title: COVID-19 risk score as a public health tool to guide targeted testing: A demonstration study in Qatar

abstract:
BackgroundThe objective of this study was to develop a Coronavirus Disease 2019 (COVID-19) risk score to guide targeted RT-PCR testing in Qatar.

MethodsThe Qatar national COVID-19 testing database was analyzed. This database includes a total of 2,688,232 RT-PCR tests conducted between February 5, 2020-January 27, 2021. Logistic regression analyses were implemented to identify predictors of infection and to derive the COVID-19 risk score, as a tool to identify those at highest risk of having the infection. Score cut-off was determined using the receiving operating characteristic (ROC) curve based on maximum sum of sensitivity and specificity. The scores performance diagnostics were assessed.

ResultsLogistic regression analysis identified age, sex, and nationality as significant predictors of infection and were included in the risk score. The scores scoring points were lower for females compared to males and higher for specific nationalities. The ROC curve was generated and the area under the curve was estimated at 0.63 (95% CI: 0.63-0.63). The score had a sensitivity of 59.4% (95% CI: 59.1%-59.7%), specificity of 61.1% (95% CI: 61.1%-61.2%), a positive predictive value of 10.9% (95% CI: 10.8%-10.9%), and a negative predictive value of 94.9% (94.9%-95.0%). The risk score derived early in the epidemic, based on data until only April 21, 2020, had a performance comparable to that of a score based on a year-long testing.

ConclusionsThe concept and utility of a COVID-19 risk score were demonstrated in Qatar. Such a public health tool, based on a set of non-invasive and easily captured variables can have considerable utility in optimizing testing and suppressing infection transmission, while maximizing efficiency and use of available resources.


title: Role of IL-23 neutralization in psoriasis: insights from a mechanistic PK/PD model and meta-analysis of clinical data

abstract: Blocking of IL-23 has shown a profound effect on patient outcomes in psoriasis. The current IL-23 binding monoclonal antibodies show differences in dosing regimens, pharmacokinetics, affinity for the target, and efficacy outcomes in the clinic. The goal of the current work is to use a mechanistic pharmacokinetics/pharmacodynamics mathematical model to estimate projected free IL-23 neutralization for the different therapeutic molecules and connect it to clinical efficacy outcomes. The meta-analysis indicates a sigmoid-like relationship and suggests that the best current anti-IL23 antibodies are close to saturating the efficacy that can be achieved by this pathway in psoriasis.

category: pharmacology and therapeutics


title: A Fundamental Distinction in Early Neural Processing of Implicit Social Interpretation in Schizophrenia and Bipolar Disorder

abstract:
BackgroundSocial cognition impairment is a key phenomenon in serious mental disorders such as schizophrenia (SCZ) and bipolar disorder (BPD). Although genetic and neurobiological studies have suggested common neural correlates, here we hypothesized that a fundamental dissociation of social processing occurs at an early level in these conditions.

MethodsBased on the hypothesis that key structures in the social brain, namely the temporoparietal junction, should present distinctive features in SCZ and BPD during low-level social judgment, we conducted a case-control study in SCZ (n=20) and BPD (n=20) patients and controls (n=20), using task-based fMRI during a Theory-of-Mind (ToM) visual paradigm leading to interpretation of social meaning based on simple geometric figures.

ResultsWe found opposite neural responses in two core ToM regions : SCZ patients showed social content-related deactivation (relative to controls and BPD) of the right supramarginal gyrus, a region which activity is required to overcome egocentric "overmentalizing", while the opposite pattern was found in BPD; reverse patterns, relative to controls and SCZ, were found in the left posterior superior temporal gyrus, a region involved in inferring others intentions. Receiver-operating-characteristic curve analysis showed 88% accuracy in discriminating the two clinical groups based on these neural responses.

ConclusionsThese contrasting activation patterns of the temporoparietal junction in SCZ and BPD represent mechanistic differences of social cognitive dysfunction that may be explored as biomarkers or therapeutic targets.

category: psychiatry and clinical psychology


title: Brain structure and function show distinct relations with genetic predispositions to mental health and cognition

abstract: Mental health and cognitive achievement are partly heritable. To identify the underlying neural mechanisms, we associated genetic predispositions to various mental health and cognitive traits with a large set of structural and functional brain measures from the UK Biobank (N=36,799). We show that genetic predispositions to attention deficit hyperactivity disorder, smoking initiation, and cognitive traits have stronger associations with brain structure than with brain function, whereas genetic predispositions to most other psychiatric disorders have stronger associations with brain function than with brain structure. These results reveal that genetic predispositions to mental health and cognitive traits have distinct brain profiles.


title: Categorizing the Status of COVID-19 Outbreaks Around the World

abstract:
Although the SARS-CoV-19 virus spread rapidly around in world in early 2020, disease epidemics in different places evolved differently as the year progressed - and the state of the COVID-19 pandemic now varies significantly across different countries and territories. We have created a taxonomy of possible categories of disease dynamics, and used the evolution of reported COVID-19 cases relative to changes in disease control measures, together with total reported cases and deaths, to allocate most countries and territories among the possible categories. As of 31 January 2021, we find that the disease was (1) kept out or suppressed quickly through quarantines and testing & tracing in 39 countries with 29 million people, (2) suppressed on one or more occasions through control measures in 74 countries with 2.49 billion people, (3) spread slowly but not suppressed, with cases still increasing or just past a peak, in 31 countries with 1.45 billion people, (4) spread through the population, but slowed a result of control measures, leading to a "flattened curve" and fewer infections than if the epidemic were unmitigated, in 32 countries with 2.24 billion people, and (5) spread through the population with some but limited mitigation in 5 countries with 168 million people. In addition, several countries have experienced increases in cases after disease appeared to have finished spreading due to declining numbers of susceptible people. For some of these countries - for example Kenya, Pakistan and Afghanistan - the resurgences can be explained by the relaxation of control measures (and may have been enhanced by disease spread in population segments that experienced lower infection levels during the first waves). For other countries, the resurgences point to the effects of new virus variants with higher transmissibility or immunity resistance - including most countries in Southern Africa (where the B.1.351 variant has been identified) and several countries in West Africa (potentially due to the B.1.1.7 or other variants). These findings are consistent with mounting evidence of high infection rates in several low- and middle-income countries, both from seroprevalence studies and estimates of actual deaths from COVID-19 combined with estimates of expected mortality rates. We estimate that 1.3-3.0 billion people, or 17-39% of the global population, have been infected by SARS-CoV-2 to date, and that at least 4.5 million people have died from COVID-19 - much higher than reported cases and deaths. Disease control policies and vaccination strategies should be designed based on the state of the COVID-19 epidemic in the population - and consequently may need to be different in different countries.

Key Points The state of the COVID-19 pandemic varies significantly in different countries and territories around the world - and policies for disease control and vaccination will need to be tailored accordingly.
In any epidemic, there are several possibilities for how the disease will spread over time - and our analysis finds that, in fact, as of 31 January 2021, there were many countries and territories in each of the main categories of COVID-19 epidemic dynamics that might have been expected:
O_LIKept out or suppressed quickly through quarantines and testing & tracing - in 39 countries with 29 million people (0.4% of the global population), mostly small island states and a few countries in Southeast Asia. [Category H in the following map and table]
C_LIO_LISuppressed through control measures (social distancing, hygiene and testing & tracing) -in 74 countries with 2.49 billion people (31.9% of global population), mostly in Europe, East Asia and the Pacific. [Categories F and G]
C_LIO_LISpread slowly but not suppressed, with cases still increasing or just past a peak - in 31 countries with 1.45 billion people (18.6% of global population), including many countries in Latin America, Eastern Europe and the Middle East, as well as the United States and Russia. [Categories D and E]
C_LIO_LISpread through the population, but slowed as a result of control measures, leading to a "flattened curve" and fewer infections than if the epidemic were unmitigated - in 32 countries with 2.24 billion people (28.8% of global population), mostly in South and Southeast Asia (including India) and Africa. [Category B]
C_LIO_LISpread through the population with some but limited mitigation or "flattening the curve" -in 5 countries with 168 million people (2.2% of global population). [Category A]
C_LIO_LIExperienced increases in cases after disease appeared to have finished spreading, which in some countries might have been solely due to relaxation of control measures (especially in wealthier population segments which experienced low infection levels during the first wave) - for example in Kenya and in Pakistan and some Central Asian countries - but which in some countries is likely to be due to new virus variants with higher transmissibility or immunity resistance - for example in most countries in Southern Africa and several in West Africa, and possibly also in parts of South and Central America. [Category J and many countries in Category K]
C_LI
These findings are backed up by mounting evidence of high infection rates in several low- and middle-income countries. Seroprevalence studies in Kenya, Nigeria, Pakistan and South Africa have reported finding antibodies for SARS-CoV-2 in large percentages of the studied populations - and suggest that current infection levels are likely above 50% in each country. Studies of actual deaths due to COVID-19, combined with estimates of expected mortality rates, similarly suggest that SARS-CoV-2 has, by now, infected more than half of the populations in Bolivia, Ecuador, Peru, Mexico, South Africa, Sudan, Syria, Yemen and Zambia.
Countries of all income levels, and from all regions, appear in each of the main disease dynamics categories; however, there are clear income and geographical patterns in states of COVID-19 epidemics around the world. Most high-income countries have controlled the spread of SARS-CoV-2 through measures. Middle-income countries are spread across all categories, and account for 45 of the 63 countries which have slowed the disease significantly but not fully suppressed it. Some low-income have experienced largely unmitigated susceptibility-driven dynamics, while others have "flattened the curve" to varying degrees.
We estimate that between one and two out of every five people globally has been infected by SARS-CoV-2 to date, and that at least 4.5 million people have died from COVID-19. Our estimate of total infections - 1.3-3.0 billion people, or 17-39% of the global population - is between 13 and 30 times the number of confirmed cases, and twice to four times as much as previous estimates of total infection numbers. We estimate that 4.6-10.0 million people have died from COVID-19, between 2.1 and 4.5 times the number of deaths attributed to COVID-19.
An estimated 8.9-12.5 million lives remained at risk from COVID-19 as of the end of January 2021, prior to vaccination efforts - mainly in high-income countries (2.4-2.9 million), China (2.1 million) and India (1.7-2.9 million). Vaccinations, of course, have already started to reduce these numbers substantially.
Our analytical approach is simple but useful - providing insight into the epidemic status even in many low-income countries with limited disease monitoring, and with potential to provide early warnings of significant new variants. We compare the evolution of reported cases with changes in stringency of disease control measures, and check that infection levels are plausible given total reported cases and deaths and the income level of the country. Anomalies in which changes in the evolution of reported cases cannot be explained by changes in the stringency index provide indications of possible significant variants of the virus. Up to the end of January, the data provide indications of the presence of significant new variants in:
O_LIMost countries in Southern Africa (where the B.1.351 variant, with higher transmissibility and some resistance to immunity, was first identified in South Africa)
C_LIO_LISeveral countries in West Africa (likely with higher transmissibility and resistance to immunity, possibly the B.1.1.7 variant, which was first identified in the UK and has been found in Ghana and Nigeria, or possibly a different variant).
C_LI
They also suggest, with less certainty, that the disease dynamics may be affected by new variants in several countries in South and Central America (perhaps the P.1 variant descended from the B.1.1.28 variant which was first identified as coming from the Brazilian Amazon).
Different countries should adopt different disease control policies, according to the state of the COVID-19 epidemic in the population.
O_LIFor countries that have kept the disease out or suppressed outbreaks through control measures, their measures need to be kept in place - and potentially strengthened especially in the face of higher-transmissibility variants - until vaccines have been widely administered.
C_LIO_LIFor countries in which the disease is spreading slowly, full control measures should be maintained at least until new case numbers fully decline from the peak; later, it may be possible to relax some measures, but if measures are relaxed too soon or too much after cases peak, then significant further outbreaks can be expected (as has already happened in several such countries).
C_LIO_LIFor countries in which cases have declined following a flattened curve, there may be room to relax control measures that have the greatest negative health, economic and social consequences - but the most effective control measures will need to be maintained (even when cases remain low for extended periods), and measures may need to be strengthened to tackle variants which higher transmissibility or ability to evade immune responses.
C_LIO_LIFor countries in which the disease spread was largely unmitigated, many control measures could be relaxed for most people - although there may be risks if sizeable population segments have much lower infection levels than the general population or from variants with a high degree of immunity resistance.
C_LI
These findings may have implications for the optimal distribution of early batches of vaccines within countries.
O_LIFor countries that have kept the disease out or suppressed outbreaks through control measures, vaccinations should be given first to frontline healthcare and essential workers and to elderly and vulnerable groups (starting with the oldest and most vulnerable).
C_LIO_LIFor countries in which the disease is spreading slowly, detailed modelling should be done to determine whether the optimal strategy is to vaccinate at-risk groups first or to vaccinate key transmitters to halt the outbreak and "crush the curve" while waiting for further vaccine supplies to arrive. For any country choosing the key transmitter strategy - as Indonesia has done and has been suggested for the United States - it will be essential to maintain control measures, and to keep higher transmissibility variants out, or otherwise the benefits of a key transmitter vaccination strategy could be lost.
C_LIO_LIFor countries in which the cases declined following a flattened curve, vaccinations should probably be given first to elderly and vulnerable groups, but the optimal strategy may switch to vaccinating key transmitters if there are resurgences in cases due to higher-transmissibility or immunity-resistant variants.
C_LIO_LIFor countries in which the disease spread was largely unmitigated, vaccination should concentrate on elderly and vulnerable people, because population-level immunity already exists, and the greatest danger lies in vulnerable people becoming infected due to endemic SARS-CoV-2 from variants that will likely circulate over many years.
C_LI
These findings may also have implications for the optimal distribution of the first vaccines across countries. For most countries, the optimal allocation of vaccines doses is likely still to be according to population size - as current recommendations suggest. However, the global optimal allocation strategy might include providing somewhat greater supplies, during the next few months, to countries where using the vaccine to halt spread of the disease might be possible (provided that disease control measures are maintained in those countries).
Vaccination strategies will need to account for current and potential future virus variants as well as the likelihood that immunity from vaccination will wane over time. Higher-transmissibility variants of the SARS-CoV-2 virus increase the urgency of distributing vaccines in countries which have controlled the disease to date, and may alter the optimal strategy for countries deciding between vaccination first of elderly and vulnerable people or of key transmitters. Immunity-resistant variants of the virus may reduce the effectiveness of current vaccines, but are not likely to negate fully the protection they offer. Immunity acquired through vaccination is likely to wane over time - like immunity acquired through infection. In many, perhaps most, countries, the time to vaccinate the whole population will exceed the timeframe in which immunity from vaccination wanes or new immunity-resistant variants emerge. Looking to the longer term, therefore, new virus variants and waning immunity are likely to necessitate re-vaccination (with vaccines tailored to the latest variants) on a regular basis - and the optimal long-term strategies for ongoing vaccination will vary widely across countries and will depend on many factors.

O_FIG O_LINKSMALLFIG WIDTH=154 HEIGHT=200 SRC="FIGDIR/small/21252586v3_ufig1.gif" ALT="Figure 1">
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org.highwire.dtl.DTLVardef@c39b02org.highwire.dtl.DTLVardef@1f5ccceorg.highwire.dtl.DTLVardef@590b3dorg.highwire.dtl.DTLVardef@1f0f1c5_HPS_FORMAT_FIGEXP  M_FIG C_FIG O_FIG O_LINKSMALLFIG WIDTH=151 HEIGHT=200 SRC="FIGDIR/small/21252586v3_ufig2.gif" ALT="Figure 2">
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org.highwire.dtl.DTLVardef@190e169org.highwire.dtl.DTLVardef@bec2a2org.highwire.dtl.DTLVardef@1dc3cf0org.highwire.dtl.DTLVardef@24d56b_HPS_FORMAT_FIGEXP  M_FIG C_FIG SummaryThe state of the COVID-19 pandemic varies significantly in different countries and territories around the world - and policies for disease control and vaccination will need to be tailored accordingly. Although the SARS-CoV-19 virus spread rapidly around in world in early 2020, the state of disease epidemics in different countries diverged rapidly as the year progressed. Many high-income countries have had second or third waves; other countries have seen cases continue to increase gradually; still others have experienced declines in cases to low levels after peaks in mid-2020. Facing different situations, different countries might need to adopt different policies in the coming months, including different disease control measures and vaccination strategies.

Each country needs to know its COVID-19 status. There are several possible courses that a disease epidemic can take in a population. The disease can spread rapidly until its runs out of people remaining to infect; the disease can be slowed with control measures but still spread until large numbers of people are infected and immune; the disease can be suppressed or "crushed" by control measures; or the disease can be kept out completely. More complex disease dynamics will occur when a virus mutates, if new variants evade immune responses in people already infected or spread faster than before, or if the disease spreads differently in different segments of a population. Our research suggests that different countries have experienced outbreaks in each of the main possible categories:

O_LISusceptibility-Driven Dynamics with Limited Mitigation [Category A] - in which the disease spread until it infect most people and declined due to low susceptibility levels (i.e., low share of the population still able to be infected).
C_LIO_LISusceptibility-Driven Dynamics Mitigated by Measures [Categories B and C] - in which the disease curve was "flattened" by control measures, but the disease still spread and declined after infecting large numbers of people (but fewer than if there were no mitigation).
C_LIO_LISusceptibility-plus-Measures-Driven Dynamics [Categories D and E] - in which the disease was slowed significantly but not suppressed, i.e., the curve was "flattened" but not "crushed", and the disease is still spreading in the population.
C_LIO_LIMeasures-Driven Dynamics [Categories F and G] - in which the disease has been constrained to date mainly through control measures (social distancing, hygiene and testing & tracing), but, of course, could spread again if measures are relaxed because only a minority of the population has been infected.
C_LIO_LIIndex-Case-Control Dynamics [Category H] - in which the disease has been kept out or suppressed to date through strict control measures (especially quarantines and testing & tracing).
C_LIO_LIComplex Disease Dynamics due to Differences Across Population Segments and/or New Variants [Categories I and J, and many countries in Category K] - in which the disease experienced an apparently susceptibility-driven curve but with low overall infection levels (i.e., share of population infected) because some segments of the population have not had many infections, or in which the disease later shows an unexpected resurgence, due to spreading within the previously less-affected population segments or due to the emergence of immunity-evading strains of the virus.
C_LI

From reported data on COVID-19 cases and disease control measures, we can categorize, for most countries and territories, the dynamics of the disease to date. First, we compare the timing of increases and/or decreases in reported new cases with the timing of changes in the "Stringency Index" of control measures compiled by the Oxford COVID-19 Government Response Tracker - and select the appropriate disease dynamics category. Second, we check if the infection levels expected for the category or categories indicated in the first step, are consistent with predicted ranges from the total numbers of reported cases and deaths using plausible ranges for the case detection rate, death detection rate and infection fatality ratio (IFR) given the countrys income level. This approach yields definitive categories for most countries and territories. COVID-19 disease dynamics are complicated in many countries, due to changes in control measures, seasonal patterns, geographical differences within countries, variability in case testing over time and emergence of new variants; such effects can be seen in the reported cases and deaths for many countries, but they do not obscure the basic drivers of disease dynamics - in other words, which of the categories applies - for most countries.

The results suggest that there is a wide variation in the state of the COVID-19 epidemic around the world - as of 31 January 2021 - as illustrated in the map and the table below. COVID-19 has been suppressed through control measures - Categories F, G and H - in 113 countries and territories with 2.52 billion people or about 32.3% of the global population. However, the rest of the world are in different situations. A total of 31 countries, with populations of 1.45 billion people (18.6% of global population), fall into Categories D and E, meaning that the disease spread has been slowed but not suppressed and cases are currently still increasing or just past their peak. In the 23 countries of Category B, home to 2.05 billion people (26.3%), the disease was slowed but not suppressed, and cases have declined fully from the peak. In a further 9 countries with 0.19 billion people (2.5%), the disease spread through the population after initial waves were suppressed. COVID-19 outbreaks in 5 countries with 0.17 billion people (2.2%) were only somewhat mitigated by control measures and the virus has likely infected most of the population, falling into Category A.

For several countries, which have apparent anomalies and fall outside the "basic" categories, the methodology provides important insights into epidemic status - pointing to situations where significant differences may exist across population segments or providing early warnings of new variants with higher transmissibility or resistance to immunity. For 5 Arabian Peninsula countries (3 of which are in Category I) and Singapore, it is likely that the virus has spread widely among migrant worker communities but has been controlled in the rest of the population. Categories J and K include 28 countries in which reported cases have surged after first waves which were likely or possibly susceptibility-driven, with curves flattened to various extents as a result of control measures which mitigated the epidemics. For some countries - including (1) Kenya, (2) Pakistan, Afghanistan, Kyrgyzstan and Kazakhstan, and (3) Egypt and Sudan - the second peaks are likely due to relaxation of measures but larger than might be expected due to disproportionate effects of the second waves on population segments (likely more affluent groups) which had lower infection levels during the first waves. For other countries - including (1) most countries in Southern Africa and (2) many countries in West Africa - the data suggest the presence of new virus variants with higher transmissibility and possible resistance to immunity, because resurgences or accelerations in cases happened in several neighbouring countries around the same time, and often without changes in control measures, and the second surges in cases usually involved faster increases than the first waves. The B.1.351 variant, with higher transmissibility and some resistance to immunity, was first identified in South Africa and is known to have caused most cases in the countrys second wave; the B.1.1.7 variant, which has higher transmissibility, has been found in Ghana and Nigeria. Several countries in South and Central America have experienced second waves or surges in cases: Surinames might be due to a higher-transmissibility variant (perhaps the P.1 variant that was first identified as coming from the Brazilian Amazon); Bolivias was large but could be explained by a significant decline in control measures; increases in Brazil and several other countries across South and Central America might simply be due to relaxation of social distancing behaviours over the Christmas and New Year holiday season although a role for virus variants cannot be discounted.

Countries of all income levels appear in each of the main disease dynamics categories; however there are clear correlations between income groups and COVID-19 status categories. Most high-income countries have controlled the spread of SARS-CoV-2 through measures (and thus fall in Categories F, G and H). Middle-income countries are spread across all categories, and account for 45 of the 63 countries which have slowed the disease significantly but not fully suppressed it (Categories B, C, D and E). Some low-income countries have experienced largely unmitigated susceptibility-driven dynamics (Category A), while others have "flattened the curve" to varying degrees (Categories B, C, D and E). A mix of low- and middle-income countries are among the 34 countries in Categories J and K.

Clear geographical patterns have emerged in the states of COVID-19 epidemics. There was more diversity in the state of the epidemic within regions earlier in the pandemic, but regional patterns had become clear by the end of January 2021.

O_LIIn the Americas, the disease has spread slowly but has not been suppressed (Categories D and E) in most countries, including those with the largest populations, while many (but not all) of the Caribbean islands have kept SARS-CoV-2 out or under control (Category H).
C_LIO_LIWestern and Northern European countries have, for the most part, controlled the disease through social distancing and hygiene measures, through two or three waves, and fall in Categories F and G.
C_LIO_LIAcross Eastern Europe, the Levant, the Caucuses and Iran, all countries have constrained growth of the disease significantly, but infection levels in most have grown to moderate levels: different countries in these regions are included in Categories C, D/E and F/G, although their infection levels may all be in the moderate range.
C_LIO_LIIn South and Central Asia, the virus has spread widely in most countries and cases have declined. In India, Bangladesh, Nepal and Uzbekistan, the case curve was flattened considerably, and current infection levels are likely moderate (Category B). In Pakistan, Afghanistan, Kyrgyzstan, and Kazakhstan (all in Category J), there have been two peaks in cases. Bhutan has contained the outbreaks of the virus to date (Category F).
C_LIO_LIMany countries in East and South-East Asia have largely kept the disease under control or kept it out (Categories F, G and H). However, Malaysia, Mongolia and Myanmar experienced widespread outbreaks in the second half of 2020, the Philippines appears to be past the peak of its epidemic (Category B), and Indonesia has had a continuous but very slow rise in cases since the start of the pandemic (Category E).
C_LIO_LIIn Australia, New Zealand and most Pacific Island States, SARS-CoV-2 has been excluded through quarantines, together with testing and tracing and lockdowns when the virus has spread beyond quarantined individuals (Categories F and H).
C_LIO_LIAfrican countries appear to have differed greatly in how the disease has spread. Many countries appear to have experienced widespread epidemics followed by declines in case numbers, with varying degrees of "curve flattening" due to control measures (Categories A and B). In some countries - Tunisia, Libya, Togo, Botswana and Mozambique - cases spread very slowly (Categories D and E). A few countries appear to have kept the disease out, and a few others appear to have experienced full outbreaks after having previously kept the virus largely out. As described earlier, most countries in Southern Africa and many in West Africa experienced rapid growth in case numbers in December and January (putting many in Categories J and K) - suggestive of the presence of one or more new variants with higher transmissibility and possible resistance to immunity.
C_LI

We estimate that 1.3-3.0 billion people have been infected by SARS-CoV-2 to date, or about 17-39% of the global population. This estimate is between 13 and 30 times the number of confirmed cases, and perhaps twice to four times as much as previous estimates of total infection numbers. We estimate that 4.6-10.0 million people have died from COVID-19, between 2.1 and 4.5 times the number of deaths attributed to COVID-19.

An estimated 8.9-12.5 million lives remain at risk from COVID-19, which can be saved through appropriate disease control measures and effective deployment of vaccines. Of these estimated extra deaths, if 90% of the population were to contract SARS-CoV-2, high-income countries account for about 2.4-2.9 million, China for about 2.1 million, and India for about 1.7- 2.9 million. Vaccinations, of course, have already started to reduce these numbers substantially.

The findings of this report are backed up by mounting evidence of high infection rates in several low- and middle-income countries. Immunity testing provides direct evidence of the current state of the COVID-19 epidemic. Serological studies in several cities and regions in Brazil, India, Kenya, Pakistan, Qatar and South Africa have already reported finding antibodies for SARS-CoV-2 in large percentages of the studied populations. Note, however, that serological testing will underestimate the number of people who have been infected, due to waning of SARS-CoV-2 antibodies which affects significant numbers of people at about 4-6 months after infection. Consequently, serological testing might understate the actual degree of immunity in a population, because some people may have antibodies at levels below the detection threshold of the serology tests or may have memory B cell or T cell responses, either or both of which will likely reduce the severity of their illness if reinfected, and may reduce their vulnerability to reinfection and their likelihood to pass on the virus to other people if reinfected. In some places, reliable estimates of actual deaths due to COVID-19 may be a substitute for immunity testing to determine the share of population infected to date, at least approximately. Estimates, using a variety of methodologies, in Bolivia, Ecuador, Mexico, Peru, South Africa, Sudan, Syria, Yemen and Zambia all indicate that moderate to high shares of their populations have already been infected.

Different countries should adopt different disease control policies, according to the state of the COVID-19 epidemic in the population. The following recommendations for countries in different categories take into account their current infection levels and the potential for additional infections if measures are relaxed or if new variants become common in a country.

[tpltrtarr]Category A: Control measures should be relaxed for most people; such relaxation is not likely to lead to many more cases and deaths. In some low- and middle-income countries, wealthier population segments may have implemented greater degrees of social distancing during the epidemic to date, and have much lower infection levels than in the overall population; these segments should maintain social distancing, until vaccines arrive, because otherwise they could experience substantial outbreaks (which may have generated "second waves" in some countries). If and when new virus strains with higher transmissibility and/or resistance to immunity arrive, control measures should be strengthened again to avoid new outbreaks, if the new variants cause high mortality levels and if it seems likely that control measures will be more effective at controlling the new outbreaks than they were during the initial outbreaks.
[tpltrtarr]Categories B and C: Control measures currently in place that have the greatest negative health, economic and social consequences could be relaxed. However, many control measures, especially the most effective in limiting virus spread, will need to be maintained, even though current case numbers are low; otherwise, significant resurgences can take place (as has happened, for instance, in Kenya and Bolivia). Population segments that may have maintained lower infection levels during the outbreak to date will need to maintain social distancing. If and when new virus strains with higher transmissibility and/or resistance to immunity arrive, control measures will likely have to be strengthened again to avoid new outbreaks.
[tpltrtarr]Categories D and E: Control measures should be maintained at least until new case numbers fully decline from the peak; if measures are relaxed too soon after cases peak, then significant further outbreaks can be expected (as has happened, for instance, in Brazil, Colombia and Paraguay). Once cases fully decline from the peak - through further infections or as a result of vaccination programmes - then, and only then, some of the disease control measures with the greatest negative health, economic and social consequences could be relaxed. For some countries in Categories D and E, it may be possible to push R0_e below 1 and hence "crush the curve" by introducing some additional control measures or improving compliance with existing measures. New virus strains, especially with higher transmissibility, can generate resurgences or accelerations in growth of cases (as seen, for example, in Mozambique and Togo).
[tpltrtarr]Categories F and G: COVID-19 control measures, put in place by governments and implemented by citizens, have saved perhaps 13.1-14.2 million lives. To continue to protect these lives, control measures need to be maintained until vaccines become widely available - and strengthened, if necessary, to compensate for new virus variants with higher transmissibility.
[tpltrtarr]Category H: Measures to keep the disease out - mainly strict quarantines for new arrivals and testing & tracing of suspected cases - should be maintained until vaccines become widely available.

The findings of this report may have implications for the optimal distribution of early batches of vaccines within countries. Current policies in several countries call for deployment of vaccines first to healthcare workers and then by age cohort, starting with the oldest. These plans are aligned with the results of modelling (by Imperial College London and others) which suggest that, when the supply of vaccines is limited, the optimal strategy is to target the elderly and other high-risk groups. However, the models indicate that, if the supply is sufficient to stop transmission of the virus, the optimal strategy switches to targeting key transmitters (e.g., working age people and potentially children) to indirectly protect the elderly and vulnerable. Consequently, the optimal strategy may vary according to the disease status category for each country:

[tpltrtarr]Category A: Vaccination should concentrate on elderly and vulnerable people, starting with the oldest and most vulnerable. There is no alternative strategy to consider because population-level immunity already exists, and the greatest danger lies in vulnerable people becoming infected due to endemic SARS-CoV-2.
[tpltrtarr]Categories B and C: Vaccinations should probably be given first to elderly and vulnerable groups, and to frontline healthcare and other essential workers. However, if there are resurgences in cases across the population due to higher-transmissibility or immunity-resistant variants, then the optimal strategy may switch to targeting key transmitters, similar to some countries in Categories D and E.
[tpltrtarr]Categories D and E: In some of these countries, the optimal strategy may to be vaccinate key transmitters - while maintaining current disease control measures - because it may be possible to halt the outbreak and "crush the curve", while waiting for further vaccine supplies to arrive (after which disease control measures could be released). This strategy is being pursued by Indonesia and was suggested for the United States of America in a recent paper. However, careful modelling and planning would be necessary, for any country considering such an approach, to determine if a key transmitter strategy would in fact be optimal and if it would be feasible to implement. Further, for such a strategy to work, it will be necessary to keep control measures in place and to keep high-transmissibility variants of the virus out, until enough people have been vaccinated.
[tpltrtarr]Categories F, G and H: Vaccinations should be given first to frontline healthcare and other essential workers and to elderly and vulnerable groups (starting with the oldest and most vulnerable).

These findings may also have implications for the optimal distribution of the first vaccines across countries. Modelling by the Imperial College London COVID-19 Response Team suggests that the optimal allocation of vaccine doses among countries "is sensitive to many assumptions and will vary depending both on the vaccine characteristics and the stage of the epidemic in each country at vaccine introduction," and concluded that, "[g]iven this uncertainty, allocating vaccine doses according to population size appears to be the next most efficient approach." Our findings reinforce the uncertainty strongly: it is very likely that that stage of the epidemic varies greatly across countries. For most countries, the optimal allocation of vaccines doses is likely still to be according to population size - and then for those countries to give doses first to elderly and vulnerable people. However, the global optimal allocation strategy might include providing somewhat greater supplies, during the next few months, to Category D and E countries where using the vaccine to halt spread of the disease might be possible (provided that disease control measures are maintained in those countries). It is clear, in any case, that further modelling of vaccine allocation strategies is essential, taking into account the actual vaccine efficacies and projected available doses by month, as well as allowing for disease stage categories in different countries.

Vaccination strategies will need to account for current and potential future virus variants as well as the likelihood that immunity from vaccination will wane over time. Higher-transmissibility variants of the SARS-CoV-2 virus increase the urgency of distributing vaccines, especially in Category F and G countries which may struggle to keep the disease suppressed, and might cause vaccination of key transmitters to be a less effective strategy for Category D and E countries if higher-transmissibility variants mean that they cant suppress the disease fully with limited vaccinations. Immunity-resistant variants of the virus may reduce the effectiveness of current vaccines, but are not likely to negate fully the protection offered by existing vaccines. Immunity acquired through vaccination is likely to wane over time - like immunity acquired through infection. Looking to the longer term, new virus variants and waning immunity are likely to necessitate re-vaccination (with vaccines effective against the latest variants) on a regular basis. In many, perhaps most, countries, the time to vaccinate the whole population will exceed the timeframe in which immunity from vaccination wanes or new immunity-resistant variants emerge. In making long-term plans, therefore, countries may face a wide range of options for who to vaccinate (elderly and vulnerable populations, key transmitters or entire populations) and for frequency of vaccination (every 6 months, annual, or once if residual benefits are sufficient). Optimal strategies for each country will be complicated to determine, as the choice will depend on many factors, including vaccine effectiveness in reducing mortality and in reducing transmission, how effectiveness wanes over time, mortality rates and transmissibility of new variants (in general and in previously infected or vaccinated people), and, once the risks to life and health from "endemic COVID" decrease to the point where COVID-19 is not an overriding issue, comparison with other health and budgetary priorities.

category: public and global health


title: A quantitative risk estimation platform for indoor aerosol transmission of COVID-19

abstract:
Aerosol transmission has played a significant role in the transmission of COVID-19 disease worldwide. We developed a COVID-19 aerosol transmission risk estimation platform to better understand how key parameters associated with indoor spaces and infector emissions affect inhaled deposited dose of aerosol particles that convey the SARS-CoV-2 virus. The model calculates the concentration of size-resolved, virus-laden aerosol particles in well-mixed indoor air challenged by emissions from an index case(s). The model uses a mechanistic approach, accounting for particle emission dynamics, particle deposition to indoor surfaces, ventilation rate, and single-zone filtration. The novelty of this model relates to the concept of "inhaled & deposited dose" in the respiratory system of receptors linked to a dose-response curve for human coronavirus HCoV-229E. We estimated the volume of inhaled & deposited dose of particles in the 0.5 to 4 m range expressed in picoliters (pL) in a well-documented COVID-19 outbreak in restaurant X in Guangzhou China. We anchored the attack rate with the dose-response curve of HCoV-229E which provides a preliminary estimate of the average SARS-CoV-2 dose per person, expressed in plaque forming units (PFUs). For a reasonable emission scenario, we estimate approximately three PFU per pL deposited, yielding roughly 10 PFUs deposited in the respiratory system of those infected in Restaurant X. To explore the platforms utility, we tested the model with four COVID-19 outbreaks. The risk estimates from the model fit reasonably well with the reported number of confirmed cases given available metadata from the outbreaks and uncertainties associated with model assumptions.

Practical ImplicationsThe model described in this paper is more mechanistic in nature than standard probabilistic models that fail to account for particle deposition to indoor materials, filtration, and deposition of particles in the respiratory system of receptors. As such, it provides added insights into how building-related factors affect relative infection risk associated with inhaled deposited dose. An online version of this mechanistic aerosol risk estimation platform is available at Safeairspaces.com. Importantly, the modular nature of this approach allows for easy updates when new information is available regarding dose-response relationships for SARS-CoV-2 or its variants.


title: Effectiveness of a telerehabilitation program for COVID-19 survivors (TERECO) on exercise capacity, pulmonary function, lower limb muscle strength, and quality of life: a randomised controlled trial

abstract:
ObjectivesTo investigate superiority of a telerehabilitation program for Covid-19 (TERECO) over no rehabilitation with regard to functional exercise capacity, lower-limb muscle strength (LMS), pulmonary function, health-related quality of life (HRQOL), and perceived dyspnoea.

DesignParallel-group randomised controlled-trial with 1:1 block-randomisation.

SettingThree major hospitals from Jiangsu and Hubei provinces, China.

Participants120 Covid-19 survivors with modified Medical Research Council (mMRC) dyspnoea score of 2-3 who had been discharged from hospital were randomised. 61 were allocated to the control group and 59 to the TERECO group.

InterventionThe control group received educational instructions. The TERECO group participated in a 6-week home-based, pulmonary rehabilitation program delivered via smartphone and monitored with chest-worn heart rate telemetry. Exercise types comprised breathing control and thoracic expansion, aerobic exercise, and LMS exercise.

OutcomesPrimary outcome was 6-minute walking distance (6MWD) in metres. Secondary outcomes were LMS measured as squat time in seconds; pulmonary function assessed by spirometry with parameters being forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC, maximum voluntary ventilation (MVV), and peak expiratory flow; HRQOL measured with SF-12 physical component score (PCS) and mental component score (MCS); and mMRC dyspnoea, favourable outcome (no dyspnoea). Outcomes were assessed at 6 weeks (post-treatment) and 28 weeks (follow-up).

Results120 patients were randomised, 15 (12.5%) were lost to follow-up at study endpoint. No serious adverse events occurred. 38 participants in the TERECO group complied with the exercise protocol (64.41% of randomized). The adjusted between-group difference in change in 6MWD from baseline was 65.45 metres (95% CI 43.8-87.1, p<0.001) at post-treatment and 68.62 metres (95% CI 46.39-90.85, p<0.001) at follow-up. Treatment effects for LMS were 20.12 seconds (95% CI 12.34-27.9, p<0.001) post-treatment and 22.23 seconds (95% CI 14.24-30.21, p<0.001) at follow-up. No group differences were found for lung function apart from post-treatment MVV (10.57 litres/minute, 95% CI 0.26-17.88, p=0.005). Increase in SF-12 PCS was greater in the TERECO group with treatment effects estimated as 3.79 (95% CI 1.24-6.35, p=0.004) at post-treatment and 2.69 (95% CI 0.06-5.32, p=0.045) at follow-up. No significant between-group differences were found for improvements in SF-12 MCS. At post-treatment 90.4% endorsed a favourable outcome for mMRC dyspnoea in the TERECO group vs. 61.7% in control (adjusted RR 1.46, 1.17-1.82, p=0.001).

ConclusionsThis trial demonstrated superiority of TERECO over no rehabilitation for 6MWD, LMS, and SF-12 PCS. We found no persistent effects on pulmonary function, SF-12 MCS, and perceived dyspnoea.

Trial registrationChinese Clinical Trial Registry: ChiCTR2000031834, 11 Apr 2020, URL: http://www.chictr.org.cn/showproj.aspx?proj=52216

KEY POINTSO_ST_ABSWhat is already knownC_ST_ABSMany Covid-19 survivors discharged from hospital have reduced exercise capacity, impaired pulmonary function, muscle weakness, and reduced quality of life, all of which might be addressed with pulmonary rehabilitation.

However, evidence on effective pulmonary rehabilitation measures for this population is currently lacking. As delivery of conventional rehabilitation services is furthermore limited due to pandemic control measures, telerehabilitation programs represent a possible alternative.

What the study addsWe developed a telerehabilitation program for Covid-19 survivors (TERECO program) that is delivered via smartphone and can be carried out at home.

Our study suggests that TERECO was safe and participants of the TERECO program had improved exercise capacity, lower-limb muscle strength, and physical quality of life. No relevant group differences were found for lung function, self-reported breathlessness, and mental quality of life.

The TERECO program is inexpensive and could be implemented on a large scale to improve physical health of Covid-19 survivors after discharge from hospital.

category: respiratory medicine


title: Evaluating strategies to combat a major syphilis outbreak in Australia among Aboriginal and Torres Strait Islander peoples in remote and regional Australia through mathematical modelling.

abstract:
BackgroundAn ongoing infectious syphilis outbreak, first reported among Australian Aboriginal and Torres Strait Islander people in 2011, has resulted in >3000 notifications to the end of 2019 with multiple congenital syphilis cases and infant deaths. In 2017, the Australian Government introduced an enhanced test and treat response. We evaluate the impact of this response and the potential impact of further expansion of testing interventions.

MethodsWe developed a mathematical model to capture the transmission of infectious syphilis among young heterosexual Indigenous Australians aged 15-29 years living in regional and remote areas. We used the model to assess the impact of existing and hypothetical outbreak responses on infectious syphilis prevalence.

FindingsThe increase in testing coverage achieved through the enhanced response (18% coverage in 2011, to 39% in 2019) could lead to a stabilisation of the epidemic from 2021. To return to the pre-outbreak level (<0{middle dot}2%) within five years, testing coverage needs to reach 60%. With the addition of a biannual community-wide screening program, using outreach to test 30% of youth in communities over 6 weeks,, a return to pre-outbreak levels can be achieved within 2 years. If testing coverage alone was scaled-up to 60% at the start of outbreak in 2011, syphilis prevalence would have returned to pre-outbreak levels by 2014.

InterpretationModelling suggests that to control the syphilis outbreak the response needs to be delivered with further potency. The reduction in prevalence could be hastened with community-wide screening at similar time periods across all communities along with increases in annual testing coverage.

FundingThe research was undertaken by the Kirby Institute, UNSW Sydney, for the Multi-jurisdictional Syphilis Outbreak Working Group (MJSO) with funding from the Australian Department of Health.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe search PubMed with the terms (("syphilis"[MeSH Terms] OR "syphilis"[All Fields]) AND ("disease outbreaks"[MeSH Terms] OR ("disease"[All Fields] AND "outbreaks"[All Fields]) OR "disease outbreaks"[All Fields] OR "outbreak"[All Fields])) AND "model "[All Fields]) on 12 March 2020 and identified 27 articles. Most articles focused on men who have sex with men and/or populations with HIV co-infection, neither of which is common in our target population (Indigenous Australians: predominantly aged 15-29; heterosexual and living in regional and remote areas). Of the remaining articles that consider syphilis control through screening interventions, the most relevant paper to our study is a modelling paper by Pourbohloul et al. in 2003, which demonstrated that community-wide treatment has no lasting effect on syphilis transmission.

Added value of this studyWe developed a mathematical model to assess the impact of an enhanced response to a major syphilis outbreak in remote Aboriginal and Torres Strait Islander populations of Australia and whether it can be controlled by increasing testing coverage. The model captures sexual behaviour information and short-term population mobility patterns across regional and remote communities of Australia and was calibrated against the most recent infectious syphilis notification data to-date (up to 2019) and testing coverage data from the affected regions. Our findings provide an insight into the role of increasing testing coverage in controlling syphilis outbreaks among populations living in remote communities globally.

Implications of all the available evidenceExisting evidence suggests that enhanced surveillance, expanded clinical and laboratory services, enhanced health promotion, strengthened community involvement and a rapid outbreak response are core components to controlling syphilis outbreaks. Our study focuses on modelling the impact of expanded clinical services and ability to expand testing among the target population. Our study suggests that increasing testing coverage of the Aboriginal and Torres Strait Islander population aged 15-29 living in remote and regional communities to a level of 60%, would stabilise the epidemic and reduce overall prevalence to pre outbreak levels in around five years. Combining the 60% testing coverage with bi-annual community screening over a 6-week period involving outreach (minimum coverage of 30%) would reduce the time period to around 2 years.

We believe these findings have implications for other Indigenous populations across the world who often live in remote regions with limited access to healthcare and are disproportionately affected by STIs.

category: sexual and reproductive health


title: Uterine fluid transcriptome as potential non-invasive biomarker for predicting endometrial receptivity

abstract:
BackgroundThe synchrony between the embryo and the receptive endometrium is essential for successful implantation. Therefore, a reliable non-invasive ER prediction method is highly demanded. We aimed to establish a method that could be used to predict endometrium receptivity non-invasively and to evaluate its clinical application potential in patients undergoing IVF.

MethodsThe non-invasive RNA-seq based endometrial receptivity test (nirsERT) was established by sequencing and analyzing the RNA of uterine fluid from 48 IVF patients with normal ER. Subsequently, 22 IVF patients were recruited and analyzed the correlation between the predicted results of nirsERT and pregnancy outcomes.

Results87 marker genes and 3 hub genes were selected to establish the nirsERT. 10-fold cross-validation resulted in a mean accuracy of 93.0%. A small cohort retrospective observation showed that 77.8% (14/18) of IVF patients predicted with normal WOI had successful intrauterine pregnancies, while none of the 3 patients with displaced WOI had successful pregnancy.

ConclusionsnirsERT is potential for a non-invasive, accurate and same cycle testing for ER in reproductive clinic.

FundingFunded by the National Natural Science Foundation of China (grant no. 8187061497) and the National Key Research and Developmental Program of China (grant no. 2018YFC1004800).

Clinical trial numberChiCTR-DDD-17013375.

category: obstetrics and gynecology


title: Protocol for disease-oriented Russian disc degeneration study (RuDDS) biobank facilitating functional omics studies of lumbar disc degeneration

abstract:
IntroductionLumbar intervertebral disc degeneration (DD) disease is one of the main risk factors for low back pain. The social and economic importance of low back pain is very high: back pain is among the leading causes of absenteeism and the cost of treating back pain exceeds the cost of treatment of many other serious diseases (cancer, in particular); however, therapy does not always provide the desired result. Despite the variability of biological studies of lumbar DD, it is still not fully understood, partially due to the fact that there are only few studies using systematic and integrative approaches. Hence, more integrative omics studies are needed to link all pieces of knowledge together, build a complete picture of biology of lumbar DD and obtain a deeper understanding of the processes underlying this pathology.

Methods and analysisThis disease-oriented biobank to study lumbar disc degeneration will be recruited from two clinical centers. A total of 1100 participants with available lumbar MRI will be enrolled during the three-year period. General information about a patient, medical history, lumbar MRI parameters and biological material (whole blood and plasma) will be collected in the centers at baseline. Then, from those patients, who will undergo a spine surgery during the treatment, disc tissue samples will be gained. Eventually, postoperative clinical data will be collected from operated patients during the follow-up.

Ethics and disseminationThe study will be performed according to the Helsinki Declaration. The study protocol was approved by the Local Ethical Committee of NRITO ([numero]034/20 dated 02 Oct 2020) and by the Local Ethical Committee of Priorov CITO ([numero]1/21 dated 25 Feb 2021). Preliminary and final results will be presented in peer-reviewed journals, at national and international congresses.

Trial registration numberNCT04600544

ARTICLE SUMMARYO_ST_ABSSTRENGTHS AND LIMITATIONS OF THIS STUDYC_ST_ABSO_LITwo-center and multiple-discipline study: the study includes two centers (Moscow in the European and Novosibirsk in the Asian part of Russia), with research teams specializing in following fields: (1) clinical aspects of lumbar disc degeneration disease, (2) biology and genetics of pain, (3) generation of omics data and (4) multi-omics data analysis
C_LIO_LICollection of variable biological material: whole blood, plasma and, for part of the participants, intraoperative material of the lumbar disc (with different DD status) will be available for omics studies
C_LIO_LIObjective diagnosis: lumbar DD status is confirmed by MRI, not self-reported diagnosis
C_LIO_LISample size is limited compared to nationwide biobanks
C_LIO_LIPatients with severe lumbar DD status will be more prevalent in the biobank than these with mild or no lumbar DD compared to the general population
C_LI

category: genetic and genomic medicine


title: Ethical and human subject burdens of trials conducted to evaluate biosimilars

abstract:
Background/AimsWith a policy goal of introducing price competition into the market for biologic drugs after their period of market monopoly is over (called  loss of exclusivity), policymakers created a pathway for companies to make copies of those treatments and termed them  biosimilars. But unlike generic drugs, biosimilar drug copies must be studied in human trials to assure they have the same clinical effect as the original biologic products. The burden that this places on human subject participants, and the opportunity cost on the clinical trial system generally, have not been considered in detail.

MethodsFor all biosimilar drugs in development, approved, or that failed to obtain approval in the US, we abstracted from clinicaltrials.gov registry the number of subjects enrolled at each phase of development.

ResultsWe identified 105 clinical trials for approved or withdrawn biosimilars and another 20 studies that are either planned, ongoing or completed for biosimilars in development. These studies collectively enrolled (or plan to enroll) 38,169 human subjects. Most (28,130) are enrolled in phase 3 studies. The mean number of human subject participants per approval is 1,045, about 25% of the number required for a new drug approval on average.

ConclusionsA consequential number of human subjects are required for the testing of biosimilar drugs prior to approval. The explicit and sole purpose of biosimilars is to induce competition in order to lower prices of biologic drugs after loss of exclusivity. The burden the biosimilar approval trials place on human subjects with no direct clinical benefits but definite risks, and the possibility that they rob subjects from trials that are of more scientific importance, are ones policymakers might consider. Price regulation of biologic drugs after loss of exclusivity could achieve lower prices as well, without the burdens of the current approach.

Funding SourceArnold Ventures (Grant to support Drug Pricing Lab at Memorial Sloan Kettering Cancer Center)

category: health policy


title: Predicting vaccine hesitancy from area-level indicators: A machine learning approach

abstract: Vaccine hesitancy (VH) might represent a serious threat to the next COVID-19 mass immunization campaign. We use machine-learning algorithms to predict communities at a high risk of VH relying on area-level indicators easily available to policymakers. We illustrate our approach on data from child immunization campaigns for seven non-mandatory vaccines carried out in 6408 Italian municipalities in 2016. A battery of machine learning models is compared in terms of area under the Receiver Operating Characteristics (ROC) curve. We find that the Random Forest algorithm best predicts areas with a high risk of VH improving the unpredictable baseline level by 24% in terms of accuracy. Among the area-level indicators, the proportion of waste recycling and the employment rate are found to be the most powerful predictors of high VH. This can support policy makers to target area-level provaccine awareness campaigns.


title: A general computational framework for COVID-19 modelling, with applications to testing varied interventions in education environments

abstract: We construct a spatially-compartmental individual-based model of the spread of Covid-19 in indoor spaces. The model can be used to predict the infection rates in a variety of locations when various non-pharmaceutical interventions (NPIs) are introduced. Tasked by the Welsh Government, we apply the model to secondary schools and Further and Higher Education environments. Specifically, we consider student populations mixing in a classroom and in halls of residence. We focus on assessing the potential efficacy of Lateral Flow Devices (LFDs) when used in broad-based screens for asymptomatic infection or in  test-to-release scenarios in which individuals who have been exposed to infection are released from isolation given a negative result. LFDs are also compared to other NPIs; we find that, although LFD testing can be used to mitigate the spread of Covid-19, it is more effective to invest in personal protective equipment, e.g. masks, and in increasing ventilation quality. In addition, we provide an open-access and user-friendly online applet that simulates the individual-based model, complete with user tutorials to encourage the use of the model to aid educational policy decisions as input infection data evolves (https://bit.ly/CV19_INTER_IBM).


title: A general computational framework for COVID-19 modelling with applications to testing varied interventions in education environments


title: The plasmablast response to SARS-CoV-2 mRNA vaccination is dominated by non-neutralizing antibodies that target both the NTD and the RBD

abstract: In this study we profiled vaccine-induced polyclonal antibodies as well as plasmablast derived mAbs from subjects who received SARS-CoV-2 spike mRNA vaccine. Polyclonal antibody responses in vaccinees were robust and comparable to or exceeded those seen after natural infection. However, that the ratio of binding to neutralizing antibodies after vaccination was greater than that after natural infection and, at the monoclonal level, we found that the majority of vaccine-induced antibodies did not have neutralizing activity. We also found a co-dominance of mAbs targeting the NTD and RBD of SARS-CoV-2 spike and an original antigenic-sin like backboost to seasonal human coronaviruses OC43 and HKU1 spike proteins. Neutralizing activity of NTD mAbs but not RBD mAbs against a clinical viral isolate carrying E484K as well as extensive changes in the NTD was abolished, suggesting that a proportion of vaccine induced RBD binding antibodies may provide substantial protection against viral variants carrying E484K.

category: infectious diseases


title: SARS-COV-2 antibody prevalence in patients on dialysis in the US in January 2021

abstract:
BackgroundTo estimate seroprevalence of SARS-CoV-2 antibodies in the US, the country with the worlds largest absolute numbers of COVID19 cases and deaths, we conducted a cross-sectional assessment from a sample of patients receiving dialysis in January 2021.

MethodsWe tested remainder plasma of 21,424 patients receiving dialysis through the third-largest US dialysis organization, with facilities located nationwide. We used the Siemens spike protein receptor binding domain total antibody assay to estimate crude SARS-CoV-2 seroprevalence, and then estimated seroprevalence for the US dialysis and adult population by standardizing by age, sex and region. We also compared January 2021 seroprevalence and case-detection rates to that from a similar subsample of patients receiving dialysis who had been tested in July 2020.

ResultsPatients in the sample were disproportionately from older age and minority race/ethnic groups. Seroprevalence of SARS-CoV-2 was 18.9% (95% CI: 18.3-19.5%) in the sample, 18.7% (18.1-19.2%) standardized to the US dialysis population, and 21.3% (20.3-22.3%) standardized to the US adult population (range 15.3-20.8% in the Northeast and South respectively). Younger age groups (18-44 years), and persons self-identifying as Hispanic or living in Hispanic neighborhoods, and persons living in the poorest neighborhoods were among the subgroups with the highest seroprevalence (25.9% (24.1-27.8%), 25.1% (23.6-26.4%), 24.8% (23.2-26.5%) respectively). Compared to data from July 2020, we observed diminished variability in seroprevalence by geographic region and urban-rural status. Estimated case detection rate increased from 14% to 23% in July 2020 to January 2021.

ConclusionsA year after the first case of SARS-CoV-2 infection was detected in the US, fewer than one in four adults have evidence of SARS-CoV-2 antibodies. Vaccine roll out to majority minority neighborhoods and poorer neighborhoods will be critical to disrupting the spread of infection.

FundingAscend Clinical Laboratories funded remainder-plasma testing.


title: Single-Arm, Open-Label Phase 2 Trial of Preemptive Methylprednisolone to Avert Progression to Respiratory Failure in High-Risk Patients with COVID-19

abstract:
IntroductionCovid-19 is a triphasic disorder first typified by a viral phase that lasts from the first onset of symptoms until seven days later. This is followed by a second and third phase, initially characterized by the appearance of lung infiltrates, followed in 20% by respiratory failure. The second phase is usually heralded by an elevation of serologic inflammatory markers including CRP, ferritin, IL-6, LDH as well as D-dimers. Approximately 20% proceed to the second phase and are usually then treated with dexamethasone, provided they are oxygen-dependent since these are the only cases that benefit from dexamethasone. If we had objective criteria to predict this 20% that develop severe illness, they could preemptively be treated with steroids. In this exploratory study we investigated the early use of preemptive steroids in the setting of early disease, in high-risk non-oxygen dependent cases.

MethodsEligible patients were those 21 years or older with a diagnosis of Covid-19 and oxygen saturation [≥]91%. For patients to be classified as high-risk, they had to exhibit two or more of the following abnormalities 7-10 days after first symptom: IL-6 [≥] 10 pg/ml, ferritin > 500 ng/ml, D-dimer > 1 mg/L (1,000 ng/ml), CRP > 10 mg/dL (100 mg/L), LDH above normal range lymphopenia (absolute lymphocyte count <1,000 /{micro}L), oxygen saturation between 91-94%, or CT chest with evidence of ground glass infiltrates. Primary endpoint was progression to respiratory failure. CALL score method was used to predict the expected number of cases of respiratory failure. High risk patients received methylprednisolone (MPS) 80 mg IV daily x 5 days starting no earlier than seven days from first onset of symptoms. The primary endpoint was progression to hypoxemic respiratory failure defined as PaO2 <60 mm Hg or oxygen saturation [≤]90%. Secondary endpoints included survival at 28 days from registration, admission to intensive care and live discharge from the hospital. Change in levels of inflammatory markers and length of hospitalization were also assessed.

ResultsIn 76 patients, the expected number with respiratory failure was 30 (39.5%), yet only 4 (5.3%) developed that complication (p=.00001). Survival at 28 days was 98.6%.

Improvement in inflammatory markers correlated with favorable outcome.

ConclusionsOur results are encouraging and suggest that this approach is both effective and safe.


title: Transmission of SARS-CoV-2 by children attending school. Interim report on an observational, longitudinal sampling study of infected children, contacts, and the environment

abstract:
BackgroundAssessing transmission of SARS-CoV-2 by children in schools is of critical importance to inform public health action. We assessed frequency of acquisition of SARS-CoV-2 by contacts of children with COVID-19 in schools and households, as well as the amount of virus shed into the air and onto fomites in both settings.

MethodsCases of COVID-19 in children in London schools were identified via notification. Weekly sampling for 3-4 weeks and PCR testing for SARS-CoV-2 of immediate classroom contacts (the "bubble"), non-bubble school contacts, and household contacts was undertaken supported by genome sequencing, along with surface and air sampling in the school and home environment.

ResultsWithin schools, secondary transmission was not detected in 28 individual bubble contacts, representing 10 distinct bubble classes. Across 8 non-bubble classes, 3/62 pupils tested positive- all three were asymptomatic and tested positive in one setting on the same day, unrelated to the original index case. In contrast, the secondary attack rate in naive household contacts was 14.3% (5/35) rising to 19.1% (9/47) when considering all household contacts. Environmental contamination with SARS-CoV-2 was rare in schools, regardless of school type; fomite SARS-CoV-2 RNA was identified in 4/189 (2.1%) samples in bubble classrooms, 2/127 (1.6%) samples in non-bubble classrooms, and 5/130 (3.8%) samples in washrooms. This contrasted with fomites in households, where SARS-CoV-2 RNA was identified in 60/248 (24.2%) bedroom samples, 66/241 (27.4%) communal room samples, and 21/188 (11.2%) bathroom samples. Air sampling identified SARS-CoV-2 RNA in just 1/68 (1.5%) of school air samples, compared with 21/85 (24.7%) of air samples taken in homes.

SummaryThe low levels of environmental contamination in schools are consistent with low transmission frequency and adequate levels of cleaning and ventilation in schools during the period of study. Secondary transmission in schools was rare. The high frequency of secondary transmission in households associated with evident viral shedding throughout the home suggests a need to improve advice to households with infection in children in order to prevent onward community spread by sibling and adult contacts. The data highlight that transmission from children is very likely to occur when precautions are reduced.


title: Transmission of SARS-CoV-2 by children in schools and households: a prospective cohort and environmental sampling study in London


title: Analysis of antibody data using Finite Mixture Models based on Scale Mixtures of Skew-Normal distributions

abstract: Finite mixture models have been widely used in antibody (or serological) data analysis in order to help classifying individuals into either antibody-positive or antibody-negative. The most popular models are the so-called Gaussian mixture models which assume a Normal distribution for each component of a mixture. In this work, we propose the use of finite mixture models based on a flexible class of scale mixtures of Skew-Normal distributions for serological data analysis. These distributions are sufficiently flexible to describe right and left asymmetry often observed in the distributions associated with hypothetical antibody-negative and antibody-positive individuals, respectively. We illustrate the advantage of these alternative mixture models with a data set of 406 individuals in which antibodies against six different human herpesviruses were measured in the context of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

category: epidemiology


title: Vaccine effectiveness after 1st and 2nd dose of the BNT162b2 mRNA Covid-19 Vaccine in long-term care facility residents and healthcare workers - a Danish cohort study

abstract:
BackgroundAt the end of 2020, Denmark launched an immunization program against SARS-CoV-2. The Danish health authorities prioritized persons currently living in long-term care facilities (LTCF residents) and frontline healthcare workers (HCW) as the first receivers of vaccination. Here we present preliminary population based vaccine effectiveness (VE) estimates in these two target groups.

MethodsThe study was designed as a retrospective registry- and population-based observational cohort study including all LTCF residents and all HWC. The outcome was a polymerase chain reaction confirmed SARS-CoV-2, and VE was estimated for different periods following first and second dose. We used Poisson and Cox regressions to estimate respectively crude and calendar time-adjusted VE for the BNT162b2 mRNA Covid-19 Vaccine from Pfizer/BioNTech with 95% confidence intervals (CI) for vaccinated versus unvaccinated.

ResultsA total of 39,040 LTCF residents (median age at first dose; 84 years, Interquartile range (IQR): 77-90) and 331,039 HCW (median age at first dose; 47 years, IQR: 36-57) were included. Among LTCF residents, 95.2% and 86.0% received first and second dose from 27 December 2020 until 18 February 2021, for HWC the proportion was 27.8% and 24.4%. During a median follow-up of 53 days, there were 488 and 5,663 confirmed SARS-CoV-2 cases in the unvaccinated groups, whereas there were 57 and 52 in LTCF residents and HCW within the first 7 days after the second dose and 27 and 10 cases beyond seven days of second dose. No protective effect was observed for LTCF residents after first dose. In HCW, VE was 17% (95% CI; 4-28) in the > 14 days after first dose (before second dose). Furthermore, the VE in LTCF residents at day 0-7 of second dose was 52% (95% CI; 27-69) and 46% (95% CI; 28-59) in HCW. Beyond seven days of second dose, VE increased to 64% (95% CI; 14-84) and 90% (95% CI; 82-95) in the two groups, respectively.

ConclusionThe results were promising regarding the VE both within and beyond seven days of second vaccination with the BNT162b2 mRNA Covid-19 Vaccine currently used in many countries to help mitigate the global SARS-CoV-2 pandemic.

Impact of the researchSo far, observational studies of the real-word effectiveness of the mRNA Vaccine BNT162b2 has been limited to the period after the administration of the first dose. This is the first report to date to present vaccine effectiveness (VE) estimates after the second BNT162b2 mRNA Covid-19 Vaccine. We estimated a VE of 52% and 46% in LTCF residents and HCW within seven days, which increased to 64% and 90% in the two groups respectively beyond seven days of immunization. These findings supports maintaining a two-dose schedule of the BNT162b2 mRNA Covid-19 Vaccine.


title: Beliefs about Mask Efficacy and the Effect of Social Norms on Mask Wearing Intentions for COVID-19 Risk Reduction

abstract: In the absence of widespread vaccination for COVID-19, governments and public health officials have advocated for the public to wear masks during the pandemic. The decision to wear a mask in public is likely affected by both beliefs about its efficacy and the prevalence of the behavior. Greater mask use in the community may encourage others to follow this norm, but it also creates an incentive for individuals to free ride on the protection afforded to them by others. We report the results of two vignette-based experiments conducted in the United States and Italy to examine the causal relationship between beliefs, social norms, and reported intentions to engage in mask promoting behavior. We find that providing factual information about how masks protect others increases the likelihood that someone would wear a mask or encourage others to do so in the United States, but not in Italy. There is no effect of providing information about how masks protect the wearer in either country. Additionally, greater mask use increases intentions to wear a mask and encourage someone else to wear theirs properly in both the United States and Italy. Thus, community mask use may be self-reinforcing.


title: Demonstrate, observe, assist perform (DOAP) versus structured educational video (SEV) in imparting standard skill in male urinary bladder catheterisation

abstract:
IntroductionConventional teaching and learning methods have been seen to fail to assure achievement of competencies in male bladder catherization in the Indian Medical Graduate (IMG) with wide variation noted in competencies. This could be remedied by introduction of Structured training methods.

Aims and ObjectiveThe study aimed to investigate DOAP method of training in a Skill Lab against training through a Structured Educational Video (SEV) with the objective of comparing their efficacy in training Final MBBS Students in the psychomotor skill of performing male bladder catheterisation.

Material & MethodsFinal MBBS students fulfilling selection criteria were randomly allocated into two comparable groups. One group underwent Skill lab training using DOAP method while the other group underwent training using a SEV by the same instructor. CRRI interns, regularly performing MBC at work by virtue of conventional training, with 6-8 months experience formed a control group. All participants underwent assessment of skill in MBC by skill lab OSCE evaluation, by assessors who were blinded to the participants method of training. Data was recorded and analysed using standard statistical software. Trial evaluation from the trial groups was obtained using Survey monkey tool.

ObservationThere was no statistically significant difference in the ability of DOAP group or SEV group in being able to safely perform MBC though a higher level of confidence was expressed with their training by DOAP group. Both trial groups statistically outperformed the control group.

ConclusionStructured training assures competence. Video-assisted Training produces comparable results though DOAP method is preferred by students. A combination of the techniques may facilitate optimal training.

category: medical education


title: COVID-19 is associated with multiple sclerosis exacerbations that are prevented by disease modifying therapies

abstract:
BackgroundInfections can trigger exacerbations of multiple sclerosis (MS). The effects of the coronavirus disease 2019 (COVID-19) on MS are not known. The aim of this study was to understand the impact of COVID-19 on new and pre-existing symptoms of MS.

MethodsThe COVID-19 and MS study is an ongoing community-based, prospective cohort study conducted as part of the United Kingdom MS Register. People with MS and COVID-19 were invited by email to complete a questionnaire about their MS symptoms during the infection. An MS exacerbation was defined as developing new MS symptoms and/or worsening of pre-existing MS symptoms.

ResultsFifty-seven percent (230/404) of participants had an MS exacerbation during their infection; 82 developed new MS symptoms, 207 experienced worsened pre-existing MS symptoms, and 59 reported both. Disease modifying therapies (DMTs) reduced the likelihood of developing new MS symptoms during the infection (OR 0.556, 95%CI 0.316-0.978). Participants with a higher pre-COVID-19 webEDSS (web-based Expanded Disability Status Scale) score (OR 1.251, 95%CI 1.060-1.478) and longer MS duration (OR 1.042, 95%CI 1.009-1.076) were more likely to experience worsening of their pre-existing MS symptoms during the infection.

ConclusionCOVID-19 infection was associated with exacerbation of MS. DMTs reduced the chance of developing new MS symptoms during the infection.

category: neurology


title: Incidence of SARS-CoV-2 infection according to baseline antibody status in staff and residents of 100 Long Term Care Facilities (VIVALDI study)

abstract:
BackgroundSARS-CoV-2 infection represents a major challenge for Long Term Care Facilities (LTCFs) and many residents and staff are now sero-positive following persistent outbreaks. We investigated the relationship between the presence of SARS-CoV-2 specific antibodies and subsequent infection in this population.

MethodsProspective cohort study of infection in staff and residents in 100 LTCFs in England between October 2020 and February 2021. Blood samples were collected at baseline (June 2020), 2 and 4 months and tested for IgG antibodies to nucleocapsid and spike protein. PCR testing for SARS-CoV-2 was undertaken weekly in staff and monthly in residents. The primary analysis estimated the relative hazard of a PCR-positive test by baseline antibody status, from Cox regression adjusted for age and gender, and stratified by LTCF.

FindingsStudy inclusion criteria were met by 682 residents and 1429 staff. Baseline IgG antibodies to nucleocapsid were detected in 226 residents (33%) and 408 staff (29%). A total of 93 antibody-negative residents had a PCR-positive test (0.054 per month at risk) compared to 4 antibody-positive residents (0.007 per month at risk). There were 111 PCR-positive tests in antibody-negative staff (0.042 per month at risk) compared to 10 in antibody-positive staff (0.009 per month at risk). The adjusted hazard ratios for reinfection in staff and residents with a baseline positive versus negative antibody test were 0.13 (95% CI 0.05-0.40) and 0.39 ((95% CI: 0.19-0.77) respectively. Of 12 reinfected participants with data on symptoms, 11 were symptomatic. Antibody titres to spike and nucleocapsid were comparable in PCR-positive and PCR-negative cases.

InterpretationThe presence of IgG antibodies to nucleocapsid was associated with substantially reduced risk of reinfection in staff and residents for up to 10 months after primary infection.

FundingUK Government Department of Health and Social Care

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe performed a systematic search of MEDLINE (Ovid) and MedRxiv on 18 January 2021 for studies in LTCFs that described the risk of infection in individuals who were seropositive for SARS-CoV-2 compared to individuals who were seronegative. Search terms were deliberately broad to improve capture of relevant literature and included "SARS-CoV-2"OR "COVID-19" OR "coronavirus" AND "care home" OR "nursing home" OR "long term care facility" with no date or language restrictions. We did not identify any publications that focussed on risk of reinfection in seropositive individuals, but subsequent to our search one study has been published using data from two LTCFs in London, UK. This study reported a 96% reduction in the odds of reinfection in individuals who were seropositive compared to those who were seronegative based on 4-month follow-up in 161 participants. We found 10 studies that performed seroprevalence surveys in either staff or staff and residents in LTCFs in 8 cohorts. Five of these were carried out in response to SARS-CoV-2 outbreaks within the care homes, either as part of the subsequent investigation or as post-infection surveillance. The largest of these, which enrolled both staff and residents, was performed in 6 LTCFs and performed longitudinal antibody testing.

Added value of this studyWe undertook a cohort study in staff and residents from 100 LTCFs in England to investigate whether individuals with evidence of prior SARS-CoV-2 infection could be infected twice. Staff and residents were offered up to three rounds of antibody testing and antibody results were linked to PCR test results which were obtained weekly from staff and monthly from residents through the national SARS-CoV-2 testing programme. This study, which was conducted in >2000 staff and residents, suggests that antibodies provide high levels of protection against reinfection for up to 10 months. Almost all cases of reinfection were symptomatic, but no cases required hospital treatment. Amongst those with detectable baseline antibodies, quantitative antibody titres against spike protein and nucleocapsid were comparable between cases of reinfection and those who did not become reinfected.

Implications of all available evidenceDespite high background rates of infection in LTCFs, the overall risk of reinfection was low in this population. This is broadly consistent with findings from large cohort studies of hospital staff, but, importantly, extends the evidence of substantial protection to frail elderly, who are vulnerable to severe outcomes of SARS-CoV-2 due to age-related changes in immunity (immune-senescence) and high levels of comorbidity. The low risk of reinfection in our study suggests identification of immune correlates of protection in this population will require pooling of data across multiple cohorts.

As vaccination coverage in residents approaches 100% in England, it will be important to understand whether vaccination and natural infection provide comparable levels of protection against infection. Such insights will inform future policy decisions regarding re-vaccination schedules in LTCF, and the longer-term need for non-pharmaceutical interventions to prevent SARS-CoV-2 transmission, such as asymptomatic testing and visitor restrictions.

category: geriatric medicine


title: Detection of autoimmune antibodies in severe but not in moderate or asymptomatic COVID-19 patients

abstract: The heterogeneity of COVID-19 lies within its diverse symptoms and severity, ranging from mild to lethal. Acute respiratory distress syndrome (ARDS) has been shown to be the leading cause of mortality in COVID-19 patients, characterized by a hyper cytokine storm. Autoimmunity is proposed to occur as a result of COVID-19, given the high similarity of the immune responses observed in COVID-19 and autoimmune diseases. Here, we investigate the level of autoimmune antibodies in COVID-19 patients with different severities. Initial screening for antinuclear antibodies (ANA) IgG revealed that 1.6% (2/126) and 4% (5/126) of ICU COVID-19 cases developed strong and moderate ANA levels, respectively. However, all the non-ICU cases (n=273) were ANA negative. The high ANA level was confirmed by immunofluorescence (IFA) and large-scale autoantibody screening by phage immunoprecipitation-sequencing (PhIP-Seq). Indeed, the majority of the samples showed "speckled" ANA pattern by microscopy, and we demonstrate that samples of ICU patients with strong and moderate ANA levels contain autoantibody specificities that predominantly targeted proteins involved in intracellular signal transduction, metabolism, apoptotic processes, and cell death; further denoting reactivity to nuclear and cytoplasmic antigens. In conclusion, our results further support the notion of routine screening for autoimmune responses in COVID-19 patients, which might help improve disease prognosis and patient management. Further, results provide compelling evidence that ANA-positive individuals should be excluded from being donors for convalescent plasma therapy in the context of Covid-19.


title: Immune response to SARS-CoV-2 variants of concern in vaccinated individuals

abstract: The SARS-CoV-2 pandemic virus is consistently evolving with mutations within the receptor binding domain (RBD)1 being of particular concern2-4. To date, there is little research into protection offered following vaccination or infection against RBD mutants in emerging variants of concern (UK3, South African5, Mink6 and Southern California7). To investigate this, serum and saliva samples were obtained from groups of vaccinated (Pfizer BNT-162b28), infected and uninfected individuals. Antibody responses among groups, including salivary antibody response and antibody binding to RBD mutant strains were examined. The neutralization capacity of the antibody response against a patient-isolated South African variant was tested by viral neutralization tests and further verified by an ACE2 competition assay. We found that humoral responses in vaccinated individuals showed a robust response after the second dose. Interestingly, IgG antibodies were detected in large titers in the saliva of vaccinated subjects. Antibody responses showed considerable differences in binding to RBD mutants in emerging variants of concern. A substantial reduction in RBD binding and neutralization was detected for the South African variant. Taken together our data reinforces the importance of administering the second dose of Pfizer BNT-162b2 to acquire high levels of neutralizing antibodies. High antibody titers in saliva suggest that vaccinated individuals may have reduced transmission potential. Substantially reduced neutralization for the South African variant highlights importance of surveillance strategies to detect new variants and targeting these in future vaccines.


title: Agreement between commercially available ELISA and in-house Luminex SARS-CoV-2 antibody immunoassays

abstract: AO_SCPLOWBSTRACTC_SCPLOWSerological diagnostic of the severe respiratory distress syndrome coronavirus 2 (SARS-CoV-2) is a valuable tool for the determination of immunity and surveillance of exposure to the virus. In the context of an ongoing pandemic, it is essential to externally validate widely used tests to assure correct diagnostics and epidemiological estimations. We evaluated the performance of the COVID-19 ELISA IgG and IgM/A (Vircell, S.L.) against a highly specific and sensitive in-house Luminex immunoassay in a set of samples from pregnant women and cord blood. The agreement between both assays was moderate to high for IgG but low for IgM/A. Considering seropositivity by either IgG and/or IgM/A, the technical performance of the ELISA was highly imbalanced, with 96% sensitivity at the expense of 22% specificity. As for the clinical performance, the negative predictive value reached 87% while the positive predictive value was 51%. Our results stress the need for highly specific and sensitive assays and external validation of diagnostic tests with different sets of samples to avoid the clinical, epidemiological and personal disturbances derived from serological misdiagnosis.


title: High levels of common cold coronavirus antibodies in convalescent plasma are associated with improved survival in COVID-19 patients

abstract:
BackgroundCOVID-19 Convalescent plasma (CCP) is safe and effective, particularly if given at an early stage of the disease. Our study aimed to identify an association between survival and specific antibodies found in CCP.

Patients and MethodsPatients [≥]18 years of age who were hospitalized with moderate to severe COVID-19 infection and received CCP at the MD Anderson Cancer Center between 4/30/2020 and 8/20/2020 were included in the study. We quantified the levels of anti-SARS-CoV-2 antibodies, as well as antibodies against antigens of other coronavirus strains, in the CCP units and compared antibody levels with patient outcomes. For each antibody, a Bayesian exponential survival time regression model including prognostic variables was fit, and the posterior probability of a beneficial effect (PBE) of higher antibody level on survival time was computed.

ResultsCCP was administered to 44 cancer patients. The median age was 60 years (range 37-84) and 19 (43%) were female. Twelve patients (27%) died of COVID-19-related complications. Higher levels of two non-SARS-CoV-2-specific antibodies, anti-HCoV-OC43 spike IgG and anti-HCoV-HKU1 spike IgG, had PBE = 1.00, and 4 SARS-CoV-2-specific antibodies had PBEs between 0.90 and 0.95. Other factors associated with better survival were shorter time to CCP administration, younger age, and female sex.

ConclusionsCommon cold coronavirus spike IgG antibodies anti-HCoV-OC43 and anti-HCoV-HKU1 may target a common domain for SARS-CoV-2 and other coronaviruses. They provide a promising therapeutic target for monoclonal antibody production.


title: Trends over time in the risk of adverse outcomes among patients with SARS-CoV-2 infection

abstract:
ObjectivesWe aimed to describe trends in the incidence of adverse outcomes among patients who tested positive for SARS-CoV-2 between February and September 2020 within a national healthcare system.

SettingUS Veterans Affairs national healthcare system.

ParticipantsEnrollees in the VA healthcare system who tested positive for SARS-CoV-2 between 2/28/2020 and 9/30/2020 (n=55,952).

OutcomesDeath, hospitalization, intensive care unit (ICU) admission and mechanical ventilation within 30 days of testing positive.The incidence of these outcomes was examined among patients infected each month and trends were evaluated using an interrupted time-series analysis.

ResultsBetween February and July 2020, during the first wave of the US pandemic, there were marked downward trends in the 30-day incidence of hospitalization (44.2% to 15.8%), ICU admission (20.3% to 5.3%), mechanical ventilation (12.7% to 2.2%), and death (12.5% to 4.4%), with subsequent stabilization between July and September 2020. These trends persisted after adjustment for sociodemographic characteristics, comorbid conditions, and documented symptoms and after additional adjustment for laboratory test results among hospitalized patients, including among subgroups admitted to the ICU and treated with mechanical ventilation. Among hospitalized patients, use of hydroxychloroquine (56.5% to 0%), azithromycin (48.3% to 16.6%) vasopressors (20.6% to 8.7%), and dialysis (11.6% to 3.8%) decreased while use of dexamethasone (3.4% to 53.1%), other corticosteroids (4.9% to 29.0%) and remdesivir (1.7% to 45.4%) increased from February to September.

ConclusionsAmong patients who tested positive for SARS-CoV-2 in a large national US healthcare system, risk for a range of adverse outcomes decreased markedly between February and July, with subsequent stabilization from July to September. These trends were not explained by changes in measured baseline patient characteristics.