title: THE AIRBORNE CONTAGIOUSNESS OF RESPIRATORY VIRUSES: A COMPARATIVE ANALYSIS AND IMPLICATIONS FOR MITIGATION

abstract:
BackgroundThe infectious emission rate is a critical input parameter for airborne contagion models, but data are limited due to reliance on estimates from chance superspreading events. A predictive estimation approach for the quanta emission rate (ERq) was recently proposed for SARS-CoV-2 using the droplet volume concentration of various expiratory activities. This study assesses the strength of the approach and uses novel predictive estimates of ERq to compare the contagiousness of respiratory pathogens.

MethodsWe applied the predictive approach to SARS-CoV-1, SARS-CoV-2, MERS, measles virus, adenovirus, rhinovirus, coxsackievirus, seasonal influenza virus and Mycobacterium tuberculosis (TB) and compared ERq estimates to values reported in literature. We calculated infection risk in a prototypical classroom and barracks to assess the relative ability of ventilation to mitigate airborne transmission.

ResultsOur median standing and speaking ERq estimate for SARS-CoV-2 (2.6 quanta hour (h)-1) is similar to active, untreated TB (3.1 h-1), higher than seasonal influenza (0.17 quanta h-1), and lower than measles virus (15 quanta h-1). We calculated event reproduction numbers above 1 for SARS-CoV-2, measles virus, and untreated TB in both the classroom and barracks for an activity level of standing and speaking at low, medium and high ventilation rates of 2.3, 6.6 and 14 liters per second per person, respectively.

ConclusionsOur predictive ERq estimates are consistent with the range of values reported over decades of research. In congregate settings, current ventilation standards are unlikely to control the spread of viruses with upper quartile ERq values above 10 quanta h-1, such as SARS-CoV-2, indicating the need for additional control measures.


title: Multidimensional analysis of immune response identified biomarkers of recent Mycobacterium tuberculosis infection

abstract:
The risk of tuberculosis (TB) disease is higher in individuals with recent Mycobacterium tuberculosis (M.tb) infection compared to individuals with more remote, established infection. We aimed to define blood-based biomarkers to distinguish between recent and remote infection, which would allow targeting of recently infected individuals for preventive TB treatment. We hypothesized that integration of multiple immune measurements would outperform the diagnostic performance of a single biomarker. Analysis was performed on different components of the immune system, including adaptive and innate responses to my-cobacteria, measured on recently and remotely M.tb infected adolescents. The datasets were standardized using variance stabilizing (vast) scaling and missing values were imputed using a multiple factor analysis-based approach. For data integration, we compared the performance of a Multiple Tuning Parameter Elastic Net (MTP-EN) to a standard EN model, which was built to the single datasets. Biomarkers with non-zero coefficients from the optimal single data EN models were then isolated to build logistic regression models. A decision tree and random forest model were used for statistical validation. We found no difference in the predictive performances of the optimal MTP-EN model and the EN model [average area under the receiver operating curve (AUROC)=0.93]. EN models built to the integrated dataset and the adaptive dataset yielded identically high AUROC values (average AUROC=0.91), while the innate data EN model performed poorly (average AUROC=0.62). Results also indicated that integration of adaptive and innate biomarkers did not outperform the adaptive biomarkers alone (Likelihood Ratio Test{chi} 2=6.09, p=0.808). From a total of 193 variables, the level of HLA-DR on ESAT6/CFP10-specific Th1 cytokine-expressing CD4 cells was the strongest biomarker for recent M.tb infection. The discriminatory ability of this variable was confirmed in both tree-based models.

A single biomarker measuring M.tb-specific T cell activation yielded excellent diagnostic potential to distinguish between recent and remote M.tb infection.

category: infectious diseases


title: Evaluation of spike protein antigens for SARS-CoV-2 serology

abstract:
BackgroundSpike protein domains are being used in various serology-based assays to detect prior exposure to SARS-CoV-2 virus. However, there has been limited comparison of human antibody titers against various spike protein antigens among COVID-19 infected patients.

MethodsWe compared four spike proteins (RBD, S1, S2 and a stabilized spike trimer (ST)) representing commonly used antigens for their reactivity to human IgG antibodies using indirect ELISA in serum from COVID-19 patients and pre-2020 samples. ST ELISA was also compared against the EUROIMMUN IgG ELISA test. Further, we estimated time appropriate IgG and IgA seropositivity rates in COVID-19 patients using a panel of sera samples collected longitudinally from the day ofonset of symptoms (DOS).

ResultsAmong the four spike antigens tested, the ST demonstrated the highest sensitivity (86.2%; 95% CI: 77.8-91.7%), while all four antigens showed high specificity to COVID-19 sera (94.7-96.8%). 13.8% (13/94) of the samples did not show seroconversion in any of the four antigen-based assays. In a double-blinded head-to-head comparison, ST based IgG ELISA displayed a better sensitivity (87.5%, 95%CI: 76.4-93.8%) than the EUROIMMUN IgG ELISA (67.9%, 95% CI: 54.8-78.6%). Further, in ST-based assays, we found 48% and 50% seroconversion in the first six days (from DOS) for IgG and IgA antibodies, respectively, which increased to 84% (IgG) and 85% (IgA) for samples collected [≥]22 days DOS.

ConclusionsComparison of spike antigens demonstrates that spike trimer protein is a superior option as an ELISA antigen for COVID-19 serology.

HighlightsO_LISpike trimer displays the highest antibody titer in SARS-CoV-2 infections among spike protein antigens.
C_LIO_LISpike trimer IgG ELISA displays a sensitivity of 50% within six days and 86.2% after 14 days from onset of symptoms.
C_LIO_LIIgA and IgG responses to spike trimer antigen were comparable and concomitant in time after infection.
C_LIO_LI16% (IgG) and 15% (IgA) of COVID-19 RT-PCR positive patients did not seroconvert even after 21 days from onset of symptoms.
C_LI


title: SARS-CoV-2 infection and transmission in school settings during the second wave in Berlin, Germany: a cross-sectional study

abstract:
BackgroundSchool attendance during the SARS-CoV-2 pandemic is intensely debated. Modelling studies suggest that school closures contribute to community transmission reduction. However, data among school-attending students and staff are scarce. In November 2020, we examined SARS-CoV-2 infections and seroreactivity in 24 randomly selected school classes and connected households in Berlin, Germany.

MethodsStudents and school staff were examined, oro-nasopharyngeal swabs and blood samples collected, and SARS-CoV-2 infection and IgG antibodies detected by RT-PCR and ELISA. Household members performed self-swabs. Individual and institutional infection prevention and control measures were assessed. Classes with SARS-CoV-2 infection and connected household members were re-tested after one week.

Findings1119 participants were examined, including 177 primary and 175 secondary school students, 142 staff, and 625 household members. Participants reported mainly cold symptoms (19{middle dot}4%). SARS-CoV-2 infection occurred in eight of 24 classes affecting each 1-2 individuals. Infection prevalence was 2{middle dot}7% (95%CI; 1{middle dot}2-5{middle dot}0%; 9/338), 1{middle dot}4% (0{middle dot}2-5{middle dot}1%; 2/140), and 2{middle dot}3% (1{middle dot}3-3{middle dot}8%; 14/611) among students, staff and household members, respectively, including quarantined persons. Six of nine infected students were asymptomatic. Prevalence increased with inconsistent facemask use in school, way to school on foot, and case-contacts outside school. IgG antibodies were detected in 2{middle dot}0% (0{middle dot}8-4{middle dot}1%; 7/347), 1{middle dot}4% (0{middle dot}2-5{middle dot}0%; 2/141) and 1{middle dot}4% (0{middle dot}6-2{middle dot}7%; 8/576), respectively. For three of nine households with infection(s) detected at cross-sectional assessment, origin in school seemed possible. After one week, no school-related, secondary infections appeared in affected classes; the attack rate in connected households was 1{middle dot}1%.

InterpretationThese data suggest that school attendance under preventive measures is feasible, provided their rigorous implementation. In balancing threats and benefits of open versus closed schools during the pandemic, parents and society need to consider possible spill-overs into their households. Deeper insight is needed into the infection risks due to being a schoolchild as compared to attending school.

FundingSenate of Berlin.


title: The E484K mutation in the SARS-CoV-2 spike protein reduces but does not abolish neutralizing activity of human convalescent and post-vaccination sera.

abstract: One year in the coronavirus disease 2019 (COVID-19) pandemic, the first vaccines are being rolled out under emergency use authorizations. It is of great concern that newly emerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can escape antibody-mediated protection induced by previous infection or vaccination through mutations in the spike protein. The glutamate (E) to Lysine (K) substitution at position 484 (E484K) in the receptor binding domain (RBD) of the spike protein is present in the rapidly spreading variants of concern belonging to the B.1.351 and P.1 lineages. We performed in vitro microneutralization assays with both the USA-WA1/2020 virus and a recombinant (r)SARS-CoV-2 virus that is identical to USA-WA1/2020 except for the E484K mutation introduced in the spike RBD. We selected 34 sera from study participants based on their SARS-CoV-2 spike ELISA antibody titer (negative [N=4] versus weak [N=8], moderate [N=11] or strong positive [N=11]). In addition, we included sera from five individuals who received two doses of the Pfizer SARS-CoV-2 vaccine BNT162b2. Serum neutralization efficiency was lower against the E484K rSARS-CoV-2 (vaccination samples: 3.4 fold; convalescent low IgG: 2.4 fold, moderate IgG: 4.2 fold and high IgG: 2.6 fold) compared to USA-WA1/2020. For some of the convalescent donor sera with low or moderate IgG against the SARS-CoV-2 spike, the drop in neutralization efficiency resulted in neutralization ID50 values similar to negative control samples, with low or even absence of neutralization of the E484K rSARS-CoV-2. However, human sera with high neutralization titers against the USA-WA1/2020 strain were still able to neutralize the E484K rSARS-CoV-2. Therefore, it is important to aim for the highest titers possible induced by vaccination to enhance protection against newly emerging SARS-CoV-2 variants. Two vaccine doses may be needed for induction of high antibody titers against SARS-CoV-2. Postponing the second vaccination is suggested by some public health authorities in order to provide more individuals with a primer vaccination. Our data suggests that this may leave vaccinees less protected against newly emerging variants.


title: Covid-19 positive test cycle threshold trends predict covid-19 mortality in Rhode Island

abstract: The cycle thresholds (Cts) at which reverse transcriptase polymerase chain reaction (rtPCR) tests for covid-19 become positive are intimately associated with both viral load, and covid-19 infectiousness (i.e., ability to culture live virus). Clinical data indicate lower Cts--and hence larger viral loads--independently predict greater covid-19 mortality when patients are hospitalized for symptomatic covid-19 pneumonia. We merged public covid-19 mortality data from the Rhode Island Department of Health with a de-identified dataset of n=5036 positive rtPCR test Cts from the Rhode Island Department of Health State Laboratory to explore the potential relationship between positive covid-19 test Ct distribution trends, and covid-19 mortality in the state of Rhode Island, from March through early to mid-June, 2020. Mean daily covid-19 positive test Ct data were compiled, and 7-day rolling average covid-19 mortality was offset by 21-days, given the lag between infection and death. We divided the Ct data into three strata, >32, 28-32, and <28, which were operationally defined as "not infectious," "maybe infectious," and "infectious," respectively. Between late March and June, mean daily Ct values rose linearly (R-squared=0.789) so that by early June, as the covid-19 pandemic ebbed in severity, all means reached the noninfectious (Ct >32) range. Most notably, this May-June trend for Cts was accompanied by a marked, steady decline in Rhode Islands daily covid-19 mortality. Our results suggest that monitoring, and public reporting of mean population covid-19 test Cts over time is warranted to gauge the vacillations of covid-19 outbreak severity, including covid-19 mortality trends.


title: SARS-CoV-2 seropositivity and subsequent infection risk in healthy young adults: a prospective cohort study

abstract:
BackgroundThe risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) subsequent infection among seropositive young adults was studied prospectively.

MethodsThe study population comprised 3,249 predominantly male, 18-20-year-old Marine recruits. Upon arrival at a Marine-supervised two-week quarantine, participants were assessed for baseline SARS-CoV-2 IgG seropositivity, defined as a 1:150 dilution or greater on receptor binding domain and full-length spike protein enzyme-linked immunosorbent (ELISA) assays. SARS-CoV-2 infection was assessed by PCR at initiation, middle and end of the quarantine. After appropriate exclusions, including participants with a positive PCR during quarantine, we performed three biweekly PCR tests in both seropositive and in seronegative groups once recruits left quarantine and entered basic training and baseline neutralizing antibody titers on all subsequently infected seropositive and selected seropositive uninfected participants.

FindingsAmong 189 seropositive participants, 19 (10.1%) had at least one positive PCR test for SARS-CoV-2 during the six-week follow-up (1.1 cases per person-year). In contrast, 1,079 (48.0%) of the 2,247 seronegative participants tested positive (6.2 cases per person-year). The incidence rate ratio was 0.18 (95% CI 0.11-0.28, p<0.00001). Among seropositive recruits, infection was associated with lower baseline full-length spike protein IgG titers (p<0.0001). Compared with seronegative recruits, seropositive recruits had about 10-fold lower viral loads (ORF1ab gene, p<0.005), and trended towards shorter duration of PCR positivity (p=0.18) and more frequent asymptomatic infections (p=0.13). Among seropositive participants, baseline neutralizing titers were detected in 45 of 54 (83.3%) uninfected and in 6 of 19 (31.6%) infected participants during the 6 weeks of observation (ID50 difference p<.0001).

InterpretationSeropositive young adults had about one-fifth the risk of subsequent infection compared with seronegative individuals. Although antibodies induced by initial infection are largely protective, they do not guarantee effective SARS-CoV-2 neutralization activity or immunity against subsequent infection. These findings may be relevant for optimization of mass vaccination strategies.

FundingDefense Health Agency and Defense Advanced Research Projects Agency


title: Expression of deubiquitinases in human gingiva and cultured human gingival fibroblasts

abstract:
BackgroundAlthough deubiquitinating enzymes (DUBs) such as CYLD, A20 and OTULIN are expressed in multiple tissues and thought to be linked with inflammatory diseases, their expression in periodontal tissues remains to be determined. This research was designed to assess the expression of CYLD, A20 and OTULIN in human gingiva, and to evaluate the regulation of these DUBs in human gingival fibroblasts (HGFs) upon different stimuli.

MethodsImmunohistochemistry assay was conducted to determine the expression of CYLD, A20 and OTULIN in human gingiva. Immunofluorescence assay was employed to observe the protein expression of CYLD, A20 and OTULIN in HGFs. RT-PCR and western blots were carried out to assess gene and protein expression changes of these DUBs in HGFs upon LPS or TNF-.

ResultsCYLD, A20 and OTULIN were found to be expressed in human gingiva and HGFs. Further, the expression of CYLD, A20 and OTULIN in HGFs exhibited distinct regulation by different stimuli.

ConclusionsOur findings suggest that CYLD, A20 and OTULIN might play a role in the progression of periodontitis.

category: dentistry and oral medicine


title: RNA sequencing of a large number of psoriatic patients identifies 131 novel miRNAs and 11 miRNAs associated with disease severity

abstract:
BackgroundMicroRNAs are small regulatory molecules that are dysregulated in psoriasis. Despite previous efforts, much is unknown about the regulatory mechanisms of psoriasis genetics and their contributions to disease development and activity.

ObjectivesTo globally characterize the miRNAome of psoriatic skin in a large sample of psoriatic cases and controls for increased understanding of psoriasis pathophysiology.

MethodsSkin biopsies from psoriatic cases (n=75) and non-psoriatic controls (n=57) were RNA sequenced. Count data was meta-analyzed with a previously published dataset (cases, n=24, controls, n=20), increasing the number of psoriatic cases four-fold from previously published studies. Differential expression analyses were performed comparing lesional psoriatic (PP), non-lesional psoriatic (PN) and control (NN) skin. Further, functional enrichment and cell specific analyses were performed.

ResultsWe identified 439 significantly differentially expressed miRNAs (DEMs), of which 131 were novel and 11 were related to disease severity. Meta-analyses identified 20 DEMs between PN and NN, suggesting an inherent change in all psoriatic skin. By integrating the miRNA transcriptome with mRNA target interactions, we identified several functionally enriched terms, including  thyroid hormone signaling,  insulin resistance and various infectious diseases. Cell specific expression analyses revealed that the upregulated DEMs were enriched in epithelial and immune cells.

ConclusionsWe have provided the most comprehensive overview of the miRNome in psoriatic skin to date and identified a miRNA signature related to psoriasis severity. Our results may represent molecular links between psoriasis and related comorbidities and have outlined potential directions for future functional studies to identify biomarkers and treatment targets.

category: dermatology


title: Machine learning approaches to calibrate individual-based infectious disease models

abstract: Individual-based models have become important tools in the global battle against infectious diseases, yet model complexity can make calibration to biological and epidemiological data challenging. We propose a using a Bayesian optimization framework employing Gaussian process or machine learning emulator functions to calibrate a complex malaria transmission simulator. We demonstrate our approach by optimizing over a high-dimensional parameter space with respect to a portfolio of multiple fitting objectives built from datasets capturing the natural history of malaria transmission and disease progression. Our approach quickly outperforms previous calibrations, yielding an improved final goodness of fit. Per-objective parameter importance and sensitivity diagnostics provided by our approach offer epidemiological insights and enhance trust in predictions through greater interpretability.

category: epidemiology


title: Emulator-based Bayesian optimization for efficient multi-objective calibration of an individual-based model of malaria


title: Stringency of the containment measures in response to COVID-19 inversely correlates with the overall disease occurrence over the epidemic wave

abstract: Non-pharmaceutical interventions (NPIs) were the only viable choice to mitigate or suppress transmission of COVID-19 in the absence of efficient and safe vaccines. Moreover, the importance of some NPIs is likely to remain in the future, at least in specific settings, in which the limited vaccination coverage and the high rate of contacts would enable further disease transmission. Nonetheless, the benefits of NPIs have been questioned with respect to their effectiveness and societal costs. In this study of 28 European countries during the first wave of epidemic we demonstrate a significant inverse correlation between the stringency of adopted containment measures and cumulative incidences of the confirmed COVID-19 cases. Our results indicate that early implementation of the stringent containment measures prior to detection of the first confirmed case, and rapid ramp-up of containment stringency after the first case was diagnosed, were instrumental for lowering the number of COVID-19 cases during the epidemic wave. The impact of delayed adoption of containment measures could not be fully attenuated by later adoption of even more stringent community containment.


title: Ranitidine use, N-Nitrosodimethylamine (NDMA) production and variations in cancer diagnoses

abstract:
IntroductionRanitidine is a member of the H2-blocker class of medications, commonly used in the treatment gastroesophageal reflux and peptic ulcer disease. Recent laboratory analyses have demonstrated that ranitidine may yield the probable carcinogen, N-Nitrosodimethylamine (NDMA). Here, we characterized the kinetics of NDMA production from ranitidine under various simulated gastric conditions. Moreover, we conducted a cross-sectional epidemiologic analysis to evaluate potential associations between ranitidine use and various cancer presentations.

MethodsThe formation of NDMA in the presence of ranitidine was studied in a series of experiments conducted in simulated gastric fluid (SGF), while varying pH, nitrite concentration, and time of reaction. Chemical analyses of NDMA yield were performed by liquid chromatography-high resolution mass spectrometry per FDA guidelines on the detection of NDMA from ranitidine drug products.

To evaluate potential associations between ranitidine use and cancer diagnoses, we conducted a cross-sectional analysis among a population of oncology patients, following institutional review board approval. Analyses were limited to those reporting use of ranitidine or an active comparator (i.e. proton-pump inhibitor [PPI] or other H2-blocker) to partially mitigate potential confounding. Multivariable logistic regression was employed to identify associations between ranitidine and certain cancers, adjusted for age, sex, race, ethnicity, and body-mass index.

ResultsIncreasing sodium nitrite concentrations in SGF at pH 1.2 were associated with increasing NDMA yield. At a pH of 2.5, previously identified as the optimal reaction condition, samples collected at incubation times of 1, 2 and 4 hours (approximating typical gastric emptying conditions) showed a continued increase in NDMA over time. Notably, the reaction trajectory suggests NDMA may have continued to form beyond the last observed timepoint of 4 hours.

On cross-sectional analysis of an oncology population, use of ranitidine (versus active comparators) was associated with increased odds of presenting with cancers of the breast (OR=1.58; 95%CI: 1.23-2.01) as compared to presentation with another cancer. Similar positive associations were observed for cancers of the thyroid (OR=1.89; 95%CI: 1.18-2.92), bladder (OR=1.58; 95%CI: 1.10-2.21), and prostate (OR=1.80; 95%CI: 1.34-2.39). Conversely, ranitidine was inversely associated with cancers of the colorectum (OR=0.48; 95%CI: 0.30-0.74) and brain (OR=0.56; 95%CI: 0.33-0.89).

ConclusionUnder simulated gastric conditions, ranitidine yields increasing amounts of NDMA over time (up to, and likely beyond 4 hours) and with increasing concentrations of sodium nitrite. In addition, among a cohort of cancer patients reporting use of H2-blockers or PPIs at the time of diagnosis, we found an association between ranitidine use and cancers of the breast, thyroid, bladder and prostate. We further observed unexplained inverse associations with cancers of the brain and colorectum. These associations reflect the odds of presenting with different cancers exclusively among an oncology population, and do not directly represent risk in a general population (as there were no cancer-free individuals in this study). Moreover, these exploratory analyses are to be viewed as hypothesis generating and should prompt analyses of larger cohorts with longer follow-up.

category: pharmacology and therapeutics


title: Prospective and detailed behavioral phenotyping in DDX3X syndrome

abstract:
BackgroundDDX3X syndrome is a recently identified genetic disorder that accounts for 1-3% of cases of unexplained developmental delay (DD) and/or intellectual disability (ID) in females and is associated with motor and language delays, and autism spectrum disorder (ASD). To date, the published phenotypic characterization of this syndrome has primarily relied on medical record review; in addition, the behavioral dimensions of the syndrome have not been fully explored.

MethodsWe carried out multi-day, prospective, detailed phenotyping of DDX3X syndrome in 14 females and 1 male, focusing on behavioral, psychological, and neurological measures; three participants in this cohort have been previously reported. We compared results against population norms and contrasted phenotypes between individuals harboring either (i) protein-truncating variants or (ii) missense variants and in-frame deletions.

ResultsEighty percent of individuals met criteria for ID, 60% for ASD and 53% for attention-deficit/hyperactivity disorder (ADHD). Motor and language delays were common as were sensory processing abnormalities. The cohort included 5 missense, 3 intronic/splice-site, 2 nonsense, 2 frameshift, 2 in-frame deletions, and one initiation codon variant. Genotype-phenotype correlations indicated that missense variants/in-frame deletions were associated with more severe language, motor, and adaptive deficits in comparison to protein-truncating variants.

LimitationsSample size is modest, however, DDX3X is a rare and underdiagnosed disorder.

ConclusionThis study, representing a first, prospective, detailed characterization of DDX3X syndrome, extends our understanding of the neurobehavioral phenotype. Gold-standard diagnostic approaches demonstrated high rates of ID, ASD, and ADHD. In addition, sensory deficits were observed to be a key part of the syndrome. Even with a modest sample, we observe evidence for genotype-phenotype correlations with missense variants/in-frame deletions yielding a more severe phenotype.

category: psychiatry and clinical psychology


title: Risk perception of COVID-19 and its socioeconomic correlates in the United States: A social media analysis

abstract: Social media analysis provides a new approach to monitoring and understanding risk perceptions regarding COVID-19 over time. Our current understandings of risk perceptions regarding COVID-19 do not disentangle the three dimensions of risk perceptions (perceived susceptibility, perceived severity, and negative emotion) over a long enough timeframe to cover different pandemic phases. The impact of social determinants of health factors on COVID-19-related risk perceptions over time is also not clear. To address these two knowledge gaps, we extracted tweets regarding COVID-19-related risk perceptions and developed index indicators for three dimensions of risk perceptions based on over 297 million geotagged tweets posted by over 3.5 million Twitter users from January to October 2020 in the United States. We also examined correlations between index indicator scores and county-level social determinants of health factors. The three domains of risk perceptions demonstrate different trajectories. Perceived severity kept climbing throughout the whole study period. Perceived susceptibility and negative emotion declined and remained stable at a lower level after peaking on March 11 (WHO named COVID-19 a global pandemic). Attention on risk perceptions was not exactly in accordance with epidemic trends of COVID-19 (cases, deaths). Users from socioeconomically vulnerable counties showed lower attention on perceived severity and susceptibility of COVID-19 than those from wealthier counties. Examination of trends in tweets regarding the multiple domains of risk perceptions throughout stages of the COVID-19 pandemic can help policy makers frame in-time, tailored, and appropriate responses to prevent viral spread and encourage preventive behavior uptake in United States.

category: public and global health


title: Depression Symptoms during the COVID-19 Pandemic among Well-Educated, Employed Adults with Low Infection Risks

abstract: Levels and distributions of depression symptoms 8-10 months after the onset of the COVID-19 pandemic are reported in a population of faculty, staff, and students at Duke University who faced minimal infection and economic disruption due to the pandemic. Almost 5,000 respondents age 18-81 years who completed the 20-item Center for Epidemiological Studies-Depression (CES-D) battery reported high rates of depression symptoms with more than 40% reporting levels that indicate risk of moderate depression and 25% indicating risk of severe depression. There is a very steep age gradient with the highest levels reported by the youngest respondents of whom over 40% are at risk of severe depression. Symptoms are worse among those who report the demands of work often interfere with family responsibilities but these pressures neither explain the high reported rates nor the steep age gradient. Severe depression risks are highest among students. High levels of depression symptoms during the pandemic appear to be persistent and not confined to those at greatest risk of infection or economic insecurity.


title: The therapeutic effect of intra-articular facet joint injection with normal saline as a comparator for chronic low back pain: a systematic review and meta-analysis

abstract:
BackgroundIntra-articular facet joint injection (FJI) has been increasingly used as a treatment for chronic low back pain (LBP). Choice of the substance has been based on clinical experience with unclear evidence on marginal effectiveness of active substance over normal saline as a placebo control. This systematic review investigates the comparative effectiveness between normal saline and active substances on patient-reported outcomes (PROs).

MethodsSystematic search was conducted in five databases: PubMed, Embase, Scopus, Web of Science, and CENTRAL for randomized controlled trials and observational studies of evaluating the PROs of FJI comparing active injected substances with normal saline as placebo in chronic LBP patients in the English language without publication date restriction. Quality assessment was performed using ROB2 and ROBINS-I. The meta-analysis was done using a random-effects model. Mean difference with 95% CIs of efficacy outcomes including pain, numbness, disability, quality of life were measured.

ResultsOf 2,467 potential studies, three were included in the systematic review and meta-analysis (247 patients). Compared to other active substances, normal saline provided similar therapeutic effects on pain outcome within one hour (MD 2.43, 95% CI -11.61 to 16.50), at 1-1.5 months follow up (MD -0.63, 95% CI -7.97 to 6.72), and at 3 to 6 months (MD 1.90, 95% CI -16.03 to 19.83) as well as the quality of life at one and six months follow-up.

ConclusionsThe short-term and long-term clinical improvements of intra-articular FJI using normal saline are comparable to the other active substances in LBP patients.

PROSPEROregistration number CRD42020216426

category: rehabilitation medicine and physical therapy


title: Linking objective measures of physical activity and capability with brain structure in healthy community dwelling older adults

abstract: Maintaining high levels of daily activity and physical capability have been proposed as important constituents to promote healthy brain and cognitive aging. Studies investigating the associations between brain health and physical activity in late life have, however, mainly been based on self-reported data or measures designed for clinical populations. In the current study, we examined cross-sectional associations between physical activity, recorded by an ankle-positioned accelerometer for seven days, physical capability (grip strength, postural control, and walking speed), and neuroimaging based surrogate markers of brain health in 122 healthy older adults aged 65-88 years. We used a multimodal brain imaging approach offering two complementary structural MRI based indicators of brain health: white matter diffusivity and coherence based on diffusion tensor imaging and subcortical and global brain age based on brain morphology inferred from T1-weighted MRI data. The analyses revealed a significant association between global white matter fractional anisotropy (FA) and walking speed, indicating higher white matter coherence in people with higher pace. We also found a significant interaction between sex and brain age on number of daily steps, indicating younger-appearing brains in more physically active women, with no significant associations among men. These results provide insight into the intricate associations between different measures of brain and physical health in old age, and corroborate established public health advice promoting physical activity.

category: neurology


title: Multinational Prevalence of Neurological Phenotypes in Patients Hospitalized with COVID-19

abstract:
OBJECTIVENeurological complications can worsen outcomes in COVID-19. We defined the prevalence of a wide range of neurological conditions among patients hospitalized with COVID-19 in geographically diverse multinational populations.

METHODSUsing electronic health record (EHR) data from 348 participating hospitals across 6 countries and 3 continents between January and September 2020, we performed a cross-sectional study of hospitalized adult and pediatric patients with a positive SARS-CoV-2 reverse transcription polymerase chain reaction test, both with and without severe COVID-19. We assessed the frequency of each disease category and 3-character International Classification of Disease (ICD) code of neurological diseases by countries, sites, time before and after admission for COVID-19, and COVID-19 severity.

RESULTSAmong the 35,177 hospitalized patients with SARS-CoV-2 infection, there was increased prevalence of disorders of consciousness (5.8%, 95% confidence interval [CI]: 3.7%-7.8%, pFDR<.001) and unspecified disorders of the brain (8.1%, 95%CI: 5.7%-10.5%, pFDR<.001), compared to pre-admission prevalence. During hospitalization, patients who experienced severe COVID-19 status had 22% (95%CI: 19%-25%) increase in the relative risk (RR) of disorders of consciousness, 24% (95%CI: 13%-35%) increase in other cerebrovascular diseases, 34% (95%CI: 20%-50%) increase in nontraumatic intracranial hemorrhage, 37% (95%CI: 17%-60%) increase in encephalitis and/or myelitis, and 72% (95%CI: 67%-77%) increase in myopathy compared to those who never experienced severe disease.

INTERPRETATIONUsing an international network and common EHR data elements, we highlight an increase in the prevalence of central and peripheral neurological phenotypes in patients hospitalized with SARS-CoV-2 infection, particularly among those with severe disease.


title: Population Pharmacokinetics of Oxcarbazepine: A Systematic Review

abstract:
IntroductionOxcarbazepine is commonly used as a first-line drug in the treatment of partial seizures. Due to the high pharmacokinetic variability of oxcarbazepine, many population pharmacokinetic models have been developed to optimise the dosing regimen of oxcarbazepine.

Areas coveredThis review summarize the published population pharmacokinetic studies of oxcarbazepine in children and adults. The quality of the identified reports from the PubMed and Embase databases was also evaluated. We also explored the significant covariates that may have an impact on the dosage regimen and clinical use of oxcarbazepine.

Expert OpinionThe oxcarbazepine dose regimen was dependent on weight and co-administration with enzyme-inducing medications. In order to achieve more accurate treatment, we should establish PK / PD model of OXC to evaluate the effectiveness of dose adjustment from pharmacodynamic indicators. Furthermore, exploring the pharmacokinetic in specifical patients, such as infants is essential to improve its safety.

Article highlightsO_LIIn this review, we identified weight, renal function, and co-administered medications as covariates that most likely to influence oxcarbazepine pharmacokinetics.
C_LIO_LIComparing to adult patients, paediatric patients show a higher clearance per kilogramme weigh which lead to higher doses per kilogramme; they may also require therapeutic drug monitoring owing to a larger variation in clearance.
C_LIO_LIFurther studies are essential to evaluate oxcarbazepine pharmacokinetics in special populations such as infants.
C_LI


title: Specific pattern of melanin-concentrating hormone (MCH) neuron degeneration in Alzheimer's disease and possible clinical implications

abstract:
Study ObjectivesThe lateral hypothalamic area (LHA) is one of the key regions orchestrating sleep and wake control. It is the site of wake-promoting orexinergic and sleep-promoting melanin-concentrating hormone (MCH) neurons, which share a close anatomical and functional relation. The aim of the study was to investigate the degeneration of MCH neurons in Alzheimers disease (AD) and progressive supranuclear palsy (PSP), and relate the new findings to our previously reported pattern of degeneration of wake-promoting orexinergic neurons

MethodsPost-mortem human brain tissue of subjects with AD, PSP and controls was examined using unbiased stereology. Double immunohistochemistry with MCH- and tau-antibodies on formalin-fixed, celloidin embedded tissue was performed.

ResultsThere was no difference in the total number of MCH neurons between AD, PSP and controls, but a significant loss of non-MCH neurons in AD patients (p=0.019). The proportion of MCH neurons was significantly higher in AD (p=0.0047). No such a difference was found in PSP. In PSP, but not AD, the proportion of tau+ MCH neurons was lower than the proportion of tau+ non-MCH neurons (p=0.002). When comparing AD to PSP, the proportion of tau+MCH neurons was higher in AD (p<0.001).

ConclusionsMCH neurons are more vulnerable to AD than PSP pathology. High burden of tau-inclusions, but comparably milder loss of MCH neurons in AD, together with previously reported orexinergic neuronal loss may lead to a hyperexcitability of the MCH system in AD, contributing to wake-sleep disorders in AD. Further experimental research is needed to understand why MCH neurons are more resistant to tau-toxicity compared to orexinergic neurons.

STATEMENT OF SIGNIFICANCEThis is the first study to investigate the involvement of melanin-concentrating hormone (MCH) neurons in patients with Alzheimers disease and progressive supranuclear palsy. MCH neurons are key regulators of sleep and metabolic functions, and one of the major neuronal populations of the lateral hypothalamic area (LHA), but still underexplored in humans. Uncovering the pathology of this neuronal population in neurodegenerative disorders will improve our understanding of the complex neurobiology of the LHA and the interaction between MCH and orexinergic neurons. This new knowledge may open new strategies for treatment interventions. Further, this study represents a fundament for future research on MCH neurons and the LHA in tauopathies.


title: Is vitamin D deficiency associated with the COVID-19 epidemic in Europe?

abstract: The authors have withdrawn this manuscript because, following comments received during the review process, they have updated the number of countries included in their study (and also changed from 5 to 10 years the limit for Vit-D information studies that they included), which led to non-significant correlations between mortality and infections and Vit D deficiency prevalence. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

category: nutrition


title: A Subset of Localized Prostate Cancer Displays an Immunogenic Phenotype Associated with Losses of Key Tumor Suppressor Genes

abstract:
PurposeA subset of primary prostate cancer (PCa) expresses programmed death-ligand 1 (PD-L1), but whether they have unique tumor immune microenvironment (TIME) or genomic features is unclear.

Experimental DesignWe selected PD-L1-positive high-grade and/or high-risk primary PCa, characterized tumor-infiltrating lymphocytes (TILS) with multiplex immunofluorescence, and identified genomic alterations in immunogenic and non-immunogenic tumor foci.

ResultsOne-quarter of aggressive localized PCa cases (29/115) had tumor PD-L1 expression >5%. This correlated with increased density of CD8+ T cells, a large fraction co-expressing PD-1, versus absent PD-1 expression on sparse CD8 T cells in unselected cases. Most CD8+PD-1+ cells did not express terminal exhaustion markers (TIM-3 or LAG-3), while a subset expressed TCF1. Consistent with these CD8+PD-1+TCF1+ cells being progenitors, they were found in antigen-presenting-cell niches in close proximity to MHC II+ cells. CD8 T cell density in immunogenic PCa and renal cell carcinoma (RCC) was nearly identical. Shallow RB1 and BRCA2 losses, and deep deletions of CHD1, were prevalent; the latter being strongly associated with a dendritic cell gene set in TCGA. Tumor mutation burden was variable; neither high microsatellite instability nor CDK12 alterations were present.

ConclusionsA subset of localized PCa is immunogenic, manifested by PD-L1 expression and CD8+ T cell content comparable to RCC. The CD8+ T cells include effector cells and exhausted progenitor cells, which may be expanded by ICIs. Genomic losses of RB1, BRCA2, and CHD1 may be drivers of this phenotype. These findings indicate that immunotherapies may be effective in biomarker-selected subpopulations of localized PCa patients.

Statement of Translational RelevanceProstate cancer (PCa) is generally considered poorly immunogenic, with low expression of programmed death-ligand 1 (PD-L1) and low density of tumor-infiltrating immune cells. Accordingly, response rates to PD(L)-1 inhibition in unselected patients with advanced prostate cancer have been low. Here, we find that a substantial subset of aggressive primary PCa exhibits tumor PD-L1 expression and contains a high density of tumor-infiltrating lymphocytes. These lymphocytes contain sub-populations of exhausted progenitor CD8+ T cells and differentiated effector T cells, the hallmarks of ongoing anti-tumor immune response and a prerequisite for response to checkpoint inhibition. Furthermore, we identify genomic alterations that may be contributing to immunogenicity in these cases. These findings point to immune responses elicited in a subset of primary PCa, supporting the development of immune checkpoint blockade clinical trials in early-stage disease, such as biochemically recurrent PCa, that are driven by genomic features of the tumor or the immune microenvironment.

category: oncology


title: Ownership and COVID-19 in care homes for older people: A living systematic review of outbreaks, infections, and mortalities

abstract:
BackgroundThe adult social care sector is increasingly outsourced to for-profit providers, who constitute the largest provider of care homes in many developed countries. During the COVID-19 pandemic, for-profit providers have been accused of failing their residents by prioritising profits over care, prevention, and caution, which has been reported to result in a higher prevalence of COVID-19 infections and deaths in for-profit care homes. Although many of these reports are anecdotal or based on news reports, there is a growing body of academic research investigating ownership variation across COVID-19 outcomes, which has not been systematically appraised and synthesised.

ObjectivesTo identify, appraise, and synthesise the available research on ownership variation in COVID-19 outcomes (outbreaks, infections, deaths, shortage of personal protective equipment (PPE) and staff) across for-profit, public, and non-profit care homes for older people, and to update our findings as new research becomes available.

DesignLiving systematic review.

MethodsThis review was prospectively registered with Prospero (CRD42020218673). We searched 17 databases and performed forward and backward citation tracking of all included studies. Search results were screened and reviewed in duplicate. Risk of bias (RoB) was assessed in duplicate according to the COSMOS-E guidance. Data was extracted by ABM and independently validated. The results were synthesised by country, RoB, and model adjustments, and visualised using harvest plots.

ResultsTwenty-nine studies across five countries were included, with 75% of included studies conducted in the Unites States. For-profit ownership was not consistently associated with a higher probability of a COVID-19 outbreak. However, there was compelling evidence of worse COVID-19 outcomes following an outbreak, with for-profit care homes having higher rates of accumulative infections and deaths. For-profit providers were also associated with shortages in PPE, which may have contributed to the higher incidence of infections and deaths in the early stages of the pandemic. Chain affiliation was often correlated with an increased risk of outbreak but was usually not reported to be associated with higher rates of deaths and infections.

ConclusionFor-profit ownership was a consistent risk factor for higher cumulative COVID-19 infections and deaths in the first wave of the pandemic. Thus, ownership and the characteristics associated with FP care home providers may present key regulatable factors that can be addressed to improve health outcomes in vulnerable populations and reduce health disparities. This review will be updated as new research becomes published, which may change the conclusion of our synthesis.

category: health policy


title: More than 50 Long-term effects of COVID-19: a systematic review and meta-analysis

abstract: COVID-19, caused by SARS-CoV-2, can involve sequelae and other medical complications that last weeks to months after initial recovery, which has come to be called Long-COVID or COVID long-haulers. This systematic review and meta-analysis aims to identify studies assessing long-term effects of COVID-19 and estimates the prevalence of each symptom, sign, or laboratory parameter of patients at a post-COVID-19 stage. LitCOVID (PubMed and Medline) and Embase were searched by two independent researchers. All articles with original data for detecting long-term COVID-19 published before 1st of January 2021 and with a minimum of 100 patients were included. For effects reported in two or more studies, meta-analyses using a random-effects model were performed using the MetaXL software to estimate the pooled prevalence with 95% CI. Heterogeneity was assessed using I2 statistics. This systematic review followed Preferred Reporting Items for Systematic Reviewers and Meta-analysis (PRISMA) guidelines, although the study protocol was not registered. A total of 18,251 publications were identified, of which 15 met the inclusion criteria. The prevalence of 55 long-term effects was estimated, 21 meta-analyses were performed, and 47,910 patients were included. The follow-up time ranged from 14 to 110 days post-viral infection. The age of the study participants ranged between 17 and 87 years. It was estimated that 80% (95% CI 65-92) of the patients that were infected with SARS-CoV-2 developed one or more long-term symptoms. The five most common symptoms were fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%). All meta-analyses showed medium (n=2) to high heterogeneity (n=13). In order to have a better understanding, future studies need to stratify by sex, age, previous comorbidities, severity of COVID-19 (ranging from asymptomatic to severe), and duration of each symptom. From the clinical perspective, multi-disciplinary teams are crucial to developing preventive measures, rehabilitation techniques, and clinical management strategies with whole-patient perspectives designed to address long COVID-19 care.


title: Diagnostic accuracy and utility of SARS-CoV-2 antigen lateral flow assays in medical admissions with possible COVID-19

abstract: We evaluated diagnostic accuracy of the Innova SARS-CoV-2 Antigen Rapid Qualitative Test compared to SARS-CoV-2 RT-PCR from nasopharyngeal swabs in adult admissions who met the COVID-19 case definition at a busy acute hospital in the UK. We found the Innova SARS-CoV-2 Antigen Rapid Qualitative Test had a good specificity in patients with symptoms of COVID-19 presenting to hospital. The Innova LFA can be used to rapidly identify COVID-19 cases amongst hospital admissions meeting the COVID-19 case definition, allowing patients to be allocated to COVID-19 cohort areas.


title: First detection and report of SARS-CoV-2 Spike protein N501Y mutations in Oklahoma USA

abstract: We describe the detection of SARS-CoV-2 (VOC)B.1.1.7 lineage in Oklahoma, USA. Various mutations in the S gene and ORF8 with similarity to the genome of B.1.1.7 lineage were detected in 4 of the 6 genomes sequenced and reported here. The sequences have been made available in GISAID. Presence of novel lineages indicate the need for frequent whole genome sequencing to better understand pathogen dynamics in different geographical locations.


title: A systematic review and meta-analysis on the safety and efficacy of tocilizumab in the management of COVID-19

abstract:
BackgroundThis systematic review and meta-analysis was aimed to evaluate the efficacy and safety of tocilizumab (TCZ) in treating severe coronavirus disease 2019 (COVID-19).

MethodsThe electronic search was performed using PubMed, Scopus, CENTRAL, and Google scholar to identify the retrospective observational reports. The studies published from 01 January 2020 to 30th September 2020. Participants were hospitalized COVID-19 patients. Interventions included tocilizumab versus placebo/standard of care. The comparison will be between TCZ versus standard of care (SOC)/placebo. Inconsistency between the studies was evaluated with I2 and quality of the evidences were evaluated by Newcastle-Ottawa scale.

ResultsBased on the inclusion criteria there were 24 retrospective studies involving 5686 subjects were included. The outcomes of the meta-analysis have revealed that the TCZ has reduced the mortality (M-H,RE-OR -0.11(-0.18 to -0.04) 95% CI, p =0.001, I2 =88%) and increased the incidences of super-infections (M-H, RE-OR 1.49(1.13 to 1.96) 95% CI, p=0.004, I2=47%). However, there is no significant difference in ICU admissions rate (M-H, RE-OR -0.06(-0.23 to 0.12), I2=93%), need of MV (M-H, RE-OR of 0.00(-0.06 to 0.07), I = 74%), LOS (IV -2.86(-0.91 to 3.38), I2=100%), LOS-ICU (IV: -3.93(-12.35 to 4.48), I2=100%), and incidences of pulmonary thrombosis (M-H, RE-OR 1.01 (0.45 to 2.26), I2=0%) compared to SOC/control.

ConclusionBased on cumulative low to moderate certainty evidence shows that TCZ could reduce the risk of mortality in hospitalized patients. However, there is no statistically significant difference observed between the TCZ and SOC/control groups in other parameters.


title: Efficacy and safety of tocilizumab in the management of COVID-19: A systematic review and meta-analysis of observational studies


title: Duration of SARS-CoV-2 Sero-Positivity in a Large Longitudinal Sero-Surveillance Cohort: The COVID-19 Community Research Partnership

abstract:
BackgroundEstimating population prevalence and incidence of prior SARS-CoV-2 infection is essential to formulate public health recommendations concerning the COVID-19 pandemic. However, interpreting estimates based on sero-surveillance requires an understanding of the duration of elevated antibodies following SARS-CoV-2 infection, especially in the large number of people with pauci-symptomatic or asymptomatic disease.

MethodsWe examined >30,000 serology assays for SARS-CoV-2 specific IgG and IgM assays acquired longitudinally in 11,468 adults between April and November 2020 in the COVID-19 Community Research Partnership.

FindingsAmong participants with serologic evidence for infection but few or no symptoms or clinical disease, roughly 50% sero-reverted in 30 days of their initial positive test. Sero-reversion occurred more quickly for IgM than IgG and for antibodies targeting nucleocapsid protein compared with spike proteins, but was not associated with age, sex, race/ethnicity, or healthcare worker status.

InterpretationThe short duration of antibody response suggests that the true population prevalence of prior SARS-CoV-2 infection may be significantly higher than presumed based on earlier sero-surveillance studies. The impact of the large number of minimally symptomatic COVID-19 cases with only a brief antibody response on population immunity remains to be determined.

FundingThis publication is supported by the CARES Act, of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award totaling $20,000,000. The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement, by HHS, or the U.S. Government.

O_TEXTBOXResearch in context

Evidence before this studyPrevious longitudinal studies of the humoral response to SARS-CoV-2 suggest that people with less severe disease have a more rapid decline of SARS-CoV-2 specific antibodies than people with severe disease. However, these data come from small laboratory-based investigations or studies of convenience samples identified based on symptomatic disease.

Added value of this studyThis study provides extensive longitudinal serologic follow-up in a large number of people with serologic evidence of prior infection who had little or no symptoms based on active daily symptom surveillance.

Implications of the available evidenceThe data indicate that serologic evidence of prior infection in minimally symptomatic people is fleeting, suggesting that cross-sectional sero-surveys have under-estimated the true prevalence of prior infection in populations. The data highlight the challenge of determining transmission dynamics and long-term immunity in asymptomatic cases which likely represents an even larger fraction of all cases of prior SARS-CoV-2 infection than previously presumed.

C_TEXTBOX


title: SARS-CoV-2 in Ivory Coast: serosurveillance survey among mines workers

abstract:
BackgroundEight months after the detection of the first COVID-19 case in Africa, 1,262,476 cases have been reported in African countries compared to 72 million worldwide. The real burden of SARS-CoV-2 infection in West Africa is not clearly defined. The aim of the study was to evaluate the seroprevalence of SARS-CoV-2 in half of the 3,380 workers of several mining companies operating in two mines in the Ivory Coast and having its headquarters in the economic capital Abidjan.

MethodsFrom 15th July to 13th October 2020, a voluntary serological test campaign was performed in the 3 sites where the companies operate: two mines, and the headquarters in Abidjan.We performed a COVID-PRESTO rapid test for the detection of IgG and IgM on capillary blood. A multivariate analysis was performed to identify independent sociodemographic characteristics associated with a higher SARS-CoV-2 seroprevalence rate.

ResultsA total of 1,687 subjects were tested. 91% were male (n= 1,536) and mean age was 37 years old. The overall crude seroprevalence rate was 25.1% (n=422), but differing significantly between different sites, rising from 13.6% (11.2%-16.1%) in mine A to 34.4% (31.1%-37.7%) in mine B and 34.7% (26.2%-43.2%) in Abidjan. Non-resident workers in mines had a significantly lower prevalence rate than those living full-time in mines. Seroprevalence was 26.5% in natives of the Ivory Coast, while people coming from countries other than Africa were less likely to be SARS-CoV-2 seropositive. Among the 422 positive subjects, 74 reported mild symptoms in the three previous months and one was hospitalized for a severe COVID-19 infection.

ConclusionThe prevalence of SARS-CoV-2 infection among mine workers in Ivory Coast is high. The low morbidity observed has probably led to an underestimation of the burden of this infection in West Africa. The high prevalence reported in subjects living in Abidjan, who have not any close contact with mine workers, may be indicative of the real seroprevalence in the Ivory Coast capital.


title: Risk of SARS-CoV-2 exposure among hospital healthcare workers in relation to patient contact and type of care

abstract:
AimWe aimed to assess the risk for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in a large cohort of healthcare workers (HCWs).

MethodsFrom May 11 until June 11, 2020, 3,981 HCWs at a large Swedish Emergency Care hospital provided serum samples and questionnaire data. Exposure was measured by assaying IgG antibodies to SARS-CoV-2.

ResultsThe total seroprevalence was 17.7% and increased during the study period. Among the seropositive HCWs, 10.5% had been entirely asymptomatic. Participants who worked with COVID-19 patients had higher odds for seropositivity: ORadj 1.96 (95% CI 1.59 - 2.42). HCWs from three of the departments managing COVID-19 patients had significantly higher seroprevalences, whereas the prevalence among HCWs from the Intensive Care Unit (also managing COVID-19 patients) was significantly lower.

ConclusionHCWs in contact with SARS-CoV-2 infected patients had a variable, but on average higher, likelihood for SARS-CoV-2 infections.


title: HLA-A*11:01:01:01, HLA*C*12:02:02:01-HLA-B*52:01:02:02, age and sex are associated with severity of Japanese COVID-19 with respiratory failure

abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19) was announced as an outbreak by the World Health Organization (WHO) in January 2020 and as a pandemic in March 2020. The majority of infected individuals have experienced no or only mild symptoms, ranging from fully asymptomatic cases to mild pneumonic disease. However, a minority of infected individuals develop severe respiratory symptoms. The objective of this study was to identify susceptible HLA alleles and clinical markers for the early identification of severe COVID-19 among hospitalized COVID-19 patients. A total of 137 patients with mild COVID-19 (mCOVID-19) and 53 patients with severe COVID-19 (sCOVID-19) were recruited from the Center Hospital of the National Center for Global Health and Medicine (NCGM), Tokyo, Japan for the period of February-August 2020. High-resolution sequencing-based typing for eight HLA genes was performed using next-generation sequencing. In the HLA association studies, HLA-A*11:01:01:01 [Pc = 0.013, OR = 2.26 (1.27-3.91)] and HLA-C*12:02:02:01-HLA-B*52:01:01:02 [Pc = 0.020, OR = 2.25 (1.24-3.92)] were found to be significantly associated with the severity of COVID-19. After multivariate analysis controlling for other confounding factors and comorbidities, HLA-A*11:01:01:01 [P = 3.34E-03, OR = 3.41 (1.50-7.73)], age at diagnosis [P = 1.29E-02, OR = 1.04 (1.01-1.07)] and sex at birth [P = 8.88E-03, OR = 2.92 (1.31-6.54)] remained significant. Early identification of potential sCOVID-19 could help clinicians prioritize medical utility and significantly decrease mortality from COVID-19.


title: A Rapid and Low-Cost protocol for the detection of B.1.1.7 lineage of SARS-CoV-2 by using SYBR Green-Based RT-qPCR

abstract:
BackgroundThe new SARS-CoV-2 variant VUI (202012/01), identified recently in the United Kingdom (UK), exhibits a higher transmissibility rate compared to other variants, and a reproductive number 0.4 higher. In the UK, scientists were able to identify the increase of this new variant through the rise of false negative results for the spike (S) target using a three-target RT-PCR assay (TaqPath kit).

MethodsTo control and study the current coronavirus pandemic, it is important to develop a rapid and low-cost molecular test to identify the aforementioned variant. In this work, we designed primer sets specific to SARS-CoV-2 variant VUI (202012/01) to be used by SYBR Green-based RT-PCR. These primers were specifically designed to confirm the deletion mutations {Delta}69/{Delta}70 in the spike and the {Delta}106/{Delta}107/{Delta}108 in the NSP6 gene. We studied 20 samples from positive patients, 16 samples displayed an S-negative profile (negative for S target and positive for N and ORF1ab targets) and four samples with S, N and ORF1ab positive profile.

ResultsOur results emphasized that all S-negative samples harbored the mutations {Delta}69/{Delta}70 and {Delta}106/{Delta}107/{Delta}108. This protocol could be used as a second test to confirm the diagnosis in patients who were already positive to COVID-19 but showed false negative results for S-gene.

ConclusionsThis technique may allow to identify patients carrying the VUI (202012/01) variant or a closely related variant, in case of shortage in sequencing.


title: Safety and efficacy of long-acting insulins (degludec and glargine) among type 2 diabetic Asian Population: A Systematic Review and Meta-Analysis.

abstract:
BackgroundAccording to IDF Diabetes Atlas 2019, globally, 463 million people live with Diabetes mellitus. Out of that, 88 million people are in South East Asia. By 2045, it is expected to increase by 51% globally and 74% in South East Asia. Global variation in susceptibility to diabetes, insulin sensitivity, and regimen intensity due to race and ethnic differences pose a challenge regarding the optimal choice of second-line therapy for clinicians. Asian populations are at higher risk of developing diabetes mellitus than the European population. The current study was carried out to see the relative efficacy of currently available long-acting insulins in reducing blood sugar, HbA1c and the occurrence of hypoglycemia as a complication associated with them.

MethodsA systematic literature search was done using various search engines (PubMed, Cochrane, Google Scholar, Scopus, and Embase) and included published RCTs in English before December 2019. Further, a manual search was performed by screening the reference list of the identified articles.

ResultsWe included four RCTs with 534 participants (349 in the insulin degludec group and 185 in the insulin glargine group) with T2DM. Results show that both insulin glargine and degludec are equally efficacious in reducing fasting blood glucose and HbA1c. However, insulin glargine was associated with lower risks of hypoglycemia.

ConclusionsInsulin glargine and degludec are comparable in achieving glycemic control with fewer hypoglycemic episodes in insulin glargine treated group.

category: endocrinology


title: The World Mortality Dataset: Tracking excess mortality across countries during the COVID-19 pandemic

abstract: Comparing the impact of the COVID-19 pandemic between countries or across time is difficult because the reported numbers of cases and deaths can be strongly affected by testing capacity and reporting policy. Excess mortality, defined as the increase in all-cause mortality relative to the expected mortality, is widely considered as a more objective indicator of the COVID-19 death toll. However, there has been no global, frequently-updated repository of the all-cause mortality data across countries. To fill this gap, we have collected weekly, monthly, or quarterly all-cause mortality data from 94 countries and territories, openly available as the regularly-updated World Mortality Dataset. We used this dataset to compute the excess mortality in each country during the COVID-19 pandemic. We found that in several worst-affected countries (Peru, Ecuador, Bolivia, Mexico) the excess mortality was above 50% of the expected annual mortality. At the same time, in several other countries (Australia, New Zealand) mortality during the pandemic was below the usual level, presumably due to social distancing measures decreasing the non-COVID infectious mortality. Furthermore, we found that while many countries have been reporting the COVID-19 deaths very accurately, some countries have been substantially underreporting their COVID-19 deaths (e.g. Nicaragua, Russia, Uzbekistan), sometimes by two orders of magnitude (Tajikistan). Our results highlight the importance of open and rapid all-cause mortality reporting for pandemic monitoring.


title: Beyond the new normal: assessing the feasibility of vaccine-based elimination of SARS-CoV-2

abstract: As the COVID-19 pandemic drags into its second year, there is hope on the horizon, in the form of SARS-CoV-2 vaccines which promise disease elimination and a return to pre-pandemic normalcy. In this study we critically examine the basis for that hope, using an epidemiological modeling framework to establish the link between vaccine characteristics and effectiveness in bringing an end to this unprecedented public health crisis. Our findings suggest that vaccines that do not prevent infection will allow extensive endemic SARS-CoV-2 spread upon a return to pre-pandemic social and economic conditions. Vaccines that only reduce symptomatic COVID-19 or mortality will fail to mitigate serious COVID-19 mortality risks, particularly in the over-65 population, likely resulting in hundreds of thousands of US deaths on a yearly basis. Our modeling points to the possibility of complete SARS-CoV-2 elimination with high population-level compliance and a vaccine that is highly effective at reducing SARS-CoV-2 infection. Notably, vaccine-mediated reduction of transmission is critical for elimination, and in order for partially-effective vaccines to play a positive role in SARS-CoV-2 elimination, other stackable (complementary) interventions must be deployed simultaneously.


title: Evaluation of COVID-19 vaccination strategies with a delayed second dose

abstract: Two of the COVID-19 vaccines currently approved in the United States require two doses, administered three to four weeks apart. Constraints in vaccine supply and distribution capacity, together with a deadly wave of COVID-19 from November 2020 to January 2021 and the emergence of highly contagious SARS-CoV-2 variants, sparked a policy debate on whether to vaccinate more individuals with the first dose of available vaccines and delay the second dose, or to continue with the recommended two-dose series as tested in clinical trials. We developed an agent-based model of COVID-19 transmission to compare the impact of these two vaccination strategies, while varying the temporal waning of vaccine efficacy following the first dose and the level of pre-existing immunity in the population. Our results show that for Moderna vaccines, a delay of at least 9 weeks could maximize vaccination program effectiveness and avert at least an additional 17.3 (95% CrI: 7.8 - 29.7) infections, 0.71 (95% CrI: 0.52 - 0.97) hospitalizations, and 0.34 (95% CrI: 0.25 - 0.44) deaths per 10,000 population compared to the recommended 4-week interval between the two doses. Pfizer-BioNTech vaccines also averted an additional 0.61 (95% CrI: 0.37 - 0.89) hospitalizations and 0.31 (95% CrI: 0.23 - 0.45) deaths per 10,000 population in a 9-week delayed second dose strategy compared to the 3-week recommended schedule between doses. However, there was no clear advantage of delaying the second dose with Pfizer-BioNTech vaccines in reducing infections, unless the efficacy of the first dose did not wane over time. Our findings underscore the importance of quantifying the characteristics and durability of vaccine-induced protection after the first dose in order to determine the optimal time interval between the two doses.


title: Operational response simulation tool for epidemics within refugee and IDP settlements

abstract: The spread of infectious diseases such as COVID-19 presents many challenges to healthcare systems and infrastructures across the world, exacerbating inequalities and leaving the worlds most vulnerable populations most affected. Given their density and available infrastructure, refugee and internally displaced person (IDP) settlements can be particularly susceptible to disease spread. Non-pharmaceutical public health interventions can be used to mitigate transmission, and modeling efforts can provide crucial insights on the potential effectiveness of such interventions to help inform decision making processes. In this paper we present an agent-based modeling approach to simulating the spread of disease in refugee and IDP settlements. The model, based on the JUNE open-source framework, is informed by data on geography, demographics, comorbidities, physical infrastructure and other parameters obtained from real-world observations and previous literature. Furthermore, we present a visual analytics tool which allows decision makers to distill insights by comparing the results of different simulations and scenarios. Through simulating their effects on the epidemiological development of COVID-19, we evaluate several public health interventions ranging from increasing mask wearing compliance to the reopening of learning institutions. The development and testing of this approach focuses on the Coxs Bazar refugee settlement in Bangladesh, although our model is designed to be generalizable to other informal settings.


title: The effect of SARS-CoV-2 variant B.1.1.7 on symptomatology, re-infection and transmissibility

abstract:
BackgroundSARS-CoV-2 variant B.1.1.7 was first identified in December 2020 in England. It is not known if the new variant presents with variation in symptoms or disease course, if previously infected individuals may become reinfected with the new variant, or how the variants increased transmissibility affects measures to reduce its spread.

MethodsUsing longitudinal symptom reports from 36,920 users of the COVID Symptom Study app testing positive for Covid-19 between 28 September and 27 December 2020, we performed an ecological study to examine the association between the regional proportion of B.1.1.7 and reported symptoms, disease course, rates of reinfection, and transmissibility.

FindingsWe found no evidence for changes in reported symptoms or disease duration associated with B.1.1.7. We found a likely reinfection rate of 0.7% (95% CI 0.6-0.8), but no evidence that this was higher compared to older strains. We found an increase in R(t) by a factor of 1.35 (95% CI 1.02-1.69). Despite this, we found that R(t) fell below 1 during regional and national lockdowns, even in regions with high proportions of B.1.1.7.

InterpretationThe lack of change in symptoms indicates existing testing and surveillance infrastructure do not need to change specifically for the new variant, and the reinfection findings suggest that vaccines are likely to remain effective against the new variant.

FundingZoe Global Limited, Department of Health, Wellcome Trust, EPSRC, NIHR, MRC, Alzheimers Society.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSTo identify existing evidence on SARS-CoV-2 variant B.1.1.7 we searched PubMed and Google Scholar for articles between 1 December 2020 and 1 February 2021 using the keywords Covid-19 AND B.1.1.7, finding 281 results. We did not find any studies that investigated B.1.1.7-associated changes in the symptoms experienced, their severity and duration, but found one study showing B.1.1.7 did not change the ratio of symptomatic to asymptomatic infections. We found six articles describing laboratory-based investigations of the responses of B.1.1.7 to vaccine-induced immunity to B.1.1.7, but no work investigating what this means for natural immunity and the likelihood of reinfection outside of the lab. We found five articles demonstrating the increased transmissibility of B.1.1.7.

Added value of this studyTo our knowledge, this is the first study to explore changes in symptom type and duration, as well as community reinfection rates, associated with B.1.1.7. The work uses self-reported symptom logs from 36,920 users of the COVID Symptom Study app reporting positive test results between 28 September and 27 December 2020. We find that B.1.1.7 is not associated with changes in the symptoms experienced in Covid-19, nor their duration. Building on existing lab studies, our work suggests that natural immunity developed from previous infection provides similar levels of protection to B.1.1.7. We add to the emerging consensus that B.1.1.7 exhibits increased transmissibility.

Implications of all the available evidenceOur findings suggest that existing criteria for obtaining a Covid-19 test in the community need not change for the rise of B.1.1.7. The fact that immunity developed from infection by wild type variants protects against B.1.1.7 provides an indication that vaccines will remain effective against B.1.1.7. R(t) fell below 1 during the UKs national lockdown, even in regions with high levels of B.1.1.7, but further investigation is required to establish the factors that enabled this, to facilitate countries seeking to control the spread of B.1.1.7.


title: Changes in symptomatology, re-infection and transmissibility associated with SARS-CoV-2 variant B.1.1.7: an ecological study


title: COVID-19 mortality: positive correlation with cloudiness and sunlight but no correlation with latitude in Europe

abstract: We systematically investigated an ongoing debate about the possible correlation between SARS-CoV-2 (COVID-19) epidemiological outcomes and solar exposure in European countries, in the period of March - August 2020. For each country, we correlated its mortality data with solar insolation (watt/square metre) and objective sky cloudiness (as cloud fraction) derived from satellite weather data. We found a positive correlation between the monthly mortality rate and the overall cloudiness in that month (Pearsons r(35)=.779, P<.001; linear model fitting the data, adjusted R2 =0.59). In Europe, in colder months, approximately 34% to 58% of the variance in COVID-19 mortality/million appears to be predicted by the cloudiness fraction of the sky, except in August in which only [~]15% of the variance was explained. The data show a low, negative correlation between the mortality rate with the overall insolation received by the country area in that entire month (Pearsons r(35)=-0.622, P<.001). Additionally, we did not find any statistically significant correlation between the mortality and the latitude of the countries when the "latitude of a country" was precisely defined as the average landmass location (country centroid). The unexpected correlation found between cloudiness and mortality could perhaps be explained by the following: 1) heavy cloudiness is linked with colder outdoor surfaces, which might aid virus survival; 2) reduced evaporation rate; 3) moderate pollution may be linked to both cloudiness and mortality; and 4) large-scale behavioural changes due to cloudiness (which perhaps drives people to spend more time indoors and thus facilitates indoor contamination).


title: Baseline functional connectivity in resting state networks associated with depression and remission status after 16 weeks of pharmacotherapy: A CAN-BIND Report

abstract:
Understanding the neural underpinnings of major depressive disorder (MDD) and its treatment could improve treatment outcomes. While numerous studies have been conducted, findings are variable and large sample replications scarce. We aimed to replicate and extend altered functional connectivity findings in the default mode, salience and cognitive control networks (DMN, SN, and CCN respectively) associated with MDD and pharmacotherapy outcomes in a large, multi-site sample. Resting-state fMRI data were collected from 129 patients and 99 controls through the Canadian Biomarker Integration Network in Depression (CAN-BIND) initiative. Symptoms were assessed with the Montgomery-[A]sberg Depression Rating Scale (MADRS). Connectivity was measured as correlations between four seeds (anterior and posterior DMN, SN and CCN) and all other brain voxels across participants. Partial least squares, a multivariate statistical technique, was used to compare connectivity prior to treatment between patients and controls, and between patients reaching remission early (MADRS [≤] 10 within 8 weeks), late (MADRS [≤] 10 within 16 weeks) or not at all. We replicated previous findings of altered connectivity in the DMN, SN and CCN in patients. In addition, baseline connectivity of the anterior/posterior DMN and SN seeds differentiated patients with different treatment outcomes. Weaker connectivity within the anterior DMN and between the anterior DMN and the SN and CCN characterised early remission; stronger connectivity within the SN and weaker connectivity between the SN and the DMN and CCN was related to late remission, of which the weaker SN - anterior DMN connectivity might specifically be associated with remission to dual pharmacotherapy; and connectivity strength between the posterior DMN and cingulate areas distinguished all three groups, with early remitters showing the strongest connections and non-remitters the weakest. The stability of these baseline patient differences was established in the largest single-site subsample of the data. Our replication and extension of altered connectivity within and between the DMN, SN and CCN highlighted previously reported and new differences between patients with MDD and controls, and revealed features that might predict remission prior to pharmacotherapy.

Trial registrationClinicalTrials.gov: NCT01655706.


title: Loneliness and the onset of new mental health problems in the general population: a systematic review

abstract:
BackgroundLoneliness is associated with poor health including premature mortality. There are cross-sectional associations with depression, anxiety, psychosis and other mental health outcomes. However, the direction of causation is unclear and clarifying the evidence from longitudinal studies is a key step in understanding this relationship.

AimsWe synthesized evidence from longitudinal studies investigating the relationship between loneliness and new onset of mental health problems, in the general population.

MethodWe systematically searched six electronic databases, unpublished sources and hand-searching of references, up to March 2020. We conducted a meta-analysis of eight independent cohorts, and narrative synthesis of the remaining studies.

ResultsWe included 20 studies, of which the majority focused on depression. Our narrative synthesis concluded that loneliness at baseline is associated with subsequent new onset of depression. The few studies on anxiety also showed an association. Our meta-analysis found a pooled adjusted odds ratio of 2.33 (95% C.I. 1.62 - 3.34) for risk of new onset depression in adults who were often lonely compared with people who were not often lonely. This should be interpreted with caution given evidence of heterogeneity. Most of the studies were in older adults.

ConclusionLoneliness is a public mental health issue. There is growing evidence it is associated with the onset of depression and other common mental health problems. Future studies should explore its impact across the age range, look beyond depression, and explore the mechanisms involved.


title: The Experience of Two Independent Schools with In-Person Learning During the COVID-19 Pandemic

abstract:
BACKGROUNDIn 2020, U.S schools closed due to SARS-CoV-2 but their role in transmission was unknown. In fall 2020, national guidance for reopening omitted testing or screening recommendations. We report the experience of 2 large independent K-12 schools (School-A and School-B) that implemented an array of SARS-CoV-2 mitigation strategies that included periodic universal testing.

METHODSSARS-CoV-2 was identified through periodic universal PCR testing, self-reporting of tests conducted outside school, and contact tracing. Schools implemented behavioral and structural mitigation measures, including mandatory masks, classroom disinfecting, and social distancing.

RESULTSOver the fall semester, School-A identified 112 cases in 2320 students and staff; School-B identified 25 cases (2.0%) in 1200 students and staff. Most cases were asymptomatic and none required hospitalization. Of 69 traceable introductions, 63(91%) were not associated with school-based transmission, 59 cases (54%) occurred in the 2 weeks post-Thanksgiving. In 6/7 clusters, clear noncompliance with mitigation protocols was found. The largest outbreak had 28 identified cases and was traced to an off-campus party. There was no transmission from students to staff.

CONCLUSIONSAlthough school-age children can contract and transmit SARS-CoV-2, rates of COVID-19 infection related to in-person education were significantly lower than those in the surrounding community. However, social activities among students outside of school undermined those measures and should be discouraged, perhaps with behavioral contracts, to ensure the safety of school communities. In addition, introduction risks were highest following extended school breaks. These risks may be mitigated with voluntary quarantines and surveillance testing prior to re-opening.


title: Induction of labour during the COVID-19 pandemic: a national survey of impact on practice in the UK

abstract:
BackgroundInduction of labour (IOL) is one of the most commonly performed interventions in maternity care, with outpatient cervical ripening increasingly offered as an option for women undergoing IOL. The COVID-19 pandemic has changed the context of practice and the option of returning home for cervical ripening may now assume greater significance. This work aimed to examine whether and how the COVID-19 pandemic has changed practice around IOL in the UK.

MethodWe used an online questionnaire to survey senior obstetricians and midwives at all 156 UK NHS Trusts and Boards that currently offer maternity services. Responses were analysed to produce descriptive statistics, with free text responses analysed using a conventional content analysis approach.

FindingsResponses were received from 92 of 156 UK Trusts and Boards, a 59% response rate. Many Trusts and Boards reported no change to their IOL practice, however 23% reported change in methods used for cervical ripening; 28% a change in criteria for home cervical ripening; 28% stated that more women were returning home during cervical ripening; and 24% noted changes to womens response to recommendations for IOL. Much of the change was reported as happening in response to attempts to minimise hospital attendance and restrictions on birth partners accompanying women.

ConclusionsThe pandemic has changed practice around induction of labour, although this varied significantly between NHS Trusts and Boards. There is a lack of formal evidence to support decision-making around outpatient cervical ripening: the basis on which changes were implemented and what evidence was used to inform decisions is not clear.

category: obstetrics and gynecology


title: Objective adherence to an online FAVAS therapeutic game for treating amblyopia in children

abstract:
AimThis retrospective study was to evaluate whether an updated version of attention binding digital therapeutic games based on the principle of Focal Ambient Visual Acuity Stimulation (FAVAS) would result in an improved patient adherence of patching in 4- to 12-year-old patients with amblyopia.

MethodsWe analyzed pseudonymised electronically recorded data from patients treated with two different versions of attention binding digital therapeutic games in 2015 and 2020. Two groups of children treated with occlusion therapy and attention binding digital therapeutic games, divided in treatment version, were compared. Patients in Group 2015 used the old version of therapeutic games without tablet computer functionality, while Group 2020 used more attractive therapeutic games with tablet computer functionality. Objective adherence was calculated by comparing the amount of minutes using the therapeutic games as monitored in the automatized logbook versus prescribed minutes of using the games.

ResultsChildren in Group 2015 spent on average 2009.3{+/-}1372.1 (36 to 5472) minutes using FAVAS; children in Group 2020 spent on average 2695.5{+/-}1526.8 (37.5 to 5672) minutes using the improved therapy. Meaning, Group 2020 spent 686.2 more minutes on FAVAS than Group 2015 (t=3.87, P<0.001). Although patient adherence was very variable, it significantly improved up to 78% {+/-} 46% in Group 2020 compared to the 57% {+/-} 34% in Group 2015 (t=4.3, P<0.001).

ConclusionFAVAS 2020 with an improved gamification aspect as well as tablet computer functionality increased adherence significantly compared to the earlier version FAVAS 2015, indicating that FAVAS 2020 could be an effective approach to support patching amblyopia treatment.

category: ophthalmology


title: The prevalence of olfactory dysfunction and its associated factors in patients with COVID-19 infection

abstract:
ObjectiveTo determine the prevalence of olfactory dysfunctions, mainly, anosmia and to identify its associated factors in patients with COVID-19 infection.

Study designA hospital-based prospective observational cohort study

SettingA COVID dedicated hospital, Square Hospitals Ltd., Dhaka, Bangladesh.

MethodsWe collected patients information including laboratory-confirmed COVID-19 test results. We used Pearson Chi-square test and logistic regression model to assess the associations between demographic and clinical characteristics and olfactory outcomes.

ResultsOut of 600 COVID-19 positive patients, 38.7% were diagnosed with olfactory dysfunction. Our analyses showed that patients age, smoking status, cough, dyspnea, sore throat, asthenia, and nausea or vomiting were significantly associated with the anosmia. We observed the risk of developing anosmia was greater in younger patients than in older patients, and this risk decreased as age increased [odds ratio (OR) range for different age groups: 1.26 to 1.08]. Smoking patients were 1.73 times more likely to experience anosmia than non-smoking patients [OR=1.73, 95% confidence interval (CI) = 1.01-2.98]. In addition, patients complained asthenia had a significantly double risk of developing the anosmia [OR = 1.96, CI = 1.23-3.06].

ConclusionsOur study shows that about 39% of patients diagnosed with olfactory dysfunction. Patients age, smoking status, and asthenia are significantly positively associated with the anosmia. Since anosmia can be a significant marker for the diagnosis of COVID-19, we suggest regular screening of olfactory dysfunction in patients with early symptoms of COVID-19, particularly younger patients, smoker, and complained asthenia.

category: otolaryngology


title: Self-Reported Mask Wearing Greatly Exceeds Directly Observed Use: Urgent Need for Policy Intervention in Kenya

abstract:
BackgroundMany countries in sub-Saharan Africa have so far avoided large outbreaks of COVID-19, perhaps due to the strict lockdown measures that were imposed early in the pandemic. Yet the harsh socio-economic consequences of the lockdowns have led many governments to ease the restrictions in favor of less stringent mitigation strategies. In the absence of concrete plans for widespread vaccination, masks remain one of the few tools available to low-income populations to avoid the spread of SARS-CoV-2 for the foreseeable future.

MethodsWe compare mask use data collected through self-reports from phone surveys and direct observations in public spaces from population-representative samples in Ugunja subcounty, a rural setting in Western Kenya. We examine mask use in different situations and compare mask use by gender, age, location, and the riskiness of the activity

FindingsWe assess mask use data from 1,960 phone survey respondents and 9,549 direct observations. While only 12% of people admitted in phone interviews to not wearing a mask in public, 90% of people we observed did not have a mask visible (77.7% difference, 95% CI 0.742, 0.802). Self-reported mask use was significantly higher than observed mask use in all scenarios (i.e. in the village, in the market, on public transportation).

InterpretationWe find limited compliance with the national government mask mandate in Kenya using directly observed data, but high rates of self-reported mask use. This vast gap suggests that people are aware that mask use is socially desirable, but in practice they do not adopt this behavior.

Focusing public policy efforts on improving adoption of mask use via education and behavioral interventions may be needed to improve compliance.

FundingWeiss Family Foundation, International Growth Centre


title: Emergence and evolution of Plasmodium falciparum histidine-rich protein 2 and 3 deletion mutant parasites in Ethiopia

abstract: Malaria diagnostic testing in Africa is threatened by Plasmodium falciparum parasites lacking histidine-rich protein 2 (pfhrp2) and 3 (pfhrp3) genes. Among 12,572 subjects enrolled along Ethiopias borders with Eritrea, Sudan, and South Sudan and using multiple assays, we estimate HRP2-based rapid diagnostic tests would miss 9.7% (95% CI 8.5-11.1) of falciparum malaria cases due to pfhrp2 deletion. Established and novel genomic tools reveal distinct subtelomeric deletion patterns, well-established pfhrp3 deletions, and recent expansion of pfhrp2 deletion. Current diagnostic strategies need to be urgently reconsidered in Ethiopia, and expanded surveillance is needed throughout the Horn of Africa.


title: Passing the Test: A model-based analysis of safe school-reopening strategies

abstract:
BackgroundThe COVID-19 pandemic has induced historic educational disruptions. In December 2020, at least two-thirds of US public school students were not attending full-time in-person education. The Biden Administration has expressed that reopening schools is a priority.

ObjectiveTo compare risks of SARS-COV-2 transmission in schools across different school-based prevention strategies and levels of community transmission.

DesignWe developed an agent-based network model to simulate transmission in elementary and high school communities, including home, school, and inter-household interactions.

SettingWe parameterized school structure based on average US classrooms, with elementary schools of 638 students and high schools of 1,451 students. We varied daily community incidence from 1 to 100 cases per 100,000 population.

Patients (or Participants)We simulated students, faculty/staff, and adult household members.

InterventionsWe evaluated isolation of symptomatic individuals, quarantine of an infected individuals contacts, reduced class sizes, alternative schedules, staff vaccination, and weekly asymptomatic screening.

MeasurementsWe projected transmission among students, staff and families during one month following introduction of a single infection into a school. We also calculated the number of infections expected for a typical 8-week quarter, contingent on community incidence rate.

ResultsSchool transmission risk varies according to student age and community incidence and is substantially reduced with effective, consistent mitigation measures. Nevertheless, when transmission occurs, it may be difficult to detect without regular, frequent testing due to the subclinical nature of most infections in children. Teacher vaccination can reduce transmission to staff, while asymptomatic screening both improves understanding of local circumstances and reduces transmission, facilitating five-day schedules at full classroom capacity.

LimitationsThere is uncertainty about susceptibility and infectiousness of children and low precision regarding the effectiveness of specific prevention measures, particularly with emergence of new variants.

ConclusionWith controlled community transmission and moderate school-based prevention measures, elementary schools can open with few in-school transmissions, while high schools require more intensive mitigation. Asymptomatic screening should be a key component of school reopenings, allowing reopening at higher community incidence while still minimizing transmission risk.


title: Sequencing Data of North American SARS-CoV-2 Isolates Shows Widespread Complex Variants

abstract:
Several new variants of the SARS-CoV-2 have been isolated in the United States, Mexico, and Canada. Many of the variants contain single variants of functional significance (e.g. S: N501Y increases transmissibility). To study the occurrence and co-circulation of these variants, we have developed an easy-to-use dashboard at janieslab.github.io/sars-cov-2.

We created a multiple sequence alignment workflow and processing script to generate a variant dataset, which populates this dashboard. We then use the features of the dashboard, such as visualization of the single and complex nucleotide variants geospatially and in a color-coded matrix format. Users also interact with the dashboard to filter the underlying data to regions of interest and or variants of interest. The user can export reports based on the desired filters, which we intend to be used for regionally specific pandemic response. We find in Genbank, an isolate from Massachusetts containing [(S: Q677H), (ORF3a: Q57H), (M: A85S), (N: D377Y)] collected on September 11, 2020.

Moreover, we find that many viral isolates bear a marker of increased transmissibility (S: N501Y) in linkage with at least one variant of concern isolated from Ohio also range across the Untied States and stretch from British Columbia, Canada to Mexico. When we analyze co-circulation of more complex variant constellations with (S: N501Y), we note that the Upper Midwest and Northeast United States contain these isolates.

In summary, the viral variants that have raised concern in a few US States in recent reports are widespread. Based on the increase in the proportion of variant viruses being sampled and some empirical evidence in the United Kingdom, South Africa, and Ohio, these variants are likely to lead to increased transmission of SARS-CoV-2 across North America in the coming months.


title: The effectiveness of the first dose of BNT162 b 2 vaccine in reducing SARS-CoV-2 infection 13-24 days after immunization: real-world evidence

abstract:
BackgroundBNT162b2 vaccines showed high efficacy against COVID-19 in a randomised controlled phase-III trial. A vaccine effectiveness evaluation in real life settings is urgently needed, especially given the global disease surge. Hence, we assessed the short-term effectiveness of the first dose of BNT162b2-vaccine against SARS-CoV-2 infection. Given the BNT162b2 Phase-III results, we hypothesized that the cumulative incidence of SARS-CoV-2 infection among vaccinees will decline after 12 days following immunization compared to the incidence during the preceding days.

MethodsWe conducted a retrospective cohort study using data from 2{middle dot}6 million-member state-mandated health provider in Israel. Study population consisted of all members aged 16 or above years who were vaccinated with BNT162b2-vaccine between December/19/2020 and January/15/2021. We collected information regarding medical history and positive SARS-CoV-2 polymerase chain reaction test from days after first dose to January/17/2021. Daily and cumulative infection rates in days 13-24 were compared to days 1-12 after first dose using Kaplan-Meier survival analysis and generalized linear models.

FindingsData of 503,875 individuals (mean age 59{middle dot}7 years SD=14{middle dot}7, 47{middle dot}8% males) were analysed, of whom 351,897 had 13-24 days of follow-up. The cumulative incidence of SARS-CoV-2 infection was 0{middle dot}57% (n=2484) during days 1-12 and 0{middle dot}27% (n=614) in days 13-24. A 51{middle dot}4% relative risk reduction (RRR) was calculated in weighted-average daily incidence of SARS-CoV-2 infection from 43{middle dot}41-per-100,000(SE=12{middle dot}07) in days 1-12 to 21{middle dot}08-per-100,000(SE=6{middle dot}16) in days 13-24 following immunization. The decrement in incidence was evident from day 18 after first dose. Similar RRRs were calculated in individuals aged 60 or above (44.5%), younger individuals (50.2%), females (50.0%) and males (52.1%). Findings were similar in sub-populations and patients with various comorbidities.

ConclusionsWe demonstrated an effectiveness of 51% of BNT162b2 vaccine against SARS-CoV-2 infection 13-24 days after immunization with the first dose. Immunization with the second dose should be continued to attain the anticipated protection.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed for follow-up studies regarding the effectiveness of BNT162b2 mRNA Covid-19 Vaccine without any language restrictions. The search terms were (BNT162b2 OR mRNA Covid-19 Vaccine) AND (effectiveness OR real-world OR phase IV) until Jan 15, 2021. We found no relevant observational studies among humans. We also assessed Phase II and Phase III clinical trials with BNT162b2 mRNA vaccine.

Added value of this studyTo our knowledge, this is the first and largest phase IV study on the effectiveness of the BNT162b2 mRNA COVID-19 vaccine in real-world settings. Our findings showed that the first dose of the vaccine is associated with an approximately 51% reduction in the incidence of PCR-confirmed SARS-CoV-2 infections at 13 to 24 days after immunization compared to the rate during the first 12 days. Similar levels of effectiveness were found across age groups, sex, as well as among individuals residing in Arab or ultra-orthodox Jewish communities that display an increased COVID-19 risk.

Implications of all the available evidenceThe study results indicate that in real life the first dose of the new BNT162b2 mRNA COVID-19 vaccine confers around 50% protection against overall SARS-CoV-2 infections (symptomatic or asymptomatic). Together our findings and the 95% efficacy shown in the phase III trial, suggest that the BNT162b2 vaccine should be administered in two doses to achieve maximum protection and impact in terms of disease burden reduction and possibly reducing SARS-CoV-2 transmission. COVID-19 vaccines should be urgently deployed globally.