Villainess wrote:

Pretty exciting result for what sounds like an otc med in Europe!

On 2020-05-09 21:33:19, user christopher starling wrote:

What positive HCQ evidence does anyone have that provides usable scientific data and answers the same questions being asked here?

On 2020-05-10 12:03:31, user Zn2 plus wrote:

This preprint is now published : https://doi.org/10.3390/bio...

On 2020-05-12 20:31:26, 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. I hope that the above comments will enable them to improve their study.

On 2020-05-13 14:21:49, user Sinai Immunol Review Project wrote:

Main Findings: <br /> Given the urgent need for diagnostic testing for COVID-19, this study uses enzyme-linked immunoabsorbent assay (ELISA) to measure serum antibody levels against recombinant spike protein ectodomain as well as its receptor binding domain (RBD) to angiotensin-converting enzyme (ACE2). Twenty RT-PCR confirmed COVID-19 patients as well as 99 healthy donors were tested for IgG titers in their serum. Antibodies to spike protein ectodomain were detected in 17 out of 20 patients, of which 5 showed borderline levels. 15 out of 20 patients tested positive for antibodies against spike RBD, of which 7 indicated borderline levels. These findings suggest that while majority of COVID-19 patients develop antibodies against the RBD, some patient responses may target other epitopes of the spike protein. Furthermore, they show that circulating antibody levels (ie: positive vs borderline) do not correlate with clinical severity or recovery from COVID-19. Strikingly, 1 patient who recovered did not have detectable IgG antibodies against RBD, suggesting a potential role of cellular immunity in the clinical resolution of COVID-19. In addition, they report that 4 out of 10 healthy donor serum collected since January 2020 tested positive. This indicates that apparently healthy individuals may be asymptomatic carriers, which underscores the importance of developing effective methods for community wide testing.

Limitations: <br /> The authors cite a study in their introduction that demonstrates minimal cross reactivity of antibodies between SARS-CoV and SARS-CoV-2 patients suggesting a specific antibody response for each disease. However, their study showed that five out of 89 serum samples collected from healthy donors between 2017 to 2019 tested positive for antibodies against spike protein ectodomain, and acknowledge a possible cross reactivity from prior exposure to other strains of coronavirus. This result also stands in contrast with other recent studies*. Understanding whether or not there is indeed such cross reactivity would be important for interpreting their results and designing vaccines against this specific virus. Furthermore, their thresholds for determining positivity versus borderline antibody levels are arbitrary and can significantly influence the outcome of their assay. It will be critical to obtain a larger cohort to further validate the robustness of their thresholds for determining circulating antibody levels.

Significance: <br /> This study establishes a straightforward assay in testing for circulating antibodies against spike protein in the serum of COVID-19 patients. This is important not only for surveying the population for people with immunity, but also improves sensitivity for diagnosis when combined with RT-PCR. In addition, their finding of a patient who recovered without detectable antibodies against spike protein RBD provides important insights to designing therapies for COVID-19.

Reviewed by Joel Kim as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

References:<br /> *Amanat, F., et al. A serological assay to detect SARS-CoV_2 seroconversion in humans. medRxiv preprint (2020)

On 2020-05-15 15:29:20, user Irving Kushner wrote:

Finding a low serum vitamin D concentration does not necessarily indicate vitamin D deficiency. There is now abundant evidence that vitamin D is a negative acute phase reactant – that is, its serum concentration falls during inflammatory states, as do albumin, transferrin, zinc and iron concentrations, in contrast to C reactive protein (CRP), which is a positive acute phase reactant.https://www.ncbi.nlm.nih.gov/pubmed....

This conclusion is supported by several lines of evidence: vitamin D levels have been found to be decreased in a number of inflammatory states. https://www.ncbi.nlm.nih.go..., https://www.ncbi.nlm.nih.go...<br /> Vitamin D levels fall following a variety of inflammatory insults, such as surgical procedures. https://www.ncbi.nlm.nih.go..., https://www.ncbi.nlm.nih.go..., https://www.ncbi.nlm.nih.go...<br /> And, as the authors indicate, it is well recognized that serum CRP and vitamin D levels are inversely associated. https://www.ncbi.nlm.nih.go..., https://www.ncbi.nlm.nih.go...

There is really nothing new in this study. The abstract states that they used CRP levels as a surrogate for vitamin D levels. So what they actually found was that higher CRP levels are associated with the risk of severe COVID-19. We knew that already.<br /> From Maria Antonelli and Irving Kushner, Case Western Reserve University

On 2020-06-17 20:11:26, user LB wrote:

Zotero (a popular citation manager) says that this article has been retracted. If this is not the case, please ask Retraction Watch to correct the error.

On 2020-05-19 00:53:07, user Sinai Immunol Review Project wrote:

Main Findings:

An unusually high incidence of Kawasaki disease was reported in a pediatric center for infectious diseases in France. This is a rare post-viral vasculitis that was been associated with several viruses in the past, including coronaviruses. The authors reported 17 cases over a period of 11 days, in contrast to a mean of 1 case per 2-week period in 2018-2019. <br /> Polymorphous skin rash and bulbar conjunctival injection were the most frequent criteria for diagnosis of Kawasaki disease. The patients had a median age of 7.5 years (range 3-16); 65% (n=11) presented with shock syndrome, and 70% of the patients (n=12) had concomitant myocarditis. All patients had high inflammatory parameters, including leukocytosis with a predominance of neutrophils, and high levels of C-reactive protein, procalcitonin and interleukin-6. Compared to past descriptions of Kawasaki disease, this cohort had an 8-fold increase in procalcitonin level, what suggests a particularly strong post-viral immunological reaction to SARS-CoV-2 as compared with other viral agents. <br /> Remarkably, although the study was conducted in France, 59% of the patients were originally from sub-Saharan Africa or Caribbean islands, and 12% from Asia, pinpointing a possible genetic predisposition or a travel-associated exposure. <br /> In 82% of the cases, IgG antibodies for SARS-CoV-2 were detected, suggestion an association with coronavirus disesase 2019 (COVID-19). RT-PCR testing for SARS-CoV-2 was positive in 41% of the patients. Although only 6 patients had recent history of an acute respiratory infection, in 9 cases there was history of recent contact with family members displaying respiratory symptoms. However, all patients had gastrointestinal symptoms prior to the onset of Kawasaki disease signs.<br /> All patients were treated with intravenous immunoglobulin (IVIG) and aspirin. Some received concomitant corticosteroids (n=3) and/or broad-spectrum antibiotics (n=14). Admission to intensive care unit (ICU) was necessary in 13 cases. A total of 5 patients had IVIG resistance. Regarding the outcome, 5 patients had not yet been discharged by the time the manuscript was published.

Limitations:

This was a single-center study with a very short follow-up period of 11 days. The information about the total number of paediatric patients that tested positive for SARS-CoV-2 in this center/region during the reported period is missing. That could help to draw conclusions about the incidence of Kawasaki disease-like inflammatory syndromes in children after SARS-CoV-2 infection. Additional to the genetic predisposition hypothesis, information about potential travel-associated exposures should be discussed in the manuscript due to the apparent difference in incidence between racial groups. Furthermore, although the prevalence of COVID-19 in Europe is currently very high, an association between SARS-CoV-2 and the reported outbreak of Kawasaki disease needs further studies to determine causality.

Significance:

The temporal association between the COVID-19 pandemic and the results of RT-PCR and antibody testing suggest a causal link between Kawasaki disease and COVID-19. At the time of this writing, while this is not the first description of Kawasaki disease-like inflammatory syndromes in association with COVID-19, it is the largest published cohort. Kawasaki disease should be evaluated as part of the spectrum of post-viral immunological reactions in COVID-19 convalescent children. These findings should prompt a high degree of vigilance among all physicians, and preparedness in countries with a high proportion of children of African and Asian ancestry during the COVID-19 pandemic. The World Health Organization (WHO) has recently developed a case report form and encouraged physicians to report all suspected cases.

Reviewed by Alvaro Moreira, MD as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai

On 2020-11-20 19:44:06, user StephenSela wrote:

Can I see a real MRI/Xray picture of the damage from someone who actually has this

On 2020-11-21 23:33:56, user VirusWar wrote:

Dr Soumya Swaminathan, Scientific chief of WHO explained on ECCVID conference that in Solidarity trial, hydroxychloroquine (HCQ) was widely used in Standard of Care group, despite rules said it should not. She said they had to do some "adjustment" but this doc don't talk about this issue or any adjustment.

Dosage of Hydroxychloroquine is also far too high and patients in that group are worse at entry than the one in supposed "control" group.<br /> There is a big issue in mortality graph over time in Figure 2a for remdesivir : death rate at 28 days is supposed to be 11% but graph shows it at 13%

It is odd to compare HCQ against HCQ

On 2020-11-25 16:37:17, user Duke Pham wrote:

The main flaws of #solidarity #study can be found here : <br /> https://c19study.com/solida...

HCQ dosage very high as in RECOVERY, 1.6g in the first 24 hours, 9.6g total over 10 days, only 25% less than the high dosage that Borba et al. show greatly increases risk (OR 2.8) [1].

Authors state they do not know the weight or obesity status of patients to analyze toxicity (since they do not adjust dosage based on patient weight, toxicity may be higher in patients of lower weight).

KM curves show a spike in HCQ mortality days 5-7, corresponding to ~90% of the total excess seen at day 28 (a similar spike is seen in the RECOVERY trial).

Almost all excess mortality is from ventilated patients.

Authors refer to a lack of excess mortality in the first few days to suggest a lack of toxicity, but they are ignoring the very long half-life of HCQ and the dosing regimen - much higher levels of HCQ will be reached later. Increased mortality in Borba et al. occurred after 2 days.

An unspecified percentage used the more toxic CQ. No placebo used.<br /> [1] c19study.com/borba.html<br /> death, ?19.0%, p=0.23

According to scientific studies, #hydroxychloroquine is efficient against #covid19. <br /> This website lists all the studies (positive or negative) : www.c19study.com. <br /> Majority of the 181 studies show a reduced #mortality and #severity in the disease with patients treated with #HCQ.

On 2020-12-02 16:52:31, user Benjamin Speich wrote:

This was an interesting article, thanks for posting it!

On 2020-12-03 18:13:15, user Nicholas Lewis wrote:

In general the reasoning and modelling in the original (July<br /> 29, 2020) paper seemed sound to me., in fact I thought it was an excellent<br /> paper. The revised (October 29, 2020) version of this paper makes the argument about<br /> varying heterogeneity rather more clearly than did the original version,<br /> although I found the explanations rather too sketchy in some places.

However, it appears to me that – if I understand it<br /> correctly – the revised version introduces some unsupported and unreasonable changes<br /> in assumption, which should be reversed.

In particular, the argument that short term overdispersion has<br /> an effect on the overall epidemic dynamics is insufficiently explained and not substantiated.<br /> It is far from obvious why that should be the case, although superspreading<br /> events may affect its very early stages.

Persistent heterogeneity is quantified by reference to the<br /> characteristics of contact networks, which "are remarkably robust"<br /> and set the value of nu at approximately<br /> 1, implying lambda = 3 (page 6 of the October 29 version). It is accordingly illogical to work on the basis that an individual's number of contacts changes significantly over time, which is what your Eq.[20] and related assumptions appear to imply. In the<br /> absence of such changes, the assumed original susceptibility gamma distribution<br /> will remain gamma distributed with unchanged CV (but lower mean) as the<br /> epidemic progresses [Montalban and Gomes arXiv:2008.00098v1]. No evidence is<br /> given that, by the time that there is sufficient data to model the evolution of<br /> the epidemic, any initial heterogeneity overdispersion will affect the inferred<br /> epidemiological parameters.

One way the supposed 'short term overdispersion' effect could<br /> arise is if a person who is highly connected and, as a result, becomes infected<br /> early in the epidemic thereafter tends thereafter to have fewer contacts, so<br /> that his inability (after recovering) to infect others has less effect on<br /> slowing the future epidemic, while other (uninfected) people on average have<br /> more contacts than previously. However, such an assumption would seem<br /> unjustifiable, save perhaps to a small extent, given the robustness of contact<br /> networks.

I accept that such an effect could perhaps arise from (say) week-to-week<br /> fluctuations in the number of contacts someone has, with their being more<br /> likely to be infected during a week with an unusually high number of contacts,<br /> and possibly being more likely to have more contacts in their following<br /> infectious period. I think that may be what the paper is arguing, although if<br /> so it is not very clearly explained. But, if so, surely that would apply<br /> throughout the epidemic wave rather than being time varying? In connection with<br /> this, you state (page 6) that delta-lambda(t') decreases with time, but it is<br /> not clear to me from Eq.[19] why it should do so, given that there is (and<br /> should be) no assumption that the delta-alpha_i values decrease over time.

Further, the change to assuming zero, rather than modest,<br /> biological heterogeneity in susceptibility is unjustifiable and should be<br /> reversed. Given that individuals vary as to their immune system memory and general<br /> effectiveness, due to differences in age, genetic factors, health status and<br /> life history, they are bound to vary in their ability to resist infection by<br /> SARS-CoV-2, as stated in the July 29 version. The assumed level of biological heterogeneity in susceptibility in the July 29 version, of lamba_b = 1.3, was – as stated<br /> there – a conservative level. It should be reverted to.

On 2020-12-05 18:54:57, user Zed wrote:

Dear authors,

I'm pretty sure your preprint is now somewhere under peer-review, but I was wondering what are the main difference between your meta-analysis and Fiolet et al (https://www.clinicalmicrobi... "https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(20)30505-X/fulltext)"). It looks pretty similar or at least going in the same way.

Thanks :)

On 2020-12-11 10:13:56, user Marina Pollán wrote:

Please, notice that a new version of this paper, including additional information, has been accepted and published in the British Medical Journal:<br /> doi: 10.1136/bmj.m4509<br /> Prof. Marina Pollán in the name of all the authors

On 2020-12-15 10:58:41, user NK wrote:

Re: article pre-published at https://www.medrxiv.org/con...

There are several methodological problems in this study.

1. Findings that suggest increased ORs among primary school teachers, child care workers and secondary education teachers are not properly presented and discussed

The summary states: "Teachers had no or only moderately increased odds of COVID-19". This finding is mentioned several places in the text of the article. Teachers are repeatedly referred to as having a low risk, even when the results for teachers show a significant increase in admissions and borderline significant increase in infection rates. Quotes: «First, our findings give no reason to believe that teachers are at higher risk of infection», and in the conclusion: “Teachers had no increased risk to only a moderate increased risk of COVID-19”. We wonder why the authors find it important to repeatedly mention this<br /> result for teachers when the result for the last period does not exclude a substantial increased risk for teachers, whereas occupational groups with lower risk than teachers are not mentioned in the summary.

The part of “Supplementary table 1” does not provide a basis for such a conclusion that teachers are a low risk group.

The OR (95% CI) for 1) primary school teachers 2), child care workers and 3) secondary education teachers were 1.142 (0.99-1.32), 1.145 (1.02-1.29) and 1.095 (0.82-1.47) respectively. The upper confidence limits does not exclude 29 % to 47 % increased ORs, which represent substantial increases.

Concerning the results on the risk of admission, it is stated: «None of the included occupations had any particularly increased risk of severe COVID-19, indicated by hospitalization, when compared with all infected in their working age (Figure 3, S-table 2), apart from dentists, who had 7 ( 2-18) times increased odds ratio, and pre-school teachers, child care workers and taxi, bus and tram drivers who had 1-2 times increased odds ratio”.

This finding is not discussed or mentioned in the summary, even if the findings were statistically significant for pre-school teachers as well as for child care workers.

1. The study periods include periods when the schools were closed and include no period with high infection rate among children and youths.

It is not to be expected that teachers have higher infection rates than the average working population in periods when school are closed and when the infection rates are low in the age groups 0 - 9 and 10 -19 years. This problem is not discussed in the paper. Schools were closed from 12 March to 27 April. For a majority of the schools, holiday started from Friday 19 June.

The first study period lasted from February 27 to July 17. Thus, schools were closed for over 70 days of the first study period of 139 days. The infection rates in children at school age in the first study period were rather low (3.6 per 100 000 children per week between in the age group 10 -19 in week 19, 1.1 per 100 0000 children per week in week 25). In the last study period, the infection rates varied between 7 to 17 per 100 000 per week in the age group 10 - 19. Even if these rates are much lower than later weeks that were no studied (after week 42), the results from this second part of the study suggest an increased risk for teachers.

Thus, the infection rates among children started to increase from week 43, after the end of the study period. By not including this period, the study design excludes the possibility to detect if these high rates among pupils could be related to increase infection rates among teachers.

It is a problem that the results from this pre-published study has been quoted in the media and referred to as if teachers have no excess risk, or even possibly a reduced risk at the time that several municipalities were to decide what type of restrictions at schools should be introduced to reduce the risk of transmission among school children, see https://www.barnehage.no/korona/ny-forskning-nei-barnehagelaerere-har-ikke-okt-risiko-for -smitte/211143

On 2020-12-20 10:40:04, user Martin Reijns wrote:

Please note that this paper has now been published after peer review in PLoS Biology:

https://doi.org/10.1371/jou...

On 2020-12-21 18:08:41, user Michael Schrader wrote:

Very helpful study.<br /> Just a short comment on table: With 35 patients, precision is not better than +- one patient, corresponding to +-2.9 %. It is thus confusing to claim percentages with 4 digits like 97.12 %.

On 2020-12-24 07:31:39, user K Cornwell wrote:

Well done on your study. It is because of doctors who go the extra mile in the fight against this terrible virus. That we find that some of our medicines which may have been around for many years are having a significant impact on the treatment and recovery times. Let hope that the vaccines are enough to create some immunity across the countries and the treatment algorithms improve with better research.

On 2020-12-25 16:40:49, user Mukesh Bairwa wrote:

A novel topic chosen for systematic review and meta-analysis have medical implication for developing countries. The research question and search strategy is very clear and understandable. The results are quite impressive that M health intervention is helpful to improve the maternal and child health indicators in developing countries. The methodology is crisp and concise and readable. The work included the important parameters related to maternal and child health indicators. However, I suggest authors to include many other relevant parameters in future work.

On 2021-01-03 22:32:54, user Rodger Kram wrote:

Overall, I find this analysis to be interesting and well-conducted.

I would add Hunter et al. to the list of papers reporting improved running economy with neoteric Nikes. <br /> https://www.tandfonline.com...

Iain's treadmill was a bit slippery in the Vaporflys and I bet that accounts for their slightly lower savings.

minor points: <br /> Line 26 tongue in cheek: I know Joyner is prescient but how did he know in 1985 that he would be fascinated in 2019? Likewise for Hoogkamer 2017.

Line 42 (13) is a great paper but an odd reference here, Tung et al. would make more sense.<br /> Line 53 "led to" assumes cause-effect, horse before cart<br /> Line 82 doesn't really matter here but such directional hypotheses make 1-tailed tests legit. I am a proponent of directional hypoths<br /> Line 177 "moderated" seems like the wrong word here. plus "strongly moderated" seems like an oxymoron. like "mildly enthusiastic"<br /> Line 188-189 "average" but then "median" values are given.<br /> Line 209 cold temps too!<br /> Line 281 where does 1.5% come from? I thought the mean was 2%?<br /> Line 284 I would have provided (X%) in addition to the 4minutes since previous sentence was about %,

Line 301 I list my consulting to Nike on relevant papers, it would seem AJ should do so on this paper.

Ref (11) is 2020 not 1985

On 2021-01-05 14:01:12, user Lianna Martin wrote:

Hiya - I had suspected covid 11th March and still can barely smell. My nasal passage more recently has become painfully crusted up coinciding with most things with a strong smell coming across like bleach or petrol to me. Taste comes and goes. I can live with symptoms, but would love to be part of a study...

On 2021-01-06 12:33:57, user C'est la même wrote:

The authors state that there were 25 cases of GBS in London during the sampling period, which would lead to an estimated occurrence rate of 0.82 GBS cases per 1000 COVID-19<br /> infections.<br /> Yet they discount this by citing a claim that 17.5% of individuals London had been infected by that time. We now know that estimate was wildly inaccurate.<br /> Serological survey data collected by the ONS found that prevalence in London was just under 0.4% around that date (https://www.medrxiv.org/con... "https://www.medrxiv.org/content/10.1101/2020.07.06.20147348v1)")

Which works out to around 36,000 people in comparison to the 26,784 PCR confirmed cases. <br /> This would lead to an estimated occurrence rate of ~0.6 GBS cases per 1000 COVID-19 infections which certainly seems suggestive of an association.

The authors also performed genomic analyses to rule out molecular mimicry due to epitope similarities.

I'd like to draw attention to the fact that many of the known viral triggers of GBS also do not have evidence of molecular mimic epitopes, instead suggesting other mechanisms of generating autoimmunity including the co-capture hypothesis, (http://www.pnas.org/content... "http://www.pnas.org/content/114/4/734)"), given that spike protein interactions with gangliosides have already been characterised in a substantial number of publications to date.

As such, while the lower population incidence during the observed period is compelling, that data alone is not enough to rule out the association of GBS with SARS-CoV-2, given the impact of lockdown measures on other infectious causes that happen to have lower infectivity (basic reproduction number) than SARS-CoV-2.

On 2021-01-09 09:39:25, user Dr. Sebastian Boegel wrote:

This is a wonderful study. Congratulations. I am very honoured that you used my tool, seq2HLA. As seq2HLA also output HLA gene (and allele) expression (normalized to RPKM and the coounts), i am wondering why you additionally used AltHapAlignR for obtaining read counts for HLA genes. Did you experience any issues with seq2HLA? If yes, i am happy to help. <br /> All the best for you and keep up the great work,

Sebastian

On 2021-01-10 10:09:41, user Disqus wrote:

Gandini S et al. updated their previous preprint without, however, resolving the<br /> methodological problems, that is the errors already highlighted and the<br /> arbitrariness of most of the conclusions (see comments for the previous version<br /> here https://www.medrxiv.org/con... "https://www.medrxiv.org/content/10.1101/2020.12.16.20248134v1)").<br /> In particular in this second version the sample of public institutions increase from 81.6% to 97% of total, for a total of 7,376,698 students, thus it is not clear how on such large numbers one can hope to obtain significantly different or significantly more reliable results from such an update.

On the other hand Gandini et al. seem to have realized how their analyses suffer from the biases of an ecological study (page 13) though it is incomprehensible how the proposed additional analysis for the Veneto region only can significantly relieve the problem.

There are still also some gross errors here and there, e.g. although the authors have updated Table 8 by adding the (useless) absolute range of the number of tests per institution, the problem of standard deviations remains, certainly the result of a calculation error being compatible with negative values in the number of tests (e.g. 9-13 = -4 which would represent the lower limit for 1 standard deviation for the number of tests, see Student index case – Kindergarten row)

Finally, once again in spite of the medRxiv warning, Gandini et al. seem to consider it as a sort of personal press agency, a springboard to relaunch their studies without having to wait for the peer review, so much so that on the fb page of the first author (Gandini S.) a link to the article promptly appeared, the day after it was published on medRxiv

On 2021-01-12 17:22:08, user Ann Marie Miller wrote:

Can any one tell me if the Herpes 6/7 loads could cause a false positive Hep. C test, during a flare up? Thank you!

On 2021-01-15 14:29:13, user Serge Richard wrote:

Would you please inform the financial Interest Links between these authors and the pharmaceutical compagnies involved in the drugs refered to ?

On 2021-01-16 00:11:22, user Sandrine_G ???????? ???????? wrote:

All the people involved and mentioned above have the duty (and the obligation, for the French) to declare their conflicts of interest. Make them obey the law. Thank you !

Toutes les personnes impliquées et citées en haut ont le devoir (et l'obligation, pour les français) de déclarer leurs conflits d'intêret. Obligez les à respecter la loi. Merci

On 2021-01-15 20:36:01, user Yves Muscat Baron wrote:

Could changes in the airborne pollutant particulate matter acting as a viral vector have exerted selective pressure to cause COVID-19 evolution? Medical Hypotheses DOI: 10.1016/j.mehy.2020.110401Reference:YMEHY

On 2021-01-17 17:03:45, user kdrl nakle wrote:

Extremely important result. Shows aerosolization of the virus when it can be cultured from less than 0.5 micron particles, these are definitely aerosol size.

On 2021-01-19 15:51:45, user Alter Ego wrote:

In the text it is written: "LamPORE reliably detected SARS-CoV-2 to 20 copies/ml of sample. SARS-CoV-2 reads were detected in the 0.2 copies/ml sample but this was below the threshold for calling as positive sample in LamPORE but were not detected via RT-qPCR (Table 1, Figure 3)." - I assume that with "sample" the original saliva or NP sample is meant. If this is true the assay would be amazing .... my question: ins't there an error and it should be written 20 copies/microliter ... and also 0.2 copies/microliter. This would better fit to the rather low sensitivity of the assay in Figure 4 and an overall performance that is rather on the lower side of other LAMP reports where generally a cut of of approx CT=30 has ben reported (corresponding to approx 20'000copes/millilitre. This Figure is otherwise consistent with the idea that the N2 priers are much better than the E1 and ORF1ab primers....

On 2021-01-19 18:29:14, user Monika J. wrote:

As a Slovak citizen I can tell your that they are NOT telling the whole truth. Your can fact check my every single word.<br /> They claim that the testing was not obligatory... NOT TRUE<br /> People where forced to attend this mass testing. Prime minister admitted that they forced us to do this on the Press conference. Our Human rights where oppresed. Without negative test certificate your couldnt go to work, bank, post Office, all shops denied you to enter their premises. All services where denied to your without certificate. Even some doctors refused to treat patients without cerificate. You could only go to grocery store, pharmacy and drugstore without certificate. There were some exceptions, but not important. Some employers called the police on employees who wanted to go to work (they where healthy, had no symptoms) but didnt hlave the certificate. A lot of employees were fired, because they refused to get tested.

Lets talk about the study. They claim that they have participant conset.... NOT TRUE we havent sign anythig. Nobody informed people what kind of test they are using, who will hlave their samples afterwards, who will procesed their personal information..yes they hlave our personal numer and wrote some information from our ID....we dont know which information they collected.

Thay claim that tests where done ONLY by profesionals.. NOT TRUE. Tests where done by non medical personnel too - in some cities - those people braged about it on Facebook. There is NO name of person who tested you. You can not check if this person <br /> is profesionall or not.<br /> In some cities testing was done outside. People where forced to stand for multiple hours in lane just to get tested, in rain, and low tempersture...<br /> I could continue on and on and on....<br /> Now they are going to do the second round od this mass testing. They are again FORCING us to do it Once again. The second round is even worst than the first one. Now they want us to stand in lane to get tested in -10 to -15°C.<br /> Now the police will be controlling us if we have the certificate or not. If your will not have the certificate you will get a fine. And they will oppresed our human rights again. Segregstion od people to two categories is called apartheid and it is illegeal....this is what they are doing. They are creating second category people. First category Has certificate and Can live relatively normaly. Second category is treated like garbage.

On 2021-01-24 11:43:28, user Zdenko Ontek wrote:

I have to express myself as a citizen of the Slovak Republic. Several points in the research conditions do not agree with reality. Test subjects did not sign informed consent or instruction. It is also untrue to claim that testing was voluntary. The Government of the Slovak Republic created direct and indirect pressure, for example, through employers, who conditioned the entry of their employees into the workplace by passing testing. I note that the translation is machine, so I apologize for the English. Affected citizen of the Slovak Republic.

On 2021-01-21 15:04:47, user CB Bass wrote:

Been saying this for 9 months but Ignored by all MSM outlets. Our published study found that the culprit in the cytokine storm and Covid severity is IL-6. Guess what else? Your gut bacteria- specifically Bifidobacterium regulate IL-6. This is why we are not seeing severe cases of covid in children. They have much higher concentrations of Bifidobacterium in their guts than adults do and it down regulates IL-6 which is pro inflammatory, while up regulates interferon and IL-10 which are anti inflammatory.

Also a study coming out of Hong Kong university last week not only confirmed what our Initial study and discovery showed, it found that patients with Covid severity had deficiencies in Bifidobacterium.

Here is a summary of our study if you’d like to read more on how IL-6 plays a major role in Covid severity in high risk individuals.

https://www.worldhealth.net...

On 2021-01-22 21:53:47, user Takashi Nakano wrote:

The article was peer-reviewed and published on JMIR in November, 2020. <br /> Nakano T, Ikeda Y<br /> Novel Indicator to Ascertain the Status and Trend of COVID-19 Spread: Modeling Study<br /> J Med Internet Res 2020;22(11):e20144<br /> URL: https://www.jmir.org/2020/1...<br /> DOI: 10.2196/20144<br /> PMID: 33180742<br /> PMCID: 7708296<br /> https://www.jmir.org/2020/1...

On 2021-01-27 10:19:32, user Fred wrote:

I am not convinced of the data. Eg for Germany it is presumed that only about 1 of 10 infections is detected. The data I know from Germany say this number ist only 2-4 . So the IFR for Germany would not be O.2% but at least o.4 or even near to 1 %

On 2021-01-29 18:28:35, user hlritter wrote:

The stated 51% reduction in daily incidence reflects only that half as many cases occurred in the second 12 days as in the first 12. But that does not take into account the fact that the curves don't begin to diverge until 6 days into the second 12-day interval. What's important is the improvement in incidence that occurs after immunity develops, not after the halfway point to some arbitrary date. It appears that only about 1/6 as many new cases occurred in the 6 days after the onset of relative immunity at Day 6 as occurred in any 6-day interval prior to this. This supports an efficacy in the range of 80%-85%, not 51%.

On 2021-02-06 06:12:34, user Scott Huffman wrote:

So what exactly was the n value in the non-vaccinated group, and what was the n value in the vaccinated group? How was a positive case defined? Was it merely a positive PCR test, or was it an actual symptomatic case where a person was sick? And importantly, what was the average cycle rate of the PCR testing? What is the Absolute Risk Reduction? What's the NNT? These are legitimate questions that must be asked. The answers should be very simple.

On 2021-01-31 18:53:06, user Timotheus123 wrote:

This is clearly not a serious study. No apparant controls for age or comorbidity, no random assignment of treatment or control, an "inverse probability of treatment" adjustment.. etc etc.

And yet a strong conclusion debunking ivermectin?

This is NOT science.

On 2021-02-01 15:59:31, user Victoria Gates wrote:

What about the studies done by the FLCCC Front Line COVID-19 Critical Care Alliance? They present strong evidence to the contrary.

On 2021-02-02 16:30:41, user Martha Albertson wrote:

This is a poorly-designed study that looked at very few trials of ivermectin. The authors picked the studies that portrayed ivermectin in the worst light and ignored the many studies showing that ivermectin is a safe and effective treatment for Covid-19. I wonder who funded this study. Ivermectin is so much more effective than the expensive treatments promoted by the pharmaceutical industry. I can't imagine this biased study will survive peer review.

On 2021-02-02 22:45:20, user Elizabeth McNally wrote:

We are running similar ELISA assays after vaccination and not seeing this same robust IgG response. I would like to see more data prior making any recommendations about deviating from the vaccination protocols followed in the clinical trials.

On 2021-02-10 17:50:30, user Humanitarian wrote:

This is a wonderful application of science for common good, I love it. One question is the mass spectrometer affordable and portable to be useful in a surgical environment? It may be early, how much it would cost a surgery department to buy?

On 2021-02-14 17:53:25, user Bruce Aronow wrote:

Is Children's National seeing a recent rise in MIS-C cases and do you think this variant may be responsible?

On 2021-02-27 07:05:42, user jeromee5000 wrote:

published

doi

10.22034/jzd.2021.43762.1097

On 2021-03-03 01:17:29, user Dawn Christine Khan wrote:

I am a covid survivor, and said the same. 95 symptoms was incomplete. <br /> I had 150. This is the most comprehensive Long Haul research I have seen. I recommended it for CDC/NIH publication. Community NEEDS this!! May I receive a text or spreadsheet list of symptoms and categorization used? for more information http://www.linkedin.com/in/...

On 2020-10-31 00:01:20, user Joe Feist wrote:

It is funny that the CDC has issued a statement that wearing masks to filter smoke particles around the california fires isn't recommended because the smoke particles are too small. Yet the particles are at least twice the size of the covid 19 virus particles. Can you offer any explanation?

Also what do you mean exactly when you say ultra-fine particles? What size ranges?

On 2020-11-02 00:38:07, user Md Mokhlesur Rahman wrote:

The peer-reviewed version of this paper has been accepted and published online. You can find the paper at the following link.

https://www.mdpi.com/2071-1...

On 2020-11-03 20:27:05, user SteveH wrote:

Vitamin D levels do not decline quickly enough to explain the October surge. https://www.hindawi.com/jou...

On 2020-11-06 09:08:27, user Maksim wrote:

This is a nice point. “ plasma levels of total catechins are at submicromolar level, which is below the effective dose in many in vitro studies, tissue dispositions could be much higher “ (DOI: 10.5772/intechopen.74190). Besides, in the throat (during tea consumption) catechins levels could be much higher, though for a short period of time. (The latter is just a speculative idea to think about).

On 2020-11-17 00:14:37, user Laurence Renshaw wrote:

Apart from one sentence, this paper does not discuss deaths that are not directly attributable to the disease - for example, it does not appear to consider future deaths caused by the massive economic downturn as a result of people staying at home and businesses failing or downsizing.<br /> So how can it predict that people born in 2020 will expect to live 1 year less? People born in 2020 will certainly not die from Covid19, and the paper does not discuss anything else that could affect their life expectancy.<br /> Even for the over-65 group, how can a 0.1% population fatality rate (let's say that's 0.3 or 0.4% over over-65's) bring down their future life expectancy by several percent?<br /> This paper is very short on methods and data, and very long on conclusions.<br /> It also dismisses the impact of what it refers to as 'harvesting', and claims that few of the Covid19 deaths would have died soon - this contradicts all other studies that I have seen.<br /> It may well be that life expectancy, for those not killed by Covid19, will be reduced for decades to come, due to the economic and social impacts of the virus and our reactions to it (lockdowns and other restrictions), but deaths from the virus itself (a one-time loss of 0.1% of the population, with the vast majority over 70) can only have a tiny impact on life expectancy.

On 2020-11-17 21:24:47, user George wrote:

The two leading comorbidities associated with COVID-19 mortality, SCD and kidney disease, are mechanistic causes of selenium deficiency. Selenium deficiency is associated with hemolysis in SCD and has been strongly associated with mortality and other outcomes in 4 COVID-19 studies so far. High-dose sodium selenite infusion is safe and well-tolerated in dialysis patients.<br /> Vitamin D and dexamethasone both alter selenoprotein expression, and thus may be ineffective if selenium is deficient.

On 2021-09-13 14:36:27, user Chadwick wrote:

It is incredibly odd that the study authors provide us copious odds ratios but never the number of participants in each condition with each outcome. It's absence is quite strange.

On 2021-08-26 08:55:34, user William Richard Dubourg wrote:

Because of the voluntary nature of testing, testing rates as an outcome measure are on their own unreliable. There is reason to think the propensity to get tested is different between the vaccinated and infected groups. You need a model to predict testing propensity.

Your Table S1 does not match the text. Odds ratios and CIs are different.

My main concern relates to underlying health status. The infected group will exclude people who have previously died from COVID. The vaccinated group will not. Thus, there is reason to believe the infected group will have better underlying health status than the vaccinated group. This might explain why there were marginally more hospitalisations (a better and less biased outcome measure) in the vaccinated group than the infected group.

It should also be noted that there was no difference in deaths between the two groups.

Your conclusions about the beneficial effect of infection vs vaccination are therefore unwarranted.

On 2021-08-27 14:34:28, user Jonathan Bennett wrote:

Does this mean I should be allowed to travel anywhere, given I have prior infection, and people who are merely vaccinated should be subject to tight restrictions?

On 2021-08-27 15:57:52, user Jacky wrote:

The study does not account for survivor bias (i.e., those who got COVID and died; however, hardly anyone--probably nobody--who got a <br /> vaccine died); the estimates they report are confounded and not <br /> interpretable. Also, it does not account for time differences of when <br /> the person was vaccinated and when when the person got COVID. If most <br /> individuals were vaccinated say 6 months ago and they are compared <br /> individuals that got Delta recently, then of course the latter will have<br /> more antibodies than the former (antibodies will wane in both groups). <br /> Thus, this study has sever methodological challenges.

On 2021-08-29 03:38:56, user julie kemp wrote:

I've heard many different reports , and most agree , that if you recover from Covid 19 your immunity is greater than a vaccinated person. A lab test would prove it. I had the vaccines, my friend had the Covid 19 virus, and doesn't want the vaccine. Why can't she just have a lab test to check her immunity ,and that should suffice.If she's immune. why force her to take a vaccine.??

On 2021-08-29 08:15:47, user Jeroen Boschma wrote:

The group of unvaccinated persons are truly survivors of their first infection, this means that many of the weak and problematic health cases have died during their first infection and are no longer present in that group. If Covid has a mortality of 1.5%, then this subgroup is 240 cases for the 16000 large group. However: all those cases of weak and problematic health who likely die from an unprotected infection are still present in the group of SARS-CoV-2-naïve vaccinees. So a selection was done where the most vulnerable persons were taken out of the unvaccinated group (death), but that selection is not done in the vaccinated group simply because it is not possible to predict at forehand who will die from an unprotected Covid infection. Although the groups are finally selected on equal risk factors, the above observation will always introduce a huge statistical bias.

I am quite sure that the group of cases found in the 'vaccine' group are largely those persons who would have died from an unprotected Covid infection. Because those persons are by definition not present in the unvaccinated group (they died during the first infection) you can explain the number of cases in both groups precisely by the above described mechanism. The conclusion then is that the found cases have nothing to do with 'better resistance due to an earlier infection'.

EDIT: I see now below that William Richard Dubourg made the same comment about the deaths due to Covid. I had problems with my Disqus account and could not post for a couple of days. Moreover: yesterday I saw 0 comments below this article while today suddenly comments appear that are 3 days old. Strange behavior....

On 2021-08-30 19:37:56, user 0/0 wrote:

It's ironic that so many lay-people from the US are commenting on (and mostly complaining about) a study that shows something contrary to the public narrative. They are clearly not aware of the large number of studies showing the effectiveness of natural immunity that have been published since the first of the year.

To the point, survivor bias is not relevant to the study or the conclusion; it's an attempt to extrapolate, or more accurately to correct for the lack of, alignment with a desired narrative. The study examines cohorts of existing people to determine effectiveness of the sources of immunity in those *already protected* cohorts. These findings do not recommend a course of action for those who are not yet protected - that's an entirely different study, and the explanatory narrative explicitly reinforces the importance of vaccination for those populations.

On 2021-09-01 10:08:16, user Jonh Peter wrote:

About Graphene’s health effects summarised in new guide (European Commission Feb.2015)<br /> At the level of the whole body, the authors indicate that there are two main safety factors to consider regarding exposure to CNTs and graphene. The first is their ability to generate a response by the body’s immune system; the second is their ability to cause inflammation and cancer.

On 2021-08-19 07:37:44, user dixon pinfold wrote:

The bulk of these comments cover in a more or less cogent manner the various ways the survey results could be wrong—the portion, that is, concerning respondents who reported holding doctoral degrees. No one questions the other findings, which are all congenial to ordinary educated prejudices.

Few are dissatisfied with the survey's respondents having self-selected, which I view as the chief problem with it. I am inclined to say quite flatly: Not a random sample, not valid. But then, if self-selection were the main objection in these comments, all the education-category results would fall under similar doubt, not just one. Is that why this objection seems not to have occurred to many?

I read anxiety and indignation into the tone of most of the comments. I confess to a slight doubt about the depth of their sincerity. I feel quite certain that if the survey showed a mere 1% of doctorate holders were vaccine-hesitant, the commenters would instead be saying "See? The more educated you are, the less likely you are to be vaccine-hesitant" and would express at least qualified approval of the survey.

Needless to say, these are mere opinions of mine. I should be interested to hear other people's.

(N.B. I myself have received two Moderna doses and mention it to establish my bona fides, not wishing to be pilloried for a lack of it.)

On 2021-08-27 21:37:41, user Infinite Monkeys wrote:

Why has the updated version of this article removed ~4,000 respondents from figure 1, of whom ~1,000 were PhDs? This affects the results of the survey regarding vaccine hesitancy by education, after it has been reported in the press. An explanation for discarding those results should be provided.

On 2021-08-19 11:53:03, user Brian Mowrey wrote:

Er.. Is anyone able to discern how "unvaccinated" subjects were located? The authors refer to them as "patients" - patients of what? At times in the text it seems like the study is using retroactive performance of individuals who were vaccinated - say, that if someone is vaccinated in May, they are eligible for matching for the previous months. But I don't see how that would allow them to have enough subjects for July.

On 2021-08-23 17:44:20, user Olga Matveeva wrote:

Very interesting paper, however, I can't find supplementary material.

On 2021-08-25 00:35:16, user Andrew Huang wrote:

Can I check, if my body weight is 67 kg, I need to take : Honey 67gms per day Nigella Sativa - 12,060mg = 80mg/day ? Quite a large amount of honey based on this.

On 2021-08-27 06:09:19, user William Brooks wrote:

This is interesting paper showing that the first three states of emergency (SoE) and GoTo campaign didn't have much effect on the fluctuation on K. However, rather than conclude that the medical system is at no risk of collapse and the government should copy Texas and Florida and eliminate all business restrictions, the author calls for stricter border measures, lockdown, and more tests for healthy people despite it being clear for over a year that "Rapid border closures, full lockdowns, and wide-spread testing were not associated with COVID-19 mortality per million people" [1].

Since Covid's case fatality rate in Japan is now close to 0.1%, it's hard to see the point of spending even more time, money, and effort copying testing strategies that have been ineffective even in advanced countries like Germany [2] and Denmark [3].

[1] https://doi.org/10.1016/j.e...<br /> [2] https://www.ncbi.nlm.nih.go...<br /> [3] https://doi.org/10.1101/202...

On 2021-08-29 20:06:25, user Peter A McCullough wrote:

Most in this area of China are vaccinated. Authors please confirm all these Delta cases were fully vaccinated. Data likely congruent with Chau et al in Lancet.

On 2021-08-29 21:48:43, user philipn wrote:

Thank you for this great trial!

I shared some of my thoughts in this twitter thread here: https://twitter.com/__phili....

RAAS components: preprints notes no impact of treatment on measured RAAS components. In studies I've read (non-COVID), ARBs raise Ang II (see e.g. https://pubmed.ncbi.nlm.nih...; "https://pubmed.ncbi.nlm.nih.gov/10082498/);") idea is less AT1R binding => more Ang II. But the trial found no impact on even Ang II with treatment.

Preprint doesn't mention how many participants had RAAS components measured, so maybe it wasn't enough for significance. But the preprint does give significant p-value for an association with baseline. In the above non-COVID study showing ARBs raise Ang II, n=12 wasn't enough for significance with 50mg losartan (but was for the other ARBs; 50mg losartan pictured as open diamond in Figure 4).

If argument is treatment was dosed to block AT1R sufficiently but had no impact on RAAS components, why Ang II isn't higher in the treatment group is an interesting question?

The preprint looks at PK data in n=7, "consistent with..maximal AT1R blockade." Earlier in preprint, "yielding an expected 70% inhibition of AT1R." 70% inhibition doesn't appear in citation (https://pubmed.ncbi.nlm.nih... mentions 77% at trough with 100mg bid).

In this paper (https://pubmed.ncbi.nlm.nih... "https://pubmed.ncbi.nlm.nih.gov/11392465/)") 50mg od losartan looks like ~35% in the peak window. In https://pubmed.ncbi.nlm.nih..., 50mg again looks like ~35% at peak (open diamonds in Figure 3).

I was unable to find a study that tests exactly 50mg bid losartan and looks these proxies for % AT1R blockade.

I think the preprint authors may be getting the 70% figure from an earlier citation, https://pubmed.ncbi.nlm.nih..., Fig 3 and ~205 ng/mL EXP3174 (median C_6h) => ~70% according to figure. It seems this argument is based on PK in this n=6 study. The PK study uses SBP response to Ang II but looks pretty different from https://pubmed.ncbi.nlm.nih....

https://twitter.com/__phili... - side by side figures are illustrative

Compare the ~50mg losartan (open diamonds in right figure, from https://pubmed.ncbi.nlm.nih... "https://pubmed.ncbi.nlm.nih.gov/10082498/)"). Looks like ~35% at peak vs ~70%. The graphs look pretty different.

The authors of the ~35% study address this difference, stating:

"The antagonism produced by 50 mg of losartan (ie, 35% to 45% blockade of AT1 receptors) was also weaker than expected on the basis of previous results of studies using 40 mg of losartan. To explain this difference, one must consider that in our study, the placebo had no effect on blood pressure response to exogenous Ang II, whereas it blunted the effect of Ang II by almost 20% in Christen et al’s6 study. Thus, if one corrects for the placebo effect, the percentage of inhibition obtained in the 2 studies is comparable."

So once the PK study’s placebo response is adjusted, results are similar. So isn’t the value ~35%, not 70%? Would be consistent with other studies, showing proxies for % blockade being around ~35% for 50mg losartan rather than 70%. I also wonder if “Labeled Ang II %” figures may be a better proxy for % AT1R blockade than SBP (less prone to placebo etc)?

--Philip Neustrom

On 2021-08-30 22:37:50, user Dave Kavanagh wrote:

Will C.1.2 be the next pandemic wave of Covid to sweep the globe and will this potential vaccine resistant variant pose a greater problem to the WHO when considering the sharing of information to the general masses?

On 2021-08-31 03:11:22, user Judy Friend wrote:

when will this report be fully peer reviewed and when will we have more information. also how often are variants actually coded in these countries for genome sequencing

On 2021-08-30 22:44:45, user Rachel Ezzour wrote:

Is the follow up study available yet?

On 2021-08-31 19:11:00, user Andy Loening wrote:

I think this is a thought provoking model. However, I think there are some major flaws with the model (as I understand from the pre-print manuscript) that severely limit the interpretation of the results.

The biggest flaw I see is:<br /> 1) "Case-investigation of potential contacts is not conducted." So the "no testing" cases have NO contact tracing, which makes this not at all a far comparison. If they included contact tracing/testing (status quo), I would believe most (or all) the difference between their "testing" and "no testing" lines would go away.

Other flaws I see<br /> 2) As a previous comment pointed out, they assume an initial rate of infections coming into the school at ~10-20-fold greater rate then actually infection rates. Similarly the 1 new case coming into the school per week may be too high.<br /> 3) They don't seem to build in any allowance for the ~36-48 hrs it would take a RT-PCR test to get a positive result back. The model doesn't seem to take any of this delay in testing results into account. This would obviously blunt the positive effects that surveillance testing would have.<br /> 4) They seem to treat their student population as a single classroom of 500 kids, and do not take into account that kids (even in the pre-covid days) are mostly segregated into their classrooms for the majority of the day.<br /> 5) There are no error bars provided for the model. Presumably the model has randomization within it, so there should be some variation in the outputs, it would be interested to see what the spread of the outputs are to gauge the significance of the findings.

I would be really interested in the results of this manuscript if it was redone with more appropriate assumptions. My guess is that there would be a much smaller difference between the surveillance and non-surveillance groups.

On 2021-09-01 17:09:10, user Elle Tigre wrote:

Why did you choose the 2016-2017 period to monitor? Why not 2018-2019, respectively?

On 2021-09-01 21:33:26, user Paul wrote:

In reviewing your study's hospitalization rates by age group (your Figures 3 A, B and C), it shows that peak hospitalization rates per 100k in the unvaccinated population to be at about 12-13 for ages 18-49; about 35-40 for ages 50-64; and about 80-90 for ages 65+. These peaks happed mid to late April.

The hospitalization rates by age group during the worst peak of COVID in late December 2020, before the vaccines were available, were as follows (per the CDC COVID-NET data, week ending 1/9/21): 9.6 for ages 18-49; 28.4 for ages 50-64; and 71.9 for ages 65+.

Under the theory that the risk of hospitalization from COVID in the unvaccinated population did not change dramatically from December 2020 to May 2021, seems hard to explain how unvaccinated hospitalization rates were 20-30% higher in April/May peak vs. December peak when overall deaths were 6 times higher in December. I understand you cannot compare the deaths between the two periods because of vaccines, but it seems there is a disconnect between your study’s unvaccinated hospitalization rate and the hospitalization rate before the vaccines were available.

Would be interested to know if your study’s unvaccinated hospitalization rate was compared to hospitalization rates during periods when the vaccine was not available to test for reasonableness. Also would be interested to know if it is possible that your study under reported the number of hospitalizations in the vaccinated population (for example, how confident were you in matching the IIS vaccination patients to the COVID-NET hospitalized patients, how likely are providers to report a COVID vaccine to their state’s IIS database, are different provides more or less likely to report vaccines to the IIS, were any smaller follow-up surveys performed on hospitalized patients to see if their reported vaccine status is consistent with what you assumed in your study, etc.).

On 2025-10-12 13:03:25, user Ceejay wrote:

There are many other plausible mechanisms than antigenic imprinting for the "counter-intuitive" result, some vaccine-related, but others such as nutritional state and prior flu or indeed C19 exposure. May be too late for this paper, but my belief is that all such investigations should include measured Vitamin D status. The effect of Vit D on respiratory tract infection resilience is well known, and particularly over the winter months covered in this study, vitamin D titre will naturally fall due to reduced sun exposure. In similar vein, those who decline flu vaccination may adopt a significantly different health regime to those accepting vaccination, obviously not terribly easy to capture. But one I think you could capture is the C19 and C19 shots status, since I would imagine many of those tested might have taken part in your earlier studies. Those declining a flu shot could easily coincide with those declining a C19 shot. It all certainly shows vaccination science is complex.

On 2022-10-20 16:49:56, user Stefan Heber wrote:

There is already an article published in a journal corresponding to this preprint:

On 2022-10-24 11:51:28, user Indi Trehan wrote:

This article has now been published after peer review: The Journal of Pediatrics 2022; 247: 147-149. doi: 10.1016/j.jpeds.2022.05.006.

On 2022-12-04 06:38:01, user Jianyu Lai wrote:

This manuscript is now published in Microbiology Spectrum. DOI: https://doi.org/10.1128/spe...

On 2023-04-12 16:21:36, user Lizeth Perales wrote:

Hello, I would love to get access to the data. Please let me know if that is possible! thank you in advance

On 2020-04-06 19:55:46, user Sinai Immunol Review Project wrote:

Clinical Characteristics of 2019 Novel Infected Coronavirus Pneumonia:A Systemic Review and Meta-analysis

The authors performed a meta analysis of literature on clinical, laboratory and radiologic characteristics of patients presenting with pneumonia related to SARSCoV2 infection, published up to Feb 6 2020. They found that symptoms that were mostly consistent among studies were sore throat, headache, diarrhea and rhinorrhea. Fever, cough, malaise and muscle pain were highly variable across studies. Leukopenia (mostly lymphocytopenia) and increased white blood cells were highly variable across studies. They identified three most common patterns seen on CT scan, but there was high variability across studies. Consistently across the studies examined, the authors found that about 75% of patients need supplemental oxygen therapy, about 23% mechanical ventilation and about 5% extracorporeal membrane oxygenation (ECMO). The authors calculated a staggering pooled mortality incidence of 78% for these patients.

Critical analysis:<br /> The authors mention that the total number of studies included in this meta analysis is nine, however they also mentioned that only three studies reported individual patient data. It is overall unclear how many patients in total were included in their analysis. This is mostly relevant as they reported an incredibly high mortality (78%) and mention an absolute number of deaths of 26 cases overall. It is not clear from their report how the mortality rate was calculated. <br /> The data is based on reports from China and mostly from the Wuhan area, which somewhat limits the overall generalizability and applicability of these results.

Importance and implications of these findings in the context of the current epidemics:<br /> This meta analysis offers some important data for clinicians to refer to when dealing with patients with COVID-19 and specifically with pneumonia. It is very helpful to set expectations about the course of the disease.

On 2020-06-01 16:23:11, user OxImmuno Literature Initiative wrote:

https://www.immunology.ox.a...

On 2023-09-22 06:06:43, user Anikó Lovik wrote:

This preprint has not been published in The Lancet Regional Health - Europe with DOI: https://doi.org/10.1016/j.l...<br /> Please read and cite the updated new version. Thank you.

On 2023-12-12 14:56:15, user Tanmoy Sarkar Pias wrote:

This paper has been accepted to an IEEE conference. A link (& DOI) to the IEEE Xplore will be added when this article is published. Please see the following copy right details of IEEE.

2023 26th International Conference on Computer and Information Technology (ICCIT), 13-15 December, Cox’s Bazar, Bangladesh

979-8-3503-5901-5/23/$31.00 ©2023 IEEE

On 2023-12-19 12:39:03, user Christos Proukakis wrote:

Response to: “Is Gauchian genotyping of GBA1 variants reliable?”

Marco Toffoli1,2, Anthony HV Schapira1,2, Fritz J Sedlazeck2,3,4, Christos Proukakis1,2 *

1. Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, UK
2. Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA
3. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
4. Department of Molecular and Human Genetics, Baylor College of Medicine, TX, USA

* To whom correspondence should be addressed: c.proukakis@ucl.ac.uk

We recently described two methods for GBA1 analysis, which is hampered by the adjacent highly homologous pseudogene: Gauchian, a novel algorithm for analysis of short-read WGS, and targeted long-read sequencing 1. Tayebi et al have applied the former to WGS from 95 individuals, and compared it to Sanger sequencing 2. They report concordant genotypes in 85, while 11 had discrepant calls (we note that this leads to a total of 96). In addition, they report 28 false Gauchian calls in 1000 Genomes Project (1kGP) samples. Gauchian was developed because the homology of the GBA region requires a short read variant caller that does not rely solely on read alignments, and can identify specific variants known to be pathogenic. To understand the cause of these discrepancies, we reviewed their data, and conclude that they are mis-interpreting Gauchian results in 8 of the 11 discrepant samples, and incorrectly using Gauchian to analyze low-coverage 1kGP samples.

Among the 11 (11.5%) samples with inconsistent calls with Sanger (Table 1), four (Pat_08, Pat_26, Pat_28 and Pat_58) were not called as the variants are not on Gauchian’s target list, which includes all ClinVar variants in December 2021. These variants, and any others, can be easily added (see Supplementary Information). Three other samples (Pat_75, Pat_76 and Pat_79) had low data quality resulting in large variation in sequencing depth across the genome, as shown by the median absolute deviation (MAD) of genome coverage: 0.269, 0.128 and 0.127 (three highest values among all samples). Gauchian recommends trusting calls in samples with MAD values <0.11, and produces a warning message if this is exceeded. In all three samples, the GBA1+GBAP1 copy number was a no-call (marked as “None” in the output file), indicating that Gauchian could not determine the copy number due to high coverage variation. Variants were not called because no further analysis was done beyond copy number calling. These should not be viewed as false negatives, as the warning message and the report of no-calls should prompt the user to obtain higher quality data or consider alternative sequencing. Among the remaining 4 samples with inconsistent results: Pat_03 had a Gauchian call of heterozygosity for p.Asn409Ser, while Sanger reports this as homozygous. Review of the IGV trace (Tayebi et al. Supp Figure 1) shows that at least 10 reads (around a fifth of the total) have the reference base, and therefore it is hard to conclude this is homozygous. Review of the Sanger trace (not provided) could determine whether there is a low peak representing the reference allele. We cannot provide a conclusion, and additional analysis is recommended. Mosaicism could be a plausible explanation, and this has been reported in GBA1 3,4, albeit not at this position. Pat_47 had a false negative p.Leu483Pro call. Pat_16 was indeed wrongly genotyped as homozygous for p.Asn409Ser, related to the adjacent c.1263del+RecTL deletion. Pat_92 had all expected variants called, but the heterozygous p.Asp448His was mis-genotyped as homozygous. In summary, there is one false negative and two wrongly genotyped variants (heterozygous variants called homozygous). Gauchian’s precision is therefore 98.9% (175 out of 177 calls are correct). Its allele-level recall/sensitivity is 99.4% after excluding alleles not on Gauchian’s target list, and samples which could not be analyzed due to high coverage variation. Alternatively, it can be calculated as 97.2% if only samples with high coverage variation are excluded, 96.2% if only alleles not on the target list are excluded, and 94.1% if all these samples are considered .

Tayebi et al. concluded that Gauchian is not able to call recombinant variants without providing orthogonal evidence. In Pat_95, Pat_71 and Pat_16, they examined alignments in IGV and reported absence of supporting reads for Gauchian calls, but all recombinant alleles called by Gauchian were consistent with Sanger. This highlights that read mapping in this region is unreliable (variant supporting reads may align to the pseudogene), making interpretation of alignments in IGV very challenging. Gauchian is designed to untangle ambiguous alignments, locally phase haplotypes and make correct calls. Particularly, in Pat_95, they claimed that Gauchian called the expected RecNciI variant but got the mechanism of the recombinant allele wrong (gene conversion vs. gene fusion). This claim appears to be based on incorrect interpretation of IGV alignments, i.e. seeing 3’ UTR mismatches associated with GBAP1 does not necessarily indicate gene fusion, as they can be misalignments, or even part of the gene conversion. The RecNciI in Pat_95 is a gene conversion, as indicated by the normal copy number between GBAP1 and GBA1. Tayebi et al. claimed that this is a gene fusion without orthogonal evidence. In addition, they claimed that Gauchian misreported copy numbers in Pat_92, Pat_42 and Pat_72, again without orthogonal evidence. We validated Gauchian copy number gains by digital PCR in four cases 1. While particular recombinants could be prone to erroneous copy number calling, we do not know what “other techniques'' identified a different copy number in Pat_92. Orthogonal validation using digital PCR would resolve this. Finally, it is true that Gauchian does not have all possible recombinants on its target list, as it is designed to focus on recombinant variants in exons 9-11, because others are rare and detectable with standard callers.

Tayebi et al. reported 4 samples where Gauchian missed variants in GRCh38 compared to GRCh37. Among these, two (Pat_35, Pat_75) were due to incorrect alignment settings that resulted in abnormally low mapping quality throughout the region. It is likely that ALT-aware alignment was on for all samples except these two. The remaining two (Pat_16, Pat_78) reflected an area of improvement for Gauchian to better call p.Asn409Ser, which is not a GBAP1-like variant, and can thus be called well by standard callers.

We reported Gauchian calls of 1000 Genomes Project (1kGP) samples, validating some by targeted long reads 1. Gauchian called zero samples with biallelic variant in exons 9-11. However, Tayebi et al. reported a completely different set of Gauchian calls in the same samples (in their Table 4). This was caused by incorrect use of Gauchian on old low coverage WGS (median coverage <10X, https://ftp.1000genomes.ebi... "https://ftp.1000genomes.ebi.ac.uk/vol1/ftp/phase3/data/)"), rather than 30X (https://ftp-trace.ncbi.nlm.... "https://ftp-trace.ncbi.nlm.nih.gov/1000genomes/ftp/1000G_2504_high_coverage/data/)").

We are grateful to Tayebi et al for assessing Gauchian analysis of this very challenging gene 2, but note that most discrepancies were due to incorrect use or misinterpretation of results. “No call” samples due to inadequate data quality cannot be considered false negative, as no calls are provided, and warnings of noisy coverage are given where applicable. Samples with inadequate coverage should obviously be avoided, as Gauchian is expected to perform at coverage >30X. Gauchian does not call variants not on its target list, which can be expanded. We provide updated recall (99.4%) and precision (98.9%) values. We have not seen any evidence of the alleged inability of Gauchian to call recombinant variants, and would welcome orthogonal copy number assessment of discrepancies. We show that Gauchian can be used for GBA1 assessment when coverage and data quality are adequate. We do note a limitation in genotyping p.Asn409Ser, a non-recombinant variant that can be called by standard variant callers, which we recommend running together with Gauchian for a complete call set. Finally, in clinical cases where absolute certainty is required, Sanger sequencing could be considered, with targeted long read sequencing another option 1,5–7.

Table 1. Details on the 11 samples where Gauchian and Sanger are inconsistent.

Gauchian calls Sanger Assessment,Tayebi et al. Our assessmentSample Copy Number of GBA1 and GBAP1 GBAP1-like variant in exons 9-11 Other unphased variants Genotype Prediction

Pat_08 4 None p.Asn409Ser p.Asn409Ser/p.Gln389Ter False Negative Missed variant is not on Gauchian's target list

Pat_28 4 None p.Arg535His p.Arg535His/Cys381Tyr False Negative Missed variant is not on Gauchian's target list

Pat_58 4 None p.Asn409Ser, p.Arg296Ter p.Asn409Ser, p.Arg296Ter, c.203delC False Negative Missed variant is not on Gauchian's target list

Pat_26 4 None p.Asn409Ser p.Asn409Ser/p.Arg502Cys False Negative Missed variant is not on Gauchian's target list.

Tayebi et al.’s Supplementary Figure 1 shows no variant at p.Arg502Cys (c.1504C>T), but a different variant at the neighboring position, p.Arg502His (c.1505G>A), which is not on Gauchian's target list.

Pat_75 None (No Call) NA NA p.Arg502Cys/p.Arg159Trp Missed Copy number is a no-calldue to high variation in depth so no further variant calling was performed. Coverage MAD 0.269

Pat_76 None (No Call) NA NA p.Asn409Ser/p.Asn409Ser Missed Copy number is a no-call due to high variation in depth so no further variant calling was performed. Coverage MAD 0.128

Pat_79 None (No Call) NA NA p.Leu483Pro/p.Arg502Cys Missed Copy number is a no-call due to high variation in depth so no further variant calling was performed. Coverage MAD 0.127

Pat_03 4 None p.Asn409Ser p.Asn409Ser/p.Asn409Ser False Negative Gauchian call is supported by reads, see Tayebi et al.’s Supplementary Figure 1.

Pat_47 4 None p.Asn409Ser p.Asn409Ser/p.Leu483Pro False Negative True false negative

Pat_16 3 c.1263del+RecTL/ p.Asn409Ser, p.Asn409Ser p.Asn409Ser, c.1263del+RecTL False Positive Heterozygous p.Asn409Ser misgenotyped as homozygous as Gauchian did not know the exact breakpoint of the c.1263del+RecTL deletion, which is very close to p.Asn409Ser.

Pat_92 7 p.Asp448His/p.Leu483Pro,p.Asp448His p.Asp448His/ p.Leu483Pro+Rec7 False Negative There is no false negative. Rec7 is reflected in the copy number call (copy number gain). This GBAP1 duplication does not have any functional impact on GBA, so Gauchian does not report it as a GBA variant. Heterozygous p.Asp448His misgenotyped as homozygous.

Acknowledgements

We are grateful to Xiao Chen and Michael Eberle for helpful comments. They are former employees of Illumina and current employees of Pacific Biosciences. This research was funded in in part by Aligning Science Across Parkinson's [Grant numbers 000430 and 000420] through the Michael J. Fox Foundation for Parkinson's Research (MJFF).

Competing interests

FJS receives research support from PacBio and Oxford Nanopore. AHVS has received consulting fees from AvroBio, Auxilius, Coave, Destin, Enterin, Escape Bio, Genilac, and Sanofi and speaking fees from Prada Foundation.

Supplementary Information

Add new variants to Gauchian’s config file

The four new variants can be added to Gauchian’s config file as follows.

For hg38, add the following lines to gauchian/data/GBA_target_variant_38.txt

chr1 155236304 A GBAP G c.1165C>T(p.Gln389Ter)<br /> chr1 155236327 T GBAP C c.1142G>A(p.Cys381Tyr)<br /> chr1 155239989 CGGGGGT GBAP CGGGGGGT c.203delC(p.Thr69fs)

Add the following line to gauchian/data/GBA_target_variant_homology_region_38.txt<br /> chr1 155235195 T 155214568 C c.1505G>A(p.Arg502His)

For GRCh37, add the following lines to gauchian/data/GBA_target_variant_37.txt<br /> 1 155206095 A GBAP G c.1165C>T(p.Gln389Ter)<br /> 1 155206118 T GBAP C c.1142G>A(p.Cys381Tyr)<br /> 1 155209780 CGGGGGT GBAP CGGGGGGT c.203delC(p.Thr69fs)

Add the following line to gauchian/data/GBA_target_variant_homology_region_37.txt<br /> 1 155204986 T 155184359 C c.1505G>A(p.Arg502His)

Bibliography

1. Toffoli, M. et al. Comprehensive short and long read sequencing analysis for the Gaucher and Parkinson’s disease-associated GBA gene. Commun. Biol. 5, 670 (2022).

2. Tayebi, N., Lichtenberg, J., Hertz, E. & Sidransky, E. Is Gauchian genotyping of GBA1 variants reliable? medRxiv (2023) doi:10.1101/2023.10.26.23297627.

3. Filocamo, M. et al. Somatic mosaicism in a patient with Gaucher disease type 2: implication for genetic counseling and therapeutic decision-making. Blood Cells Mol. Dis. 26, 611–612 (2000).

4. Hagege, E. et al. Type 2 Gaucher disease in an infant despite a normal maternal glucocerebrosidase gene. Am. J. Med. Genet. A 173, 3211–3215 (2017).

5. Pachchek, S. et al. Accurate long-read sequencing identified GBA1 as major risk factor in the Luxembourgish Parkinson’s study. npj Parkinsons Disease 9, 156 (2023).

6. Graham, O. E. E. et al. Nanopore sequencing of the glucocerebrosidase (GBA) gene in a New Zealand Parkinson’s disease cohort. Parkinsonism Relat. Disord. 70, 36–41 (2020).

7. Leija-Salazar, M. et al. Evaluation of the detection of GBA missense mutations and other variants using the Oxford Nanopore MinION. Mol. Genet. Genomic Med. 7, e564 (2019)

On 2024-03-05 22:33:49, user Po-Kai Yang wrote:

Hi, I am the author of this preprint. The paper was published on https://jneuroengrehab.biom...

Could you make a link to the published version? Thank you!

On 2024-03-15 12:33:53, user Robin Walters wrote:

This is published, Nature Genetics 55,<br /> 410–422

On 2024-04-11 17:53:00, user eysen wrote:

JMIR Publications and PREreview are pleased to announce our next Preprint Live Review on Friday, April 19 at 9am PT / 12pm ET / 4pm UTC which discusses this preprint

Register Now at https://docs.google.com/for...

The Live Review is hosted by two facilitators from the PREreview team with experience in moderating virtual collaborative review discussions. They will guide participants through a constructive discussion of the following preprint: Assessing the Incidence of Postoperative Diabetes in Gastric Cancer Patients: A Comparative Study of Roux-en-Y Gastrectomy and Other Surgical Reconstruction Techniques - by Tatsuki Onishi

Live Review Details:

WHEN: Friday, April 19 at 9am PT / 12pm ET / 4pm UTC

WHO: The Live Review is hosted by two facilitators from the PREreview team with experience in moderating virtual collaborative review discussions.

WHAT: The participants will be guided through a constructive discussion of the following preprint: Assessing the Incidence of Postoperative Diabetes in Gastric Cancer Patients: A Comparative Study of Roux-en-Y Gastrectomy and Other Surgical Reconstruction Techniques - by Tatsuki Onishi medRxiv: https://doi.org/10.1101/202...

A review will be then written and published on PREreview.org within the following 2 weeks. Participants will have the chance to help compose the final review and be recognized as reviewing authors.

HOW: To participate, please complete the following registration form. You will receive an email from PREReview with a link to a Zoom room and a passcode.

More information on JMIRx-Med, the first pubmed-indexed preprint overlay journal: https://xmed.jmir.org/annou...<br /> https://xmed.jmir.org/announcements/457

On 2024-05-03 15:04:37, user Tamy wrote:

I am happy to see someone taking an interest in this horrific condition. My daughter has suffered for over 9 years and the mental toll, as well as, the physical toll it has taken on her overall well being has been life changing! Thank you for giving these sufferers some validation!

On 2020-08-24 17:31:53, user Mercer Creed wrote:

Where is the information regarding controls?

On 2025-03-09 21:02:55, user Dr. DP wrote:

Dear authors,<br /> Will this article be peer-reviewed/is there a path to peer-review being explored?

On 2025-05-01 12:48:20, user Ravi Sharma wrote:

Ladies and Gentlemen,

in loving memory of my late, beloved mother, a type 2 diabetic since my birth, I dedicate this research to harnessing the beneficial power of gen-AI to banish GDM from the face of the earth.

I salute my industrious and loyal research group for their dedication in this journey.

Until our work is published and linked to this DoI, kindly cite this preprint as ...

Edmund Evangelistaa, Fathima Rubab, Syed M. Salman Bukhari, Amril Nazir and Ravishankar Sharma. (2025). "Developing a GraphRAG-enabled local-LLM for Gestational Diabetes Mellitus." medRxiv preprint doi: https://medrxiv.org/cgi/content/short/2025.04.28.25326568v1

With kind regards and best wishes, Ravi

On 2022-01-27 21:10:24, user Siguna Mueller, PhD, PhD wrote:

I find it difficult to see how many individuals were in each group. I may, or may not, be able to guess some proportions. For instance, Fig. 4 suggests that there were not many in the booster group, if any at all. (This is because boosters obviously were only rolled out not too long ago). Is the small peak at approx. 35 days since injection attributable to the booster group? If so, this makes me wonder if they were sufficiently many to be statistically relevant. Again, I find it hard to infer exact numbers of participants in the different groups. This info would really be helpful. Thanks.

On 2022-02-14 04:09:55, user RBNZ wrote:

"The estimates are furthermore adjusted for vaccine status of the potential secondary case interacted with the household variant, and the vaccine status of the primary case. "

There is no information included as to how vaccination status adjusts the odds ratio.

On 2022-02-03 14:15:23, user Matt Thrun-Nowicki wrote:

Given previous studies’ evidence of a poor association between RAT results and viral culturability based on # of days after symptom onset, you guys might wanna wait to publish this paper until after those viral cultures result.

In addition, your explanation of why booster’d HCW had higher positive RAT’s is a little baffling. If your explanation was correct, wouldn’t you expect to see the percentage of positive RAT’s among booster’d HCWers drop over time, and those of unbooster’d go up? What about confounders (like demographics of the booster’d vs unbooster’d)?

On 2025-09-07 20:13:12, user S S Young wrote:

Milojevic et al. 2014 had access to all emergency room visits for all of England and Wales for the years 2003 to 2008, over 400,000 myocardial infarction (MI) events, and over 2 million CVD emergency hospital admissions. They found no effect of CO, NO2, Ozone, PM10, PM2.5, or SO2 on heart attacks, hospital admissions, or mortality, their Figures 1 and 2.

Milojevic, A., Wilkinson, P., Armstrong, B., Bhaskaran, K., Smeeth, L., Hajat, S. 2014. Short-term effects of air pollution on a range of cardiovascular events in England and Wales: Case-crossover analysis of the MINAP database, hospital admissions and mortality. Heart (British Cardiac Society) 100, 14: 1093-98. https://doi.org/10.1136/heartjnl-2013-304963 .

On 2022-02-03 18:10:45, user Rodrigo Zepeda wrote:

Methods equation 6. Y(t) is never defined. Is it the observed case count?

On 2022-02-07 10:26:48, user Daksya Siddhi wrote:

The article has now been published at<br /> https://journals.plos.org/p...

Supplemental data which includes tables on patient characteristics and D3 measurement is at<br /> https://app.dimensions.ai/d...

On 2020-04-19 16:51:41, user Sinai Immunol Review Project wrote:

Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications

Fan Wu et al.; medRxiv 2020.03.30.20047365; doi:https://doi.org/10.1101/202...

Keywords

• Neutralizing antibodies<br /> • SARS-CoV-2<br /> • pseudotype neutralization assay

Main findings

In this study, plasma obtained from 175 convalescent patients with laboratory-confirmed mild COVID-19 was screened for SARS-CoV-2-specific neutralizing antibodies (nABs) by pseudotype-lentiviral-vector-based neutralization assay as well as for binding antibodies (Abs) against SARS-CoV-2 RBD, S1 and S2 proteins by ELISA. Kinetics of neutralizing and binding Ab titers were assessed during the acute and convalescent phase in the context of patient age as well as in relation to clinical markers of inflammation (CRP and lymphocyte count at the time of hospitalization). Across all age groups, SARS-CoV-2-specific nAbs titers were low within the first 10 days of symptom onset, peaked between days 10-15, and persisted for at least two weeks post discharge. In contrast to spike protein binding Abs, nAbs were not cross-reactive to SARS-CoV-1. Moreover, nAb titers moderately correlated with the amount of spike protein binding antibodies. Both neutralizing and binding Ab titers varied across patient subsets of all ages, but were significantly higher in middle-aged (40-59 yrs) and elderly (60-85) vs. younger patients (15-39 yrs). However, plasma nAb titers were found to be below detection level in 5.7% (10/175) of patients, i.e. a small number of patients recovered without developing a robust nAb response. Conversely, 1.14% (2/175) of patients had substantially higher titers than the rest. Notably, in addition to patient age, nAb titers correlated moderately with serum CRP levels but were inversely related to lymphocyte count on admission. In summary, the authors show that patients with clinically mild COVID-19 disease mount a strong humoral response against the SARS-CoV-2 spike protein. Compared to younger patients, middle-aged and elderly patients had both higher neutralizing and binding Ab titers, accompanied by increased CRP levels and lower lymphocyte counts. These patients are usually considered at higher risk of severe disease. Therefore, robust neutralizing and binding Ab responses may be particularly important for recovery in this patient subset. Conversely, patients who failed to produce high nAb/binding Ab titers against spike protein did not progress to severe disease, indicating that binding Abs against other viral epitopes as well as cellular immune responses are equally important.

Limitations

This study provides valuable information on the kinetics of spike protein-specific nAb as well as binding Ab titers in a cohort of convalescent mild COVID-19 patients of all ages. However, similar studies enrolling larger patient numbers, including those diagnosed with moderate and severe disease as well as survivors and non-survivors, especially in the elderly group (to rule out potential bias for more favorable outcome), are warranted for reliable assumptions on the potentially protective role of Abs and nAbs in COVID-19. Moreover, longitudinal observation beyond the acute and convalescent phase in addition to stringent clinical and immunological characterization is urgently needed. <br /> In their study, Wu et al. did not measure binding Abs against non-S viral proteins, which are also induced in COVID-19 and therefore could have added valuable diagnostic information with regard to patients who seemingly failed to mount both binding and neutralizing Ab responses against the SARS-CoV-2 spike protein. Likewise, while this study excluded cross-reactivity of nAbs against SARS-CoV-1, no other coronaviruses were tested. Of additional note, neutralizing activity of plasma Abs was only assessed by pseudotype neutralization assay, not against live SARS-CoV-2. Generally, while these are widely used and reproducible assays, in vitro neutralization of pseudotyped viruses does not necessarily translate to effective protection against the respective live virus in vivo (cf. review by Burton, D. Antibodies, viruses and vaccines. Nat Rev Immunol 2, 706–713 (2002)). Further studies are therefore needed to assess the specificity and neutralizing characteristics of these Abs to test whether they could be candidates for prophylactic and therapeutic interventions. In this context, setting arbitrary cut-off values (ID50<500 vs. a detection limit of ID50 < 40) and thus classifying up to 30% of patients in this study as “weak” responders does not take into account our currently limited knowledge regarding protective capacity of these nAbs and should therefore have been avoided by the authors.

Significance

This preprint is arguably the first report on neutralizing and binding Ab titers in a larger cohort of mild COVID-19 patients. Assessing Ab titers in these patients is not only important in order to confirm whether mild COVID-19 elicits robust nAb responses, but also adds further information regarding the use of plasma from mild disease patients for convalescent plasma therapy as well as vaccine design in general. Future studies will need to address now whether the nAb responses generated in mild disease will be protective or (functionally) different from nAbs generated in moderate and severe disease. The findings in this study are therefore of great relevance and should be further explored in ongoing research on potential coronavirus therapies and prevention strategies.

This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn school of medicine, Mount Sinai.

On 2025-11-30 23:44:45, user Cyril Burke wrote:

[Note: This is the second of several rounds of review of an earlier version of our combined manuscript, aiming to reduce ‘racial’ disparity in kidney disease. The comments were kindly offered by nephrologists, through a medical journal, and we remain grateful to them for the time and care they gave to improve our manuscript.

We removed identifying features and included our responses, at the end of this comment. The changing title and line numbers refer to earlier versions.]

August 3, 2022<br /> Dear Dr. Burke III,

REDACTED.

Reviewer #1: Cyril O Burke III et al submit a revised version of their intriguing , unusual paper.

Overall, the paper remains extremely lengthy (the total , including clean and track versions and reply to reviewers is close to 200 pages !!) , whereas it contains relatively little original data.

The authors speculate and comment a lot (and most of these speculations/comments will hardly be understandable by the expected audience, primary care physicians), and this will in addition distract the reader from the main key message (which is right in the opinion of this reviewer (see first round of review) and warrants more attention and studies.

The race part is irrelevant for the key point (race does not change over time, and thus is not relevant when looking at longitudinal serum creatinine or eGFR) and should be deleted in the opinion of this reviewer. In this respect, I completely agree with the comment of reviewer 2 in the first round.

I can not resist quoting here the reply of the authors to reviewer 2. “This manuscript could be divided into three or four short papers, increasing the likelihood that any one of them would be read. However, different groups tend to read papers about screening for kidney impairment, racial disparities, cofactors in modeling physiologic parameters, or policy proposals to encourage best practices. Despite the appeal of perhaps three or four publications, we decided to tell a complete story in a single paper, but we are open to suggestions.”

My reply to their reply: nobody would read the current paper , even partially. Shorten, shorten, shorten please and focus on the key message.

Reviewer #2: Thank-you, once again, for the opportunity to review this lengthy “thesis-style” manuscript which discusses some important often over-looked topics. The under-use of serial creatinine measurements and over-reliance on often erroneous eGFR measurements is an important point which is easily missed by healthcare workers with potentially serious consequences. Likewise, the misuse of racial constructs in medicine (and elsewhere) is an important point.

I am satisfied with this re-submission and the changes which have been made to the original manuscript.

Minor points:<br /> 431: “creatinine inhibits several membrane transporters”. = Cimetidine

502: “Because mGFRs have population variation as wide as sCr, with much greater physiologic variability compared to the relatively stable sCr and serum cystatin C”<br /> As mentioned previously the cited article compares the variability of sCr and cystatin C with CrCl, I agree with the authors that CrCl is a form of mGFR, however, probably one of the poorer forms and not what a reader will think of when mGFR is mentioned. In our current age of medicine when we talk about mGFR CrCl is seldom included, studies reviewing methods of mGFR will seldom include CrCl, however CrCl may be compared to one of the mGFR methods. Likewise, if a patient is sent for a mGFR, a CrCl will not be performed. In our current age of medicine mGFR refers to methods such as the clearance of iohexol, iothalamate, Cr-EDTA, inulin, DTPA, etc; the authors themselves mention this (line 539 – 540). I fully agree with the authors that mGFR is FAR from perfect and has many inaccuracies and imprecisions (which are often overlooked)- these are well published, some of which are cited in this manuscript. If the authors wish to use the current study as a source they should state the findings in a way that cannot be misinterpreted. For example: “CrCl has much greater physiologic variability than sCr and cystatin C …” – in this case the reader can determine for themselves whether they would use CrCl as a surrogate for mGFR. Alternatively, adjust the statement and use another source which has shown the variability that exists with what we currently refer to as mGFR method.

670 – 719: As the authors specifically discuss age it would be prudent to briefly mention the short-comings, or considerations for interpretation, of serial creatinine measurements at a very young age which generally rise until late adolescence when steady muscle mass is achieved. Also note changes in creatinine and GFR from birth till 2 – 3 years.

783 – 784: Consider re-wording the grammar makes this sentence difficult to read

959 – 968: Note, editing has not been accepted (tracked changes still shown)

1116 - 1121: “Using the opioid crisis as an example…. in, for example, the opioid crisis” – same sentence

RESPONSE TO REVIEWERS:<br /> September 17, 2022<br /> Longitudinal creatinine, not ‘race’, signals pre-chronic kidney disease and decline in glomerular filtration rate

We again greatly appreciate the reviewers for offering detailed comments and guidance, which we have endeavored to incorporate as best we could.

Comments to the Author<br /> Reviewer #1: Cyril O Burke III et al submit a revised version of their intriguing, unusual paper.<br /> 1. Overall, the paper remains extremely lengthy (the total, including clean and track versions and reply to reviewers is close to 200 pages !!), whereas it contains relatively little original data.<br /> The authors speculate and comment a lot (and most of these speculations/comments will hardly be understandable by the expected audience, primary care physicians), and this will in addition distract the reader from the main key message (which is right in the opinion of this reviewer (see first round of review) and warrants more attention and studies.<br /> The race part is irrelevant for the key point (race does not change over time, and thus is not relevant when looking at longitudinal serum creatinine or eGFR) and should be deleted in the opinion of this reviewer. In this respect, I completely agree with the comment of reviewer 2 in the first round.<br /> I can not resist quoting here the reply of the authors to reviewer 2.<br /> "This manuscript could be divided into three or four short papers, increasing the likelihood that any one of them would be read. However, different groups tend to read papers about screening for kidney impairment, racial disparities, cofactors in modeling physiologic parameters, or policy proposals to encourage best practices. Despite the appeal of perhaps three or four publications, we decided to tell a complete story in a single paper, but we are open to suggestions."<br /> My reply to their reply: nobody would read the current paper, even partially. Shorten, shorten, shorten please, and focus on the key message.<br /> We fundamentally agree and have worked to shorten the text; to clarify our understanding that ‘race’ may change with time, location, and self-identification; and to add a Table of Contents to make the Parts more accessible to interested readers. We comment a lot because, in highly racialized societies, like the US [1,2], it can be difficult to see beyond ‘race’ without explicit speculation about other possible explanations for difference, which we understand, may or may not pan out under investigation. One hope is that all clinicians will pursue explanations other than ‘race’, but this seems unlikely. Busy medical researchers have little time to develop expertise outside their area of interest, which may explain why ‘Commentary’ and ‘Perspective’ articles have failed to inspire an ethical ban on the misuse of ‘race’ in medical research, journals, clinics, and elsewhere [3]. We do not know whether a suite of articles can meaningfully contribute to ending misuse of ‘race’, where so many scholarly articles have failed, but after perceiving little change over four decades, trying something completely different seemed (almost) rational.

1. Nunez-Smith M, Curry LA, Bigby J, Berg D, Krumholz HM, Bradley EH. Impact of race on the professional lives of physicians of African descent. Ann Intern Med. 2007 Jan 2;146(1):45-51. doi: 10.7326/0003-4819-146-1-200701020-00008. PMID: 17200221.

2. Betancourt JR, Reid AE. Black physicians' experience with race: should we be surprised? Ann Intern Med. 2007 Jan 2;146(1):68-9. doi: 10.7326/0003-4819-146-1-200701020-00013. PMID: 17200226.

3. McFarling UL. Troubling podcast puts JAMA, the ‘voice of medicine,’ under fire for its mishandling of race. Stat News. 2021 April 6 [Cited 2022 August 31]. Available from: https://www.statnews.com/2021/04/06/podcast-puts-jama-under-fire-for-mishandling-of-race/ <br /> Reviewer #2: Thank-you, once again, for the opportunity to review this lengthy “thesis-style” manuscript which discusses some important often over-looked topics. The under-use of serial creatinine measurements and over-reliance on often erroneous eGFR measurements is an important point which is easily missed by healthcare workers with potentially serious consequences. Likewise, the misuse of racial constructs in medicine (and elsewhere) is an important point.<br /> Thank you for again giving time for helpful criticism and comments on our manuscript.

A. I am satisfied with this re-submission and the changes which have been made to the original manuscript.<br /> Minor points:<br /> B. 431: “creatinine inhibits several membrane transporters”. = Cimetidine<br /> Corrected.

C. 502: “Because mGFRs have population variation as wide as sCr, with much greater physiologic variability compared to the relatively stable sCr and serum cystatin C”<br /> As mentioned previously the cited article compares the variability of sCr and cystatin C with CrCl, I agree with the authors that CrCl is a form of mGFR, however, probably one of the poorer forms and not what a reader will think of when mGFR is mentioned. In our current age of medicine when we talk about mGFR CrCl is seldom included, studies reviewing methods of mGFR will seldom include CrCl, however CrCl may be compared to one of the mGFR methods. Likewise, if a patient is sent for a mGFR, a CrCl will not be performed. In our current age of medicine mGFR refers to methods such as the clearance of iohexol, iothalamate, Cr-EDTA, inulin, DTPA, etc; the authors themselves mention this (line 539 – 540). I fully agree with the authors that mGFR is FAR from perfect and has many inaccuracies and imprecisions (which are often overlooked)- these are well published, some of which are cited in this manuscript. If the authors wish to use the current study as a source they should state the findings in a way that cannot be misinterpreted. For example: “CrCl has much greater physiologic variability than sCr and cystatin C …” – in this case the reader can determine for themselves whether they would use CrCl as a surrogate for mGFR. Alternatively, adjust the statement and use another source which has shown the variability that exists with what we currently refer to as mGFR method.<br /> We appreciate this comment and have both added another reference and added to the text an argument for reconsidering creatinine clearance. Many hospitals and some countries lack the resources for advanced mGFR filtration markers, which are only used for research or for screening related to kidney transplants. However, most laboratories have the tools for ‘quick-creatinine clearance’ (quick-CrCl), which may be an acceptable alternative to the classic mGFRs. If confirmed, a simple and affordable quick-CrCl might allow hospitals and laboratories worldwide an alternative measurement requiring fewer assumptions for another aspect of glomerular filtration.

D. 670 – 719: As the authors specifically discuss age it would be prudent to briefly mention the short-comings, or considerations for interpretation, of serial creatinine measurements at a very young age which generally rise until late adolescence when steady muscle mass is achieved. Also note changes in creatinine and GFR from birth till 2 – 3 years.<br /> We have added a brief discussion of the diagnosis of CKD in infants, children, and adolescents.

E. 783 – 784: Consider re-wording, the grammar makes this sentence difficult to read<br /> Done.

F. 959 – 968: Note, editing has not been accepted (tracked changes still shown).<br /> Done.

G. 1116 - 1121: “Using the opioid crisis as an example…. in, for example, the opioid crisis” – same sentence.<br /> Rewritten.

We thank you.

On 2022-03-01 05:15:31, user Nun Daled Yud wrote:

clearly serial daily or twice daily testing is needed for patients who would benefit from the early antiviral treatments particularly aged care facilities .

On 2022-03-02 17:16:42, user HF wrote:

Is there any SPSS, Strata or R code available to replicate this project?

On 2022-03-09 02:39:17, user Peter J. Yim wrote:

Vaccine efficacy based on vaccination registries is dependent on the completeness of the registries. Any missing or improperly registered data contributes to misclassification bias: https://drive.google.com/fi...<br /> This study relies on the Citywide Immunization Registry (CIR) and the NYS Immunization Information System (NYSIIS). However, no evidence is presented for the accuracy of those registries. As such, the VE estimates from this study should be regarded as uncertain.

On 2022-05-05 12:39:51, user Robert Clark wrote:

The data shows efficacy against infection becomes NEGATIVE after one month. Imperative to found out if at longer times this also happens for hosp./deaths. Review the data to found out.

Robert Clark

On 2022-03-14 13:57:25, user SleepRhythm wrote:

This paper is now in press in Frontiers in Neuroscience - section Sleep and Circadian Rhythms: https://www.frontiersin.org...<br /> The medRxiv link will be forthcoming

On 2022-03-23 02:12:03, user Guest wrote:

Hello authors,<br /> Thank you for submitting a preprint of this interesting study on the virome to a public domain. I have a few questions regarding your methods and materials.<br /> First, the detailed description of sample collection was great, but I could not find any internal standards for the PCR steps, DNA extraction, or isolation of VLP. These might have been stated, somewhere else perhaps, but I could not identify them. However, for sample collection, how did you determine the location and type of wounds that would be tested? Was there a specific location or depth for chosen wounds or just all types stated that were within the frames of the criteria?<br /> Secondly, the methods for sample processing and DNA extraction are excellent, but I cannot seem to find any information regarding the primers used or the number of cycles performed while analyzing 16S rRNA. I could not find the total number of sequences obtained per sample, however, the quality reading for the viral reads was in-depth and well covered. I did not find any profile or 16S normalization or a total quantification of bacterial or bacterial numbers (like qPCR).<br /> Thirdly, I did not find anything about OTU abundance corrected for variance in copy numbers or variance in genome size. I also could not find any method details regarding coverage of communities measured or if there was any comparison to the dominate to rare. One last question, what do you define as ‘deep sequencing’ regarding this study?<br /> Overall, I found this article very interesting and a good read. Thank you for providing such excellent work with the virome. I have not seen many studies regarding the effects of the virome on human healing, host interactions, or composition until recent years, but this article provides a great starting point for these types of studies.

SHSU5394

On 2022-04-07 15:07:03, user Addi Romero wrote:

A revised, updated version has been published as a correspondence in The Lancet Infectious Diseases. A link will be forthcoming. Meanwhile, feel free to have a look at the In Press, Corrected Proof: <br /> https://www.sciencedirect.c...

Dynamics of humoral and T-cell immunity after three BNT162b2 vaccinations in adults older than 80 years

On 2022-04-13 12:35:52, user Josué OUEDRAOGO wrote:

Hello! Thank you for this work.<br /> How can i get your dataset?

On 2022-04-23 17:06:25, user Ozzy96 wrote:

What is the all cause <br /> background rate of myocarditis in this age group pre-covid??

On 2022-04-25 13:00:30, user Sakari Jukarainen wrote:

Thank you for pointing this out, it is indeed an error, to be fixed in the next version of this work.

On 2022-04-29 17:03:47, user Madhava Setty, MD wrote:

Very interesting study. From where did the data on viral copies come from? Also, the odds of seroconversion in placebo vs treatment, stated as 13.67 at a given viral copy level, doesn't seem to be reflected in the corresponding plot (B).

On 2022-05-06 12:44:06, user Showme wrote:

Any info about the peer reviewing progress?

On 2022-05-10 08:12:41, user Zeng Zhiyu wrote:

Figure 2. All 1 dose vs none, the dot is way greater than 1, why the OR is still 0.566?

On 2022-05-21 01:10:31, user Fritz Stumpges wrote:

You need to provide ground level readings for this test, for your group (1) without masks. Without this base, we don't know if your methods are just producing extremely high readings across the board!

On 2022-05-30 22:36:58, user Stuart Turville wrote:

Now published within this manuscript here:

Congratulations<br /> Dear Stuart G. Turville

We are pleased to inform you that your article has just been published:

Title<br /> Platform for isolation and characterization of SARS-CoV-2 variants enables rapid characterization of Omicron in Australia

Journal<br /> Nature Microbiology

DOI<br /> 10.1038/s41564-022-01135-7

Publication Date<br /> 2022-05-30

Your article is available online here https://doi.org/10.1038/s41... or as a PDF here https://www.nature.com/arti....

On 2022-06-03 06:08:07, user Toby Mansell wrote:

This paper has now been published at eLife. You can view the published version of this paper at: https://doi.org/10.7554/eLi...

On 2020-05-20 00:33:44, user SizzMo wrote:

It appears that the methods of administration of hydroxychloroquine were doomed to fail before even being undertaken. A review of the full study reveals NO mention of zinc, and suggests that hydroxychloroquine was administered alone or sometimes in tandem with azithromycin, and primarily to hospitalized patients in very late stages of illness. The omission of zinc and administration only in late stages of disease defeat the mechanism of action by which the hydroxychloroquine protocol works

The primary mechanism of action in the hydroxychloroquine+zinc+azithromycin protocol uses hydroxychloroquine primarily as an ionophore for zinc, which then inhibits viral replication in the cell cytoplasm. Zinc is an essential component of this protocol, and omitting zinc appears to be a fatal flaw in all of the reviewed studies and case reports in this analysis. Furthermore, this paper repeatedly refers to hydroxychloroquine being administered to hospitalized patients. The mechanism of action is the inhibition of viral replication, which reduces viral load at early stages of disease. Giving this protocol in late stages of disease when viral load is already heavy and patients are already severely ill defeats the purpose of the protocol and practically guarantees that it will not be effective. The methods reviewed in this study overlook what is known about both the mechanism of action of viral inibitors, and the synergistic function of hydroxychloroquine and zinc in viral RNA replication, making it appear that these "studies" were designed to fail.

Clinicians employing the complete hydroxychloroquine+zinc+azithromycin protocol at early stages of disease (mild to moderate illness) are universally reporting high levels of efficacy. <br /> Additionally, researchers in an NYU Langone retrospective analysis of more than 900 patients with mild-to-moderate illness who received the protocol with or without zinc also reported significant improvements in patients who received zinc. The NYU Langone study is currently undergoing peer review, and is available at this link: https://www.medrxiv.org/con...

On 2020-05-23 22:06:14, user CKComments wrote:

The authors dismiss the finding regarding the improvement in lung health in their summary. It's messed up lungs that kill patients, so it seems worth emphasizing.

On 2022-06-10 15:22:41, user Tammi Kral wrote:

The published version of this manuscript can be found in Science Advances at the following DOI:<br /> https://www.science.org/doi...

On 2022-07-18 12:29:27, user Loretta Lorenz wrote:

Quite likely many person are vaccinated and infected in various sequences. My question is, if the SARS-CoV 2 Spike protein measurement differentiated beetween spike proteins originating from a vaccine against COVID-19 and the different Spike Proteins of the various SARS-CoV-2 mutations.

On 2022-07-20 16:59:17, user Tania Watts wrote:

The authors may want to note similar findings in our paper, Dayam et al. Accelerated waning of immunity to SARS-CoV-2 mRNA vaccines in patients with immune-mediated inflammatory diseases, JCI Insight, 10.1172/jci.insight.159721 April 2022. We show anti-TNF treated patients have lower Ab responses, no neutralization of Omicron and enhanced waning of T and Ab responses to SARS-CoV-2 mRNA vaccines after 2 doses.

On 2022-07-25 16:31:06, user Dr. D. Miyazawa MD wrote:

Please also refer to previous studies.

Hypothesis that hepatitis of unknown cause in children is caused by adeno-associated virus type 2 (08 May 2022)<br /> https://www.bmj.com/content...

Daisuke Miyazawa. Possible mechanisms for the hypothesis that acute hepatitis of unknown origin in children is caused by adeno-associated virus type 2. Authorea. May 16, 2022.<br /> DOI: 10.22541/au.165271065.53550386/v2

On 2022-07-28 17:24:57, user Mike Knudson wrote:

This paper is now published online in Transfusion.<br /> https://onlinelibrary.wiley...<br /> Major change was to add the results of eluate studies in the patients with a positive DAT following a transfusion reaction.

On 2022-07-29 13:52:30, user Stuart MacGowan wrote:

This is great work! A few years ago I worked on something similar - mapping missense variants to Pfams and defining constrained positions https://doi.org/10.1101/127050 . We also saw enrichment of pathogenic variants at constrained positions. Great to see this area moving forward!

On 2022-08-04 17:25:32, user Paul Hunter wrote:

Did you include date or week number in your model? During the study period there was a dramatic shift in the proportion of tests positive in Portugal from about 1 in 4.5 to 1 in 2 and that could explain your findings of a 3 x greater risk of hospitalisation associated with BA.5 infection irrespective of the actual risk . If you did not include week number then I think your conclusions are probably flawed.

On 2022-08-12 16:16:31, user A. M. Baxter wrote:

Alisdair Munro posted on Substack about this particular paper. It is an example of junk science spreading due to confirmation bias.

https://alasdairmunro.substack.com/p/how-junk-science-got-spread-like

"To put it bluntly, the results of this study are of no use at all. It is completely uninformative and would not pass as an undergraduate medical student assignment."

On 2022-09-28 17:51:37, user Jorge Cruz wrote:

This paper has now been published in Ann Clin Lab Sci July-August 2022 vol. 52 no. 4 651-662

On 2022-10-05 13:49:05, user Merja Rantala wrote:

Congrats for this preprint, it is an important summary what we know about protection of hybrid immunity and prior infection against cov19. However, I think that references and claims in the discussion should be checked. There was a sentence on page 13, first paragraph, claiming that covid survivors would have higher risk for dementia in addition to some other conditions. The reference cited was 36, which is not at all about risks for diseases after covid, but the other way around: risk factors for a severe covid outcome. So the ref need to be replaced. Moreover, we really don''t know at this stage whether risk for dementia is increased after covid or not, although has been under heavy speculation.

On 2020-05-26 09:28:09, user David Sbabo wrote:

5 counfounding factors with a p-value under 0.05, all in the same direction "higher chance of mortality for the no zinc group".

On 2020-05-26 12:56:20, user OxImmuno Literature Initiative wrote:

https://www.immunology.ox.a...

On 2020-05-26 17:03:03, user Sinai Immunol Review Project wrote:

The main finding of the article: <br /> Recent studies have diverged as to weather conditions are allied or not with the spreading of Covid-19. Through random-effects meta-regression analysis, this work aimed was to determine if elements linked to meteorology can influence SARS-CoV-2 incidence and the speed of its propagation. The number of Covid-19 patients and meteorological conditions at each Japanese prefectural capital city from January to April 2020 were collected. <br /> The results demonstrated a negative association between Covid-19 incidence and monthly mean air temperature (C) (coefficient -0.351), sea level air pressure (hPa) (coefficient -0.001) and the monthly mean daily maximum UV index (UV) (coefficient -0.001).

Critical analysis of the study: <br /> The manuscript would benefit from a more thorough introduction and discussion of the results in the context of previous studies. The authors could explore more the results of the supplementary table 1 (wind speed, relative humidity and sunshine). The figure caption should be better detailed, explaining the characteristics of each graph.

The importance and implications for the current epidemics: <br /> The transmission dynamics of SARS-CoV-2 depends on different factors, such as population density, demographic and clinical characteristics of the population, hygiene, local ventilation, etc., and the seasonality of SARS-CoV-2 is not yet known.<br /> The data of this manuscript suggest that higher air temperature, air pressure, and ultraviolet are associated with a lower incidence of Covid-19. Certainly, this study is a step in identifying which environmental factors can favor viral transmission.

Reviewed by Bruna Gazzi de Lima Seolin.

On 2020-05-27 02:34:42, user Aaron wrote:

It would be a good addition to show the breakdown of patient demographics for those samples included in Figure 4 to show whether there are differences in the samples collected for each clade thus far. If there are any significant differences, those could be just as important as the viral sequence, if not more so. While I see that authors tried to control for these variables, it'd still be a good idea to show this information in a table in the main figures.

Additionally, the differences in the rate of spread for each clade are probably much more attributable to the cities themselves that each clade is primarily associated with rather than any differences in the virus; there are major differences in the infrastructure and movement of individuals depending on the metropolitan area. I don't find it particularly surprising that any viral sequence(s) associated with NYC would spread faster than those found in Washington or Chicago. The differing responses of each city in shutting down public movement will also play a big role here.