title: CalScope: Monitoring SARS-CoV-2 Seroprevalence from Vaccination and Prior Infection in Adults and Children in California May 2021 to July 2021

abstract:
ImportanceUnderstanding how SARS-CoV-2 seroprevalence varies regionally across California is critical to the public health response to the pandemic.

ObjectiveTo estimate how many Californians have antibodies against SARS-CoV-2 from prior infection or vaccination.

DesignWave 1 of CalScope: a repeated cross-sectional serosurvey of adults and children enrolled between April 20, 2021 and June 16, 2021.

SettingA population-based random sample of households in seven counties in California (Alameda, El Dorado, Kern, Los Angeles, Monterey, San Diego, and Shasta) were invited to complete an at-home SARS-CoV-2 antibody test and survey instrument.

ParticipantsInvitations were sent to 200,000 randomly selected households in the seven counties. From each household, 1 adult (18 years and older) and 1 child (aged 6 months to 17 years) could enroll in the study. There were no exclusion criteria.

Main Outcome(s) and MeasuresAll specimens were tested for antibodies against the nucleocapsid and spike proteins of SARS-CoV-2. The primary outcome was serostatus category, which was determined based on antibody test results and self-reported vaccination status: seronegative, antibodies from infection only, antibodies from infection and vaccination, and antibodies from vaccination alone. We used inverse probability of selection weights and iterative proportional fitting to account for non-response.

Results11,161 households enrolled in wave 1 of CalScope, with 7,483 adults and 1,375 children completing antibody testing. As of June 2021, 27% (95%CI [23%, 31%]) of adults and 30% (95%CI [24%, 36%]) of children had evidence of prior SARS-CoV-2 infection; 33% (95%CI [28%, 37%]) of adults and 57% (95%CI [48%, 66%]) of children were seronegative. Serostatus varied regionally. Californians 65 years or older were most likely to have antibodies from vaccine alone (59%; 95%CI [48%, 69%]) and children between 5-11 years old were most likely to have antibodies from prior infection alone (36%; 95%CI [21%, 52%]).

Conclusions and RelevanceAs of June 2021, a third of adults in California and most children under 18 remained seronegative. Seroprevalence varied regionally and by demographic group, suggesting that some regions or populations might remain more vulnerable to subsequent surges than others.

Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the prevalence of vaccine and infection derived antibodies against SARS-CoV-2 in adults and children in California?

FindingsIn this population-based serosurvey that included 11,161 households, as of June 2021, 33% of adults and 57% of children were seronegative; 18% of adults and 26% of children had antibodies from infection alone; 9% of adults and 5% of children had antibodies from both infection and vaccination; and 41% of adults and 13% of children had antibodies from vaccination alone.

MeaningSerostatus varied considerably across geographic regions, suggesting that certain areas might be at increased risk for future COVID-19 surges.


title: Phenome-Wide Association Study of Actigraphy in the UK Biobank

abstract: Wrist-worn accelerometer actigraphy devices present the opportunity for large-scale data collection from people during their daily lives. Using data from approximately 100,000 participants in the UK Biobank, actigraphy-derived measures of physical activity, sleep, and diurnal rhythms were associated in exploration and validation cohorts with a full phenome-wide set of diagnoses, biomarkers and metadata. Rhythmicity was captured by two independent models based on accelerometer and skin temperature harnessing behavioral (diurnal) and molecular (circadian) components. We found that robust rhythms significantly with biomarkers, survival, and phenotypes including diabetes, hypertension, mood disorders, and chronic airway obstruction; these associations were comparable to those with physical activity and sleep. Surprisingly, associations were mostly consistent between the sexes, while modulation by age was significant. More importantly, rhythms were found to be powerful predictors of future diseases: a two standard deviation difference in wrist temperature rhythms corresponded to increases in rate of diagnosis of 61% in diabetes, 38% in chronic airway obstruction, 27% in anxiety disorders, and 22% in hypertension. Our PheWAS of actigraphy data in the UK Biobank establishes that rhythmicity is fundamental to modeling disease trajectories, as are physical activity and sleep. Integration of long-term remote biosensing into patient care could thus afford an individualized approach to risk management.

category: public and global health


title: Evaluating the number of unvaccinated people needed to exclude to prevent SARS-CoV-2 transmissions

abstract:
BackgroundVaccine mandates and vaccine passports (VMVP) for SARS-CoV-2 are thought to be a path out of the pandemic by increasing vaccination through coercion and excluding unvaccinated people from different settings because they are viewed as being at significant risk of transmitting SARS-CoV-2. While variants and waning efficacy are relevant, SARS-CoV-2 vaccines reduce the risk of infection, transmission, and severe illness/hospitalization in adults. Thus, higher vaccination levels are beneficial by reducing healthcare system pressures and societal fear. However, the benefits of excluding unvaccinated people are unknown.

MethodsA method to evaluate the benefits of excluding unvaccinated people to reduce transmissions is described, called the number needed to exclude (NNE). The NNE is analogous to the number needed to treat (NNT=1/ARR), except the absolute risk reduction (ARR) is the baseline transmission risk in the population for a setting (e.g., healthcare). The rationale for the NNE is that exclusion removes all unvaccinated people from a setting, such that the ARR is the baseline transmission risk for that type of setting, which depends on the secondary attack rate (SAR) typically observed in that type of setting and the baseline infection risk in the population. The NNE is the number of unvaccinated people who need to be excluded from a setting to prevent one transmission event from unvaccinated people in that type of setting. The NNE accounts for the transmissibility of the currently dominant Delta (B.1.617.2) variant to estimate the minimum NNE in six types of settings: households, social gatherings, casual close contacts, work/study places, healthcare, and travel/transportation. The NNE can account for future potentially dominant variants (e.g., Omicron, B.1.1.529). To assist societies and policymakers in their decision-making about VMVP, the NNEs were calculated using the current (mid-to-end November 2021) baseline infection risk in many countries.

FindingsThe NNEs suggest that at least 1,000 unvaccinated people likely need to be excluded to prevent one SARS-CoV-2 transmission event in most types of settings for many jurisdictions, notably Australia, California, Canada, China, France, Israel, and others. The NNEs of almost every jurisdiction examined are well within the range of the NNTs of acetylsalicylic acid (ASA) in primary prevention of cardiovascular disease (CVD) ([≥] 250 to 333). This is important since ASA is not recommended for primary prevention of CVD because the harms outweigh the benefits. Similarly, the harms of exclusion may outweigh the benefits. These findings depend on the accuracy of the model assumptions and the baseline infection risk estimates.

ConclusionsVaccines are beneficial, but the high NNEs suggest that excluding unvaccinated people has negligible benefits for reducing transmissions in many jurisdictions across the globe. This is because unvaccinated people are likely not at significant risk - in absolute terms - of transmitting SARS-CoV-2 to others in most types of settings since current baseline transmission risks are negligible. Consideration of the harms of exclusion is urgently needed, including staffing shortages from losing unvaccinated healthcare workers, unemployment/unemployability, financial hardship for unvaccinated people, and the creation of a class of citizens who are not allowed to fully participate in many areas of society.

RegistrationCRD42021292263

FundingThis study received no grant from any funding agency, commercial, or not-for-profit sectors. It has also received no support of any kind from any individual or organization. BH is supported by a personal research grant from the University of Wroclaw within the "Excellence Initiative - Research University" framework and by a scholarship from the Polish Ministry of Education and Science. None of these institutions were involved in this research and did not fund it directly.

Competing interestsThe authors have no competing interests to declare.

Ethical approvalNot applicable. All the work herein was performed using publicly available data.

Data reportingThe data used in this work are available at https://tinyurl.com/4m8mm4jh and https://decision-support-tools.com/.


title: Starting at the community: Treatment seeking pathways of children with suspected severe malaria in Uganda

abstract:
IntroductionCommunity health workers (CHW) usually refer children with suspected severe malaria to the nearest public health facility or a designated public referral health facility (RHF). Caregivers do not always follow this recommendation. This study aimed at identifying post-referral treatment-seeking pathways that lead to appropriate antimalarial treatment for children less than five years with suspected severe malaria.

MethodsAn observational study in Uganda enrolled children below five years presenting to CHWs with signs of severe malaria. Children were followed up 28 days after enrolment to assess their condition and treatment-seeking history, including referral advice and provision of antimalarial treatment from visited providers.

ResultsOf 2211 children included in the analysis, 96% visited a second provider after attending a CHW. The majority of CHWs recommended caregivers to take their child to a designated RHF (65%); however, only 59% followed this recommendation. Many children were brought to a private clinic (33%), even though CHWs rarely recommended this type of provider (3%). Children who were brought to a private clinic were more likely to receive an injection than children brought to a RHF (78% vs 51%, p<0.001) and more likely to receive the second or third-line injectable antimalarial (artemether: 22% vs. 2%, p<0.001, quinine: 12% vs. 3%, p<0.001). Children who only went to non-RHF providers were less likely to receive an artemisinin-based combination therapy (ACT) than children who attended a RHF (odds ratio [OR] = 0.64, 95% CI 0.51-0.79, p<0.001). Children who did not go to any provider after seeing a CHW were the least likely to receive an ACT (OR = 0.21, 95% CI 0.14-0.34, p<0.001).

ConclusionsHealth policies should recognise local treatment-seeking practices and ensure adequate quality of care at the various public and private sector providers where caregivers of children with suspected severe malaria actually seek care.


title: Proteomic Characterization of Acute Kidney Injury in Patients Hospitalized with SARS-CoV2 Infection

abstract: Acute kidney injury (AKI) is a known complication of COVID-19 and is associated with an increased risk of in-hospital mortality. Unbiased proteomics using longitudinally collected biological specimens can lead to improved risk stratification and discover pathophysiological mechanisms. Using longitudinal measurements of [~]4000 plasma proteins in two cohorts of patients hospitalized with COVID-19, we discovered and validated markers of COVID-associated AKI (stage 2 or 3) and long-term kidney dysfunction. In the discovery cohort (N= 437), we identified 413 upregulated and 40 downregulated proteins associated with COVID-AKI (adjusted p <0.05). Of these, 62 proteins were validated in an external cohort (p <0.05, N =261). We demonstrate that COVID-AKI is associated with increased markers of tubular injury (NGAL) and myocardial injury. Using estimated glomerular filtration (eGFR) measurements taken after discharge, we also find that 25 of the 62 AKI-associated proteins are significantly associated with decreased post-discharge eGFR (adjusted p <0.05). Proteins most strongly associated with decreased post-discharge eGFR included desmocollin-2, trefoil factor 3, transmembrane emp24 domain-containing protein 10, and cystatin-C indicating tubular dysfunction and injury. Using longitudinal clinical and proteomic data, our results suggest that while both acute and long-term COVID-associated kidney dysfunction are associated with markers of tubular dysfunction, AKI is driven by a largely multifactorial process involving hemodynamic instability and myocardial damage.

category: nephrology


title: Contribution of endogenous and exogenous antibodies to clearance of SARS-CoV-2 during convalescent plasma therapy

abstract:
Neutralizing antibodies are considered a key correlate of protection by current SARS-CoV-2 vaccines. The ability of antibody-based therapies, including convalescent plasma, to affect established disease remains to be elucidated. Only few monoclonal therapies and only when used at a very early stage of infection have shown efficacy. Here, we conducted a proof-of-principle study of convalescent plasma therapy in a phase I trial in 30 COVID-19 patients including immunocompromised individuals hospitalized early after onset of symptoms. A comprehensive longitudinal monitoring of the virologic, serologic, and disease status of recipients in conjunction with detailed post-hoc seroprofiling of transfused convalescent plasma, allowed deciphering of parameters on which plasma therapy efficacy depends. Plasma therapy was safe and had a significant effect on viral clearance depending on neutralizing and spike SARS-CoV-2 antibody levels in the supplied convalescent plasma. Endogenous immunity had strong effects on virus control. Lack of endogenous neutralizing activity at baseline was associated with a higher risk of systemic viremia. The onset of endogenous neutralization had a noticeable effect on viral clearance but, importantly, even after adjusting for their endogenous neutralization status recipients benefitted from therapy with high neutralizing antibody containing plasma.

In summary, our data demonstrate a clear impact of exogenous antibody therapy on the rapid clearance of viremia in the early stages of infection and provide directions for improved efficacy evaluation of current and future SARS-CoV-2 therapies beyond antibody-based interventions. Incorporating an assessment of the endogenous immune response and its dynamic interplay with viral production is critical for determining therapeutic effects.

One Sentence SummaryThis study demonstrates the impact of exogenous antibody therapy by convalescent plasma containing high neutralizing titers on the rapid clearance of viremia in the early stages of SARS-CoV-2 infection.

category: infectious diseases


title: Nipah virus outbreak in Kerala state, India amidst of COVID-19 pandemic

abstract:
BackgroundWe report here a Nipah virus (NiV) outbreak in Kozhikode district of Kerala state, India which had caused fatal encephalitis in an adolescent male and the outbreak response which led to the successful containment of the disease and the related investigations.

MethodsQuantitative real-time RT-PCR, ELISA based antibody detection and whole genome sequencing were performed to confirm the Nipah virus infection. Contacts of the index case were traced and isolated based on risk categorization. Bats from the areas near the epicenter of the outbreak were sampled for throat swabs, rectal swabs and blood samples for Nipah virus screening by real time RT-PCR and anti-Nipah virus bat IgG ELISA. Plaque reduction neutralization test was performed for the detection of neutralizing antibodies.

ResultsNipah viral RNA and anti-NiV IgG antibodies were detected in the serum of the index case. Rapid establishment of an onsite NiV diagnostic facility and contact tracing helped in quick containment of the outbreak. NiV sequences retrieved from the clinical specimen of the index case formed a sub-cluster with the earlier reported Nipah I genotype sequences from India with more than 95% similarity. Anti-NiV IgG positivity could be detected in 21% of Pteropus medius and 37.73% of Rousettus leschenaultia. Neutralizing antibodies against NiV could be detected in P.medius.

ConclusionsStringent surveillance and awareness campaigns needs to be implemented in the area to reduce human-bat interactions and minimize spill over events which can lead to sporadic outbreaks of NiV.


title: SARS-CoV-2 and endemic coronaviruses: Comparing symptom presentation and severity of symptomatic illness among Nicaraguan children

abstract: It has been proposed that as SARS-CoV-2 transitions to endemicity, children will represent the greatest proportion of SARS-Co-V-2 infections as they currently do with endemic coronavirus infections. While SARS-CoV-2 infection severity is low for children, it is unclear if SARS-CoV-2 infections are distinct in symptom presentation, duration, and severity from endemic coronavirus infections in children. We compared symptom risk and duration of endemic human coronavirus (HCoV) infections from 2011-2016 with SARS-CoV-2 infections from March 2020-September 2021 in a Nicaraguan pediatric cohort. Blood samples were collected from study participants annually in February-April. Respiratory samples were collected from participants that met testing criteria. Blood samples collected in were tested for SARS-CoV-2 antibodies and a subset of 2011-2016 blood samples from four-year-old children were tested for endemic HCoV antibodies. Respiratory samples were tested for each of the endemic HCoVs from 2011-2016 and for SARS-CoV-2 from 2020-2021 via rt-PCR. By April 2021, 854 (49%) cohort participants were ELISA positive for SARS-CoV-2 antibodies. Most participants had antibodies against one alpha and one beta coronavirus by age four. We observed 595 symptomatic endemic HCoV infections from 2011-2016 and 121 symptomatic with SARS-CoV-2 infections from March 2020-September 2021. Symptom presentation of SARS-CoV-2 infection and endemic coronavirus infections were very similar, and SARS-CoV-2 symptomatic infections were as or less severe on average than endemic HCoV infections. This suggests that, for children, SARS-CoV-2 may be just another endemic coronavirus. However, questions about the impact of variants and the long-term effects of SARS-CoV-2 remain.


title: Efficient mucosal antibody response to SARS-CoV-2 vaccination is induced in previously infected individuals

abstract: Mucosal immune responses are critical to prevent respiratory infections but it is unclear to what extent antigen specific mucosal secretory IgA (SIgA) antibodies are induced by mRNA vaccination in humans. We analyzed, therefore, paired serum and saliva samples from study participants with and without COVID-19 at multiple timepoints before and after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccination. Our results suggest that the level of mucosal SIgA responses induced by mRNA vaccination depend on pre-existing immunity. Indeed, vaccination induced only a weak mucosal SIgA response in individuals without pre-existing mucosal antibody responses to SARS-CoV-2 while SIgA induction after vaccination was efficient in COVID-19 survivors. Our data indicate that vaccinated seropositive individuals were able to swiftly induce relatively high anti-spike SIgA responses by boosting pre-existing mucosal immunity. In contrast, seronegative individuals did not have pre-existing anti-SARS-CoV-2 or cross-reacting anti-HCoV SIgA antibodies prior to vaccination, and, thus, little or no anti-SARS-CoV-2 SIgA antibodies were induced by vaccination in these individuals.

category: allergy and immunology


title: Attributable is Preventable: Corrected and revised estimates of population attributable fraction of TB related to undernutrition in 30 high TB burden countries

abstract:
IntroductionThe Global TB Report 2020 estimated the population attributable fractions (PAF) for the major risk factors of TB. Undernourishment emerged as the leading risk factor accounting for 19% of the cases. The WHO however used the terms undernourishment and undernutrition interchangeably in its computation of PAF. Undernourishment is an indirect model derived estimate of decreased per capita energy availability, while undernutrition is defined by direct anthropometric measurements of nutritional status.

MethodsWe re-estimated the PAF of undernutrition (instead of undernourishment) in 30 high TB burden countries, using the prevalence of undernutrition (age standardized estimate of BMI < 18.5 kg/m2 in adults for both sexes), and the relative risk (RR) of 3.2. Further, we revised PAF estimates of undernutrition with an RR of 4.49, in light of recent evidence.

FindingsTwenty four percent of TB in high burden countries is attributable to undernutrition. The PAF of undernutrition was highest in Asian countries, unlike the PAF of undernourishment that was highest in Africa. The corrected estimate led up to 65% increase in number of cases attributable to undernutrition in Asian countries. More than one-third to nearly half of TB cases in India could be attributable to undernutrition.

InterpretationEstimation of the PAF of TB related to undernutrition is methodologically valid and operationally relevant, rather than PAF related to undernourishment. Addressing undernutrition, the leading driver of TB in high TB burden countries (especially Asia) could enable achievement of END TB milestones of TB incidence for 2025.

category: epidemiology


title: Associations of Epstein-Barr Virus Infection with Attention Deficit Hyperactivity Disorder, Learning Disability, and Special Education in U.S. Children

abstract:
BackgroundMost infections of Epstein-Barr virus (EBV), which is potentially neurotropic, occurred in childhood, but little is known about its association with child neurodevelopmental outcomes.

MethodsWe determined whether EBV seropositivity was associated with parent-reported attention deficit hyperactivity disorder (ADHD), learning disability, or special education utilization among children, using data from the National Health and Nutrition Examination Survey (NHANES) 2003-2004. Potential confounding factors were adjusted using survey logistic regression models.

ResultsEBV seroprevalence was 69.6% (95% CI, 67.1%-72.1%) for U.S. children aged 6-19. The prevalence was 8.86% (95% CI, 7.47%-10.47%) for ADHD among 6-19 year olds, 11.70% (95% CI, 9.84%-13.87%) for learning disability among 6-15 year olds, and 10.18% (95% CI, 8.58%-12.05%) for special education among 6-17 year olds. Children with positive anti-EBV had higher crude prevalence rates of learning disability and special education but not ADHD compared with those with negative anti-EBV. The adjusted odds ratios were 2.76 (95% CI, 1.53-4.96) for learning disability, 3.58 (95% CI, 1.92-6.55) for special education, and 0.77 (95% CI, 0.42-1.38) for ADHD, when comparing children with positive and negative anti-EBV.

ConclusionsEBV seropositivity was associated with learning disability and special education among U.S. children. Future studies that longitudinally examine the associations are warranted.

category: pediatrics


title: Personal Resources, Emotion Regulation, Parenting Style, Social Support On Cyberbullying Victims: A Literature Review

abstract: Cyberbullying is a teenage phenomenon that needs attention because it causes serious short-term and long-term impacts in all aspects of health. The right coping strategies are needed by teenagers to be able to face cyberbullying so that teenagers have good resilience. The purpose of this literature review is to find out what are the important things that need to be considered in cyberbullying victims. The method of writing this article is a literature review of 25 articles with the year 2019-2021 published from the Scopus, Science direct, SAGE and Proquest databases. The method of searching and selecting articles used The Center for Review and Dissemination and the Joanna Briggs Institute Guideline and PRISMA Checklist with selection criteria using the PICOS approach. The results of the literature review show that Personal Resources, Emotional Regulation, Parenting Patterns and Support from Peers, Family/Parents, and Teachers is an important thing that needs to be considered for victims of cyberbullying. Furthermore, Adolescents need to get promotive and interventional programs to improve their abilities in coping strategies against cyberbullying and bullying so that with the right coping strategies they will feel good welfare and optimal academic achievement at school.


title: Genetic insights into smoking behaviours in 10,558 men of African ancestry from continental Africa and the UK

abstract:
Smoking is a leading risk factor for many of the top ten causes of death worldwide. Of the 1 billion smokers globally, 80% live in low- and middle-income countries, where the number of deaths due to tobacco use is expected to double in the next decade according to the World Health Organization. Genetic studies have helped to identify biological pathways for smoking behaviours, but have mostly focussed on individuals of European ancestry or living in either North America or Europe.

Here we present a genome-wide association study of two smoking behaviour traits in 10,558 men of African ancestry living in five African countries and the UK. Eight independent variants were associated with either smoking initiation or cessation at p-value < 5 x 10-6. Of these, four were monomorphic or rare in European populations. Gene prioritization strategy highlighted five genes, including SEMA6D, previously described as associated with several smoking behaviour traits. These results confirm the importance of genetic epidemiological studies in underrepresented populations.

category: genetic and genomic medicine


title: Risk of SARS-CoV-2 reinfections in children: prospective national surveillance, January 2020 to July 2021, England

abstract:
BackgroundReinfection after primary SARS-CoV-2 infection is uncommon in adults, but little is known about the risks, characteristics, severity or outcomes of reinfection in children.

MethodsWe used national SARS-CoV-2 testing data in England to estimate the risk of reinfection [≥]90 days after primary infection from 01 January 2020 to 31 July 2021, which encompassed both the Alpha and Delta waves in England. Disease severity was assessed by linking reinfection cases to national hospitalisation, intensive care admission and death registrations datasets.

FindingsReinfection rates closely followed community infection rates, with a small peak during the Alpha wave and a larger peak during the Delta wave. In children aged [≤]16 years, there were 688,418 primary infections and 2,343 reinfections. The overall reinfection rate was 66{middle dot}88/100,000 population, being higher in adults (72.53/100,000) than in children (21{middle dot}53/100,000). Reinfection rates after primary infection were 0{middle dot}68% overall, 0{middle dot}73% in adults and 0{middle dot}34% in children. Of the 109 reinfections in children admitted to hospital, 78 (72%) had underlying comorbidities. Hospitalisation rates were similar for the first (64/2343, 2{middle dot}73%) and second episode (57/2343, 2{middle dot}43%). Intensive care admission was rare after primary infection (n=7) or reinfection (n=4), mainly in children with comorbidities. 44 deaths occurred after primary infection within 28 days of diagnosis (44/688,418, 0{middle dot}01%), none after possible reinfections.

InterpretationThe risk of SARS-CoV-2 reinfection is strongly related to exposure due to community infection rates, especially during the Delta variant wave. Children had a lower risk of reinfection than adults, but reinfections were not associated with more severe disease or fatal outcomes.

FundingPHE/UKHSA

Research in ContextO_ST_ABSEvidence Before this studyC_ST_ABSWe searched PubMed with the terms "COVID-19" or "SARS-CoV-2" with "reinfection" to identify publications relating to SARS-CoV-2 reinfections from 01 January until 15 November 2021. There were few publications relating to SARS-CoV-2 reinfections, and these primarily related to adults. Published studies reported very low rates of reinfection during the first few months after primary infection in adults. COVID-19 vaccines provide effective immune protection against SARS-CoV-2 infection, but recent studies have reported increasing risk of breakthrough infection with time since primary vaccination due to waning immunity. Several SARS-CoV-2 variants, including the beta, gamma and delta variants have been shown to partially evade immunity after natural infection and vaccination, potentially increasing the risk of reinfections and breakthrough infections, respectively. Data on reinfections in children are lacking and restricted mainly to case reports in immunocompromised children.

Added Value of This StudyWe used national SARS-CoV-2 testing data during the first 19 months of the pandemic to estimate the risk of reinfection in children compared to adults during a period that encompassed both the Alpha and the Delta variant waves in England. We found that the risk of reinfection correlated with the risk of SARS-CoV-2 exposure and therefore, closely reflected community infection rates, with most reinfections occurring during the Delta variant wave. Whilst acknowledging the limitation of using national testing data, we found that children had a lower risk of reinfection compared to adults and that the risk of reinfection in children increased with age. Reinfections were not associated with severe disease in terms of hospitalization or intensive care admission and there were no fatalities within 28 days of the reinfection episode in children.

Implications of all the Available EvidenceSARS-CoV-2 reinfections are rare in children, especially younger children, and occurred mainly during the Delta wave in England. Reinfections were not associated with more severe disease or fatal outcomes in children. COVID-19 vaccination will provide further protection against primary infections and reinfections in children.


title: Aerosol emission rates from playing wind instruments -- Implications for COVID-19 transmission during music performance

abstract:
BackgroundThe pandemic of COVID-19 led to exceeding restrictions especially in public life and music business. Airborne transmission of SARS-CoV-2 demands for risk assessment also in wind playing situations. Previous studies focused on short-range transmission, whereas long-range transmission has not been assessed so far.

Methods and findingsWe measured resulting aerosol concentrations in a hermetically closed cabin of 20 m3 in an operating theatre from 20 minutes standardized wind instrument playing (19 flute, 11 oboe, 1 clarinet, 1 trumpet players). Based on the data, we calculated total aerosol emission rates showing uniform distribution for both instrument groups (flute, oboe). Aerosol emission from wind instruments playing ranged from 7 {+/-} 327 particles/second (P/s) up to 2583 {+/-} 236 P/s, average rate {+/-} standard deviation. The analysis of the aerosol particle size distribution showed that about 70 - 80% of emitted particles had a size [≤] 0.4 {micro}m and thus being alveolar. Masking the bell with a surgical mask did not reduce aerosol emission. Aerosol emission rates were higher from wind instruments playing than from speaking and breathing. Differences between instrumental groups could not be found, but high interindividual variance as expressed by uniform distribution of aerosol emission rates.

ConclusionsOur findings indicate that aerosol emission depends on physiological factors and playing techniques rather than on the type of instrument, in contrast to some previous studies. Based on our results, we present risk calculations for long-range transmission of COVID-19 for three typical woodwind playing situations.


title: Plasmodium vivax malaria serological exposure markers: assessing the degree and implications of cross-reactivity with P. knowlesi

abstract: Serological exposure markers are a promising tool for surveillance and targeted interventions for Plasmodium vivax malaria. P. vivax is closely related to the zoonotic parasite P. knowlesi, which also infects humans. P. vivax and P. knowlesi are co-endemic across much of South East Asia, making it important to design P. vivax serological markers that minimise cross-reactivity in this region. Our objective was to determine the degree of IgG antibody cross-reactivity against a panel of P. vivax serological markers in samples from human participants with P. knowlesi malaria. We observed higher levels of IgG antibody reactivity against P. vivax proteins that had high levels of sequence identity with their P. knowlesi ortholog. IgG reactivity peaked at 7 days post P. knowlesi infection and was short-lived, with minimal responses detected at 1-year post-infection. Using these data, we designed a panel of 8 P. vivax proteins with low-levels of cross-reactivity with P. knowlesi. This panel was able to accurately classify recent P. vivax infections whilst reducing misclassification of recent P. knowlesi infections.


title: Characterization of the genetic relationship between the domains of sleep and circadian-related behaviors with substance use phenotypes

abstract: Sleep problems and substance use frequently cooccur. While substance use can often manifest as specific sleep deficits, genetic pleiotropy could also explain part of the relationship between sleep and substance use. Here we assess the genetic overlap between substance use behaviors and both sleep and circadian-related activity measures by deriving genetic clusters between these domains and testing processes of causality vs. horizontal pleiotropy using the largest publicly available genome-wide summary statistics of substance use behaviors (N= 79,729 - 632,802) and sleep/activity phenotypes/endophenotypes to date (N=85,502 - 449,734). We found 31 genetic correlations between substance use and sleep/activity measures after Bonferroni correction. Two specific genetic clusters explained our patterns of overlap. Genes associated with tobacco use severity (age of first regular tobacco use and smoking cessation) share overlap with elements of sleep health (sleep duration, sleep efficiency, and chronotype). Substance consumption (drinks per day and cigarettes per day) and problematic substance use behaviors (cannabis use disorder, opioid use disorder, and problematic alcohol use) clustered strongly with problematic measures of sleep (insomnia, self-reported short sleep duration, increased number of sleep episodes, increased sleep duration variability, diurnal inactivity) as well as measures of circadian-related activity (L5, M10, and sleep midpoint). Latent causal variable analyses determined that horizontal pleiotropy (rather than causality) underlies a majority of the associations between substance use and sleep/circadian related measures, except one plausible genetically causal relationship for opioid use disorder on self-reported long sleep duration. Results indeed show significant genetic overlap between substance use and sleep/circadian-related activity measures.

category: addiction medicine


title: Machine Learning to Understand Genetic and Clinical Factors Associated with the Pulse Waveform Dicrotic Notch

abstract:
BackgroundAbsence of a dicrotic notch on finger photoplethysmography (PPG) is an easily ascertainable and inexpensive trait that has been associated with age and prevalent cardiovascular disease (CVD). However, the trait exists along a continuum, and little is known about its genetic underpinnings or prognostic value for incident CVD.

MethodsIn 169,787 participants in the UK Biobank, we identified absent dicrotic notch on PPG and created a novel continuous trait reflecting notch smoothness using machine learning. Next, we determined the heritability, genetic basis, polygenic risk, and clinical relations for the binary absent notch trait and the newly derived continuous notch smoothness trait.

ResultsHeritability of the continuous notch smoothness trait was 7.5%, compared with 5.6% for the binary absent notch trait. A genome wide association study of notch smoothness identified 15 significant loci, implicating genes including NT5C2 (P=1.2x10-26), IGFBP3 (P=4.8x10-18), and PHACTR1 (P=1.4x10-13), compared with 6 loci for the binary absent notch trait. Notch smoothness stratified risk of incident myocardial infarction or coronary artery disease, stroke, heart failure, and aortic stenosis. A polygenic risk score for notch smoothness was associated with incident CVD and all-cause death in UK Biobank participants without available PPG data.

ConclusionWe found that a machine learning derived continuous trait reflecting dicrotic notch smoothness on PPG was heritable and associated with genes involved in vascular stiffness. Greater notch smoothness was associated with greater risk of incident CVD. Raw digital phenotyping may identify individuals at risk for disease via specific genetic pathways.

category: cardiovascular medicine


title: Detection of acne by deep learning object detection

abstract:
ImportanceState-of-the art performance is achieved with a deep learning object detection model for acne detection. There is little current research on object detection in dermatology and acne in particular. As such, this work is early in this field and achieves state of the art performance.

ObjectiveTrain an object detection model on a publicly available data set of acne photos.

Design, Setting, and ParticipantsA deep learning model is trained with cross validation on a data set of facial acne photos.

Main Outcomes and MeasuresObject detection models for detecting acne for single-class (acne) and multi-class (four severity levels). We train and evaluate the models using standard metrics such as mean average precision (mAP). Then we manually evaluate the model predictions on the test set, and calculate accuracy in terms of precision, recall, F1, true and false positive and negative detections.

ResultsWe achieve state-of-the art mean average precision mAP@0.5 value of 37.97 for the single class acne detection task, and 26.50 for the 4-class acne detection task. Moreover, our manual evaluation shows that the single class detection model performs well on the validation set, achieving true positive 93.59 %, precision 96.45 % and recall 94.73 %.

Conclusions and RelevanceWe are able to train a high-accuracy acne detection model using only a small publicly available data set of facial acne. Transfer learning on the pre-trained deep learning model yields good accuracy and high degree of transferability to patient submitted photographs. We also note that the training of standard architecture object detection models has given significantly better accuracy than more intricate and bespoke neural network architectures in the existing research literature.

Key PointsO_ST_ABSQuestionC_ST_ABSCan deep learning-based acne detection models trained on a small data set of publicly available photos of patients with acne achieve high prediction accuracy?

FindingsWe find that it is possible to train a reasonably good object detection model on a small, annotated data set of acne photos using standard deep learning architectures.

MeaningDeep learning-based object detection models for acne detection can be a useful decision support tools for dermatologists treating acne patients in a digital clinical practice. It can prove a particularly useful tool for monitoring the time evolution of the acne disease state over prolonged time during follow-ups, as the model predictions give a quantifiable and comparable output for photographs over time. This is particularly helpful in teledermatological consultations, as a prediction model can be integrated in the patient-doctor remote communication.

category: dermatology


title: Increased risk of cognitive impairment and hyperglycemia-related mortality in late middle-aged African Americans with low serum adropin levels

abstract: Recent data implicate the secreted peptide adropin in the physiology of aging. In humans, adropin is highly expressed in brain tissues, and correlates positively with transcriptomic signatures of mitochondrial and synaptic functions. Adropin treatment improves performance of old mice in cognitive tests requiring learning and memory. While detected in the circulation of humans, no studies have investigated relationships between adropin, cognitive decline and aging. Here we compared serum adropin concentrations with Mini-Mental State Exam (MMSE) and animal naming test results from a cohort study of African Americans in late-middle age (baseline ages 49-65y, n=357). Using the lowest quintile of the MMSE to identify participants at risk for mild cognitive impairment (MCI) indicated lower serum concentrations (2.95{+/-}1.32 ng/ml vs. 3.31{+/-}1.56, P<0.05). Grouping into bins using 1-ng/ml increments in serum adropin concentrations further indicated an association between very low serum adropin concentrations and MCI. Using fructosamine as an indicator of moderate-term glucose levels suggested low serum adropin concentration correlate with increased risk of 10-year all-cause mortality in situations of poor glucose control. In summary, these data suggest low circulating adropin concentrations identify late-middle aged people at risk for cognitive impairment, and for all-cause mortality in situations of poor glucose control.

category: endocrinology


title: Adolescent vaccination with BNT162b2 (Comirnaty, Pfizer-BioNTech) vaccine and effectiveness of the first dose against COVID-19: national test-negative case-control study, England

abstract: Adolescents in the UK were recommended to have their first dose of mRNA vaccine during a period of high community transmission due to the highly transmissible Delta variant, followed by a second dose at an extended interval of 8-12 weeks. We used national SARS-CoV-2 testing, vaccination and hospitalisation data to estimate vaccine effectiveness (VE) using a test-negative case-control design, against PCR-confirmed symptomatic COVID-19 in England. BNT162b2 vaccination in 12-15-year-olds and 16-17-year-olds was associated with lower VE against symptomatic COVID-19 caused by Omicron compared to Delta. Data shows a rapid increase in VE against symptomatic COVID-19 after the second dose for both Delta and Omicron, although this declines to 23% against Omicron after 70+ days. Very high protection was achieved for Delta against hospitalisation after one dose. Our data highlight the importance of the second vaccine dose for protection against symptomatic COVID-19 and raise important questions about the objectives of an adolescent immunisation programme. If prevention of infection is the primary aim, then regular COVID-19 vaccine boosters will be required.


title: Adolescent vaccination with BNT162b2 (Comirnaty, Pfizer-BioNTech) vaccine and effectiveness against COVID-19: national test-negative case-control study, England


title: Psychometric Properties of a New Stress-Related Personality Scale: The Virtual Inventory of Behavior and Emotions (VIBE)

abstract:
BackgroundPersonality traits are important factors with regard to the tendency to experience and response to stress. This study introduces and tests a new stress-related personality scale called the Virtual Inventory of Behavior and Emotions (VIBE).

MethodsTwo samples totaling 5512 individuals (with 66% between the ages of 18 and 34) completed the VIBE along with other measures of personality, stress, mood, and well-being. Results: Exploratory factor analyses revealed a four-factor structure for the instrument with dimensions labelled: 1) stressed; 2) energetic; 3) social; and 4) disciplined. Confirmatory factor analytic procedures on the final 23-item version showed good psychometric properties and data fit while machine learning analyses demonstrated the VIBEs ability to distinguish between groups with similar patterns of response. Strong convergent validity was suggested through robust correlations between the dimensions of the VIBE and other established rating scales.

ConclusionOverall, the data suggest that the VIBE is a promising tool to help advance understanding of the relations between stress, personality, and related constructs.

category: psychiatry and clinical psychology


title: Mental health indicators in Sweden over a 12-month period during the COVID-19 pandemic

abstract:
BackgroundThe ongoing COVID-19 pandemic has had an unprecedented impact on the lives of people globally and is expected to have profound effects on mental health. Yet, self-reported large-scale online surveys on mental health are still relatively uncommon. Here we aim to describe the mental health burden experienced in Sweden using baseline data of the Omtanke2020 Study.

MethodSelf-reported baseline data collected over a 12-month period (June 9, 2020-June 8, 2021) from the longitudinal online survey of the Omtanke2020 Study including 27,950 adults in Sweden. Participants were volunteers or actively recruited through existing cohorts and after providing informed consent responded to monthly online questionnaires on socio-demographics, mental and physical health, COVID-19 infection, and impact. Poisson regression was fitted to assess the relative risk of high mental health burden (depression, anxiety, and COVID-19 specific PTSD).

ResultThe overall proportion of persons with high level of symptoms was 15.6%, 9.5% and 24.5% for depression, anxiety, and COVID-19 specific PTSD, respectively. Overall, 43.4% of the participants had significant, clinically relevant symptoms for at least one mental health outcome and 7.3% had significant symptoms for all three outcomes. We also observed differences in the prevalence of these symptoms across strata of sex, age, recruitment type, COVID-19 status, region, and seasonality.

ConclusionWhile the proportion of persons with high mental health burden remains higher than in pre-pandemic publications, our estimates are lower than previously reported levels of depression, anxiety, and PTSD during the pandemic in Sweden and elsewhere.


title: Down-regulation of SARS-CoV-2 neutralizing antibodies in vaccinated smokers

abstract: Vaccination is an effective approach to help control coronavirus disease 2019 (COVID-19). However, since the vaccines produce a heterogenous immune response, the risk of breakthrough infection is increased in vaccinated individuals who generate low levels of neutralizing antibodies (NAbs). It is therefore paramount in the fight against COVID-19 to identify individuals who have a higher risk of breakthrough infection despite being vaccinated. Here we addressed the effect of cigarette smoking on the production of neutralizing antibodies (NAbs) following COVID-19 vaccination since smoking profoundly suppresses the adaptive immune response to pathogen infection and the association between vaccination and smoking remains unclear. The SARS-CoV-2 Spike antibodies and NAbs (days 0, 14, 42, and 90) were measured in 164 participants received two vaccine doses of an inactivated vaccine (Sinovac-CoronaVac) longitudinally. Anti-Spike antibodies was elevated 14 and 42 days after COVID-19 vaccination compared to baseline (i.e., "Day 0"). Notably, RBD antibodies showed significantly higher expression in the nonsmoking group (n=153) than the smoking (n=11) group on day 42 (p<0.0001, Students t-test). NAbs continually increased after the first and second vaccine dose, peaking on day 42. NAbs titers then significantly decreased until day 90. Compared to nonsmokers, the NAb levels in smokers remained low throughout the period of testing. The median NAb titers in the smoking group was 1.40-, 1.32-, or 3.00-fold lower than that of nonsmoking group on day 14, 42, or 90, respectively. Altogether, our results indicate that smoking is a specific risk factor for COVID-19 breakthrough infection following vaccination.


title: COVID-19 booster vaccine attitudes and behaviors among university students and staff: the USC Trojan Pandemic Research Initiative

abstract:
IntroductionAlthough COVID-19 vaccines significantly reduce morbidity and mortality, recent evidence suggests that immunity wanes after 6-9 months, and that a third vaccine dose could further reduce COVID-19 transmission and severe illness. However, previous studies have not assessed attitudes about getting booster doses. This study examined COVID-19 booster vaccine attitudes and behaviors among university students and staff in the fall of 2021.

MethodsParticipants responded to an email invitation and completed electronic surveys. Results. In our sample, 96.2% of respondents indicated willingness to get a COVID-19 booster shot at least once per year. In both bivariate and multivariate analyses higher trust in science was associated with having higher odds of booster willingness. Those who identify as Black, on average, reported trusting science less than other racial/ethnic groups.

ConclusionsOur findings demonstrate high willingness to receive a COVID-19 booster shot and highlight the importance of educational and motivational messages that focus on trust in science to increase willingness to get the COVID-19 booster. More research is needed to better understand the impact of cultural beliefs on booster willingness and vaccine hesitancy. This understanding will help determine what messages and populations to target to increase booster willingness in the future.


title: Effects of midfoot joint mobilization on perceived ankle-foot function in chronic ankle instability. A crossover clinical trial.

abstract:
BackgroundChronic ankle instability (CAI) is a complex clinical entity that commonly includes ankle-foot impairment.

ObjectiveTo investigate the effects of midfoot joint mobilizations and a one-week home exercise program (HEP) compared to a sham intervention and HEP on pain, patient-reported outcomes (PROs), ankle-foot joint mobility, and neuromotor function in young adults with CAI.

MethodsTwenty participants with CAI were instructed in a stretching, strengthening, and balance HEP and were randomized a priori to receive midfoot joint mobilizations (forefoot supination, cuboid glide and plantar 1st tarsometatarsal) or a sham laying-of-hands. Changes in foot morphology, joint mobility, strength, dynamic balance, and PROs assessing pain, physical, and psychological function were assessed pre-to-post treatment and one-week following. Participants crossed-over to receive the alternate treatment and were assessed pre-to-post treatment and one-week following. Linear modelling was used to assess changes in outcomes.

ResultsParticipants who received midfoot mobilization demonstrated significantly greater perceived improvement immediately posttreatment in the single assessment numeric evaluation (Sham: 5.0{+/-}10.2%; Mobilization: 43.9{+/-}26.2%; {beta}: 6.8 p<0.001, Adj R2:0.17) and Global Rating of Change (Sham: -0.1{+/-}1.1; Mobilization: 1.1{+/-}3.0; {beta}: 1.8 p=0.01, Adj R2:0.12). Following the mobilization intervention, participants demonstrated greater improved rearfoot inversion mobility (Sham: 4.4{+/-}8.4{degrees}; Mobilization: -1.6{+/-}6.1{degrees}; {beta}: -6.37, p=0.01, Adj R2:0.19), plantarflexion mobility (Sham: 2.7{degrees}{+/-}6.4; Mobilization: -1.7{degrees}{+/-}4.3; {beta}: -4.36, p=0.02, Adj R2:0.07), and posteromedial dynamic balance (Sham: 2.4{+/-}5.9%; Mobilization: 6.0{+/-}5.4%; {beta}: 3.88, p=0.04, Adj R2:0.10) compared to controls at 1-week post-treatment.

ConclusionParticipants with CAI who received midfoot joint mobilization had greater perceived improvement and physical signs that may benefit this clinical population.

category: rehabilitation medicine and physical therapy


title: Cytokine release syndrome-like serum responses after COVID-19 vaccination are frequent but clinically inapparent in cancer patients under immune checkpoint therapy

abstract: Cancer patients frequently receive immune checkpoint therapies (ICT) which may modulate immune responses to COVID-19 vaccines. Recently, cytokine release syndrome (CRS) was observed in a cancer patient who received the BTN162b2 vaccine under ICT. Here, we analyzed adverse events (AEs) in patients of various solid tumor types undergoing (n=64) or not undergoing (n=26) COVID-19 vaccination under ICT as an exploratory endpoint of a prospectively planned cohort study. We did not observe clinically relevant CRS after vaccination (95% CI [0,0.056]). Short term (<4 weeks) serious AEs were rare (12.5%) and overall AEs under ICT were comparable to unvaccinated patients. Despite the absence of CRS symptoms, we observed a pairwise-correlated set of CRS-associated cytokines upregulated in 42% of patients after vaccination and ICT (>1.5fold). Hence, clinically meaningful CRS appears to be rare in cancer patients under ICT and elevated serum cytokine levels are common but not sufficient to establish CRS diagnosis.

category: oncology


title: Does the application of Robotics improve outcomes of pedicle screw insertion in spine surgery compared to conventional fluoroscopy guidance? A protocol for Systematic Review and Meta-Analysis

abstract:
BackgroundPedicle screw insertion is routinely carried out in spine surgery that has traditionally been performed under fluoroscopy guidance. Robotic guidance has recently gained popularity in order to improve the accuracy of screw placement. However, it is unclear whether the use of robotics alters the accuracy of screw placement or clinical outcomes.

ObjectivesThis systematic review aims to compare the results of pedicle screws inserted under fluoroscopy guidance, with those inserted under robotic guidance, in terms of both short-term radiographic outcomes, as well as long-term clinical outcomes.

MethodsThis systematic review will be conducted according to the PRISMA guidelines. A literature search will be conducted on the electronic databases of PubMed, Embase, Scopus, and Ovid with a pre-determined search strategy. A manual bibliography search of included studies will also be done. Original articles in English that directly compare pedicle screw insertion under robotic guidance to those inserted under fluoroscopy guidance will be included. Data on outcomes will be extracted from included studies and analysis carried out with the help of appropriate software.

category: orthopedics


title: The Intrathecal Morphine for Percutaneous Endoscopic Lumbar Discectomy (IMPELD) Study: Rationale and Protocol for a Double-blinded Randomized Placebo-controlled Trial

abstract:
BackgroundPercutaneous endoscopic lumbar discectomy (PELD), a minimally invasive spinal technique for lumbar disc herniation (LDH), has gained popularity globally and yielded satisfying results. However, PELD is often performed on awaking patients to avoid nerve injury, thus the intraoperative analgesia of PELD is sometimes insufficient. The effect of intrathecal morphine (ITM) has been well proved in various surgical specialties, and this study aims to investigate the effectiveness and safety of ITM on PELD.

MethodsThe intrathecal morphine for percutaneous endoscopic lumbar discectomy (IMPELD) trial is a double-blind, randomized, placebo-controlled trial. The 90 eligible LDH patients undergoing PELD will be randomly assigned to receive either ITM or placebo during spinal anesthesia, at a 1:1 ratio, with a one-month follow-up period. Average intraoperative pain intensity will be the primary outcome. Secondary outcome measures include intraoperative pain intensity assessed at each 30 min intraoperatively, postoperative pain intensity, perioperative analgesia requirements, functional evaluation, radiographic characteristics, overall satisfaction, other characteristics and adverse events.

DiscussionCurrently, there is a lack of scientific evidence to provide a reliable method to reduce intraoperative pain of PELD. The IMPELD trial was designed to provide evidence regarding whether 100 ug of ITM is an effective and safe coanalgesic approach for PELD procedure.

Trial registrationThe trial was registered with the Chinese Clinical Trial Registry (identifier ChiCTR2000039842). Registered on November 11th, 2020.


title: A Phenome Wide Association Study of Severe COVID-19 Genetic Risk Variants

abstract:
BackgroundGenetic loci associated with risk of severe COVID-19 infection have been identified and individuals with complicated COVID-19 infections often have multiple comorbidities.

ObjectiveIdentify known and unidentified comorbidities associated with genetic loci linked to risk of severe COVID-19 infection.

MethodsA Phenome Wide Association Study (PheWAS) was conducted in 247,448 unrelated, white individuals from the UK Biobank to test the association of 1,402 unique phenotypes with ten genome-wide significant severe-COVID risk single nucleotide polymorphisms (SNP) identified from prior studies. A validation PheWAS was conducted in 2,247 white individuals from the CATHGEN.

ResultsFour of the ten tested genetic loci showed significant phenotypic associations in UK Biobank after FDR adjustment. Vascular dementia significantly associated with rs7271165 near TMEM65 on 8q24.13 in individuals with the C risk allele (OR 5.66 [95% CI 2.21-11.85], q=0.049). We identified 40 novel phenotype associations with rs657152 on 9q34.2 coinciding with the ABO gene with individuals with the A COVID risk allele having higher odds of heart failure (OR 1.09 [95% CI 1.03-1.14], q=0.004), diabetes mellitus (OR 1.05 [95% CI 1.02-1.07], q=0.004) and hypercholesterolemia (OR 1.04 [95% CI 1.02-1.06], q=6.3x10-5). Eight phenotypes associated with rs1819040 near KANSL1 on 17q21.31 in individuals with the A risk allele including atrial fibrillation and flutter (OR 1.07 [95% CI 1.04-1.10], q=0.0084) and pulmonary fibrosis (OR 0.80 [95% CI 0.71-0.89], q=0.035). Ten novel phenotypic associations were identified in association with rs74956615 on 19p13.2 near the TYK2 gene including individuals with the A COVID risk allele having lower odds of psoriatic arthropathy (OR 0.31 [95% CI 0.20-0.47], q=4.5x10-5), rheumatoid arthritis (OR 0.83 [95% CI 0.64-0.83], p=1.4x10-6) and thyrotoxicosis with or without goiter (OR 0.77 [95% CI 0.68-0.87], p-6.9x10-5). Two associations for rs1819040 (KANSL1) and seven associations for rs74956615 (TYK2) validated in CATHGEN.

ConclusionsUsing a broad PheWAS approach in a large discovery and validation cohort, we have identified novel phenotypic associations with risk alleles for severe COVID-19 infection. Interestingly, the ABO locus was associated with comorbidities that are also risk factors for severe COVID-19 infection, suggesting that this locus has pleiotropic effects and provides a potential mechanism for this association. The 19p13 locus was associated with lower risk of autoimmune disease, these findings may have broad implications for the importance of multiple comorbidities across both infectious and non-infectious diseases and may provide insight in the molecular function of the genes near these genetic risk loci.


title: (SARS-CoV-2) COVID 19: Genomic surveillance and evaluation of the impact on the population speaker of indigenous language in Mexico

abstract: The importance of the working document is that it allows the analysis of information and cases associated with (SARS-CoV-2) COVID-19, based on the daily information generated by the Government of Mexico through the Secretariat of Health, responsible for the Epidemiological Surveillance System for Viral Respiratory Diseases (SVEERV). The information in the SVEERV is disseminated as open data, and the level of information is displayed at the municipal, state and national levels. On the other hand, the monitoring of the genomic surveillance of (SARS-CoV-2) COVID-19, through the identification of variants and mutations, is registered in the database of the Information System of the Global Initiative on Sharing All Influenza Data (GISAID) based in Germany. These two sources of information SVEERV and GISAID provide the information for the analysis of the impact of (SARS-CoV-2) COVID-19 on the population in Mexico. The first data source identifies information, at the national level, on patients according to age, sex, comorbidities and COVID-19 presence (SARS-CoV-2), among other characteristics. The data analysis is carried out by means of the design of an algorithm applying data mining techniques and methodology, to estimate the case fatality rate, positivity index and identify a typology according to the severity of the infection identified in patients who present a positive result. for (SARS-CoV-2) COVID-19. From the second data source, information is obtained worldwide on the new variants and mutations of COVID-19 (SARS-CoV-2), providing valuable information for timely genomic surveillance. This study analyzes the impact of (SARS-CoV-2) COVID-19 on the indigenous language-speaking population, it allows us to provide information, quickly and in a timely manner, to support the design of public policy on health.

category: health informatics


title: NIH Funding of COVID-19 Research in 2020: a Cross Sectional Study

abstract:
ObjectiveThis study aims to characterize and evaluate the NIHs grant allocation pattern of COVID-19 research.

DesignCross sectional study

SettingCOVID-19 NIH RePORTER Dataset was used to identify COVID-19 relevant grants.

Participants1,108 grants allocated to COVID-19 research.

Main Outcomes and MeasuresThe primary outcome was to determine the number of grants and funding amount the NIH allocated for COVID-19 by research type and clinical/scientific area. The secondary outcome was to calculate the time from the funding opportunity announcement to the award notice date.

ResultsThe NIH awarded a total of 56,169 grants in 2020, of which 2.0% (n=1,108) were allocated for COVID-19 research. The NIH had a $42 billion budget that year, of which 5.3% ($2.2 billion) was allocated to COVID-19 research. The most common clinical/scientific areas were social determinants of health (n=278, 8.5% of COVID-19 funding), immunology (n=211, 25.8%), and pharmaceutical interventions research (n=208, 47.6%). There were 104 grants studying COVID-19 non-pharmaceutical interventions, of which 2 grants studied the efficacy of face masks and 6 studied the efficacy of social distancing. Of the 83 COVID-19 funded grants on transmission, 5 were awarded to study airborne transmission of COVID-19, and 2 grants on transmission of COVID-19 in schools. The average time from the funding opportunity announcement to the award notice date was 151 days (SD: {+/-}57.9).

ConclusionIn the first year of the pandemic, the NIH diverted a small fraction of its budget to COVID-19 research. Future health emergencies will require research funding to pivot in a timely fashion and funding levels to be proportional to the anticipated burden of disease in the population.

category: health policy


title: Confirmation of multi-parallel quantitative real-time PCR as the gold standard for detecting soil-transmitted helminths in stool

abstract: Due to its simplicity and cost-effectiveness, microscopy has seen extensive field-use as the diagnostic standard for the detection of soil-transmitted helminths (STH) in stool samples. However, the sensitivity of microscopy-based detection is inadequate in reduced-transmission settings where worm burden is oftentimes low. Equally problematic, eggs of closely related species oftentimes have indistinguishable morphologies, leading to species misidentification. In light of these shortcomings, the purpose of this study was to demonstrate multi-parallel quantitative real-time PCR (qPCR) as the new "gold standard" for STH detection. Accordingly, stool samples from non-endemic participants were spiked with limited numbers of eggs or larvae (1 to 40) of five different species of STH. DNA extracts were tested using two unique multi-parallel real-time PCR-based diagnostic methods. These methods employed different target sequences (ribosomal internal transcribed spacer, or highly repetitive non-coding regions), to evaluate the detection of DNA from as little as one egg per sample. There was a statistically significant kendall correlation between egg/larvae counts and qPCR from both methods for Trichuris trichiura (0.86 and 0.872 for NHM and Baylor assays) and a strong correlation (0.602 and 0.631 for NHM and Baylor assays, respectively) for Ascaris lumbricoides. Less strong but still significant was the Kendall Tau-b value for A. duodenale (0.408 for both) and for S. stercoralis (0.483 and 0.653, respectively). In addition, using field stool samples from rural Argentina both assays had fair to moderate kappa agreement (0.329-0.454), except for Strongyloides stercoralis (0.121) that both assays had slight agreement. In spite of the small cohort of samples, both qPCR assays, targeting of two independent genomic regions, provided reproducible results and we believe that, low cost multi-parallel quantitative real-time PCR-based diagnostics should supplant microscopy as the new gold standard for stool-based detection of soil transmitted helminths in public-health and community settings.


title: Serum levels of specialised pro-resolving molecule pathways are greatly increased in SARS-CoV-2 patients and correlate with markers of the adaptive immune response.

abstract:
BackgroundSpecialised pro-resolution molecules (SPMs) halt the transition to chronic pathogenic inflammation. We aimed to quantify serum levels of pro- and anti-inflammatory bioactive lipids in SARS-CoV-2 patients, and to identify potential relationships with innate responses and clinical outcome.

MethodsSerum from 50 hospital admitted inpatients (22 female, 28 male) with confirmed symptomatic SARS-CoV-2 infection and 94 age and sex matched cohort collected prior to the pandemic, were processed for quantification of bioactive lipids. Anti-nucleocapsid and anti-spike quantitative binding assays were performed.

ResultsSARS-CoV-2 serum had significantly higher concentrations of omega-6 derived pro-inflammatory lipids and omega-6 and omega-3 derived SPMs, compared to age and sex matched controls. Levels of SPMs were not markedly altered by age. There were significant positive correlations between SPMs and other bioactive lipids and anti-spike antibody binding. Levels of some SPMs were significantly higher in patients with an anti-spike antibody value >0.5. Levels of linoleic acid (LA) and 5,6-dihydroxy-8Z,11Z,14Z-eicosatrienoic acid (5,6-DHET) were significantly lower in SARS-COV-2 patients who died.

DiscussionSARS-COV-2 infection was associated with a robust activation of the pathways that generate the specialised pro-resolution molecules and other anti-inflammatory bioactive lipids, supporting the future investigation of these pathways which may inform the development of novel treatments.


title: Disrupted functional connectivity of the brain reward system in substance use problems: a meta-analysis of functional neuroimaging studies

abstract:
ImportanceExtensive literature suggests that the brain reward system is crucial in understanding the neurobiology of substance use disorders. However, across studies on substance use problems, evidence of reliable disruptions in functional connectivity is limited.

ObjectiveTo uncover deficient functional connectivity with the brain reward system that are reliably associated with substance use problems, by meta-analytically synthesizing results of functional brain connectivity studies on substance use problems.

Data SourcesIdentification of relevant functional brain connectivity studies on substance misuse was done using PubMed, Google Scholar and EMBASE (until September 2021) with the following terms: cannabis, cocaine, substance, methamphetamine, amphetamine, alcohol, tobacco, nicotine, functional connectivity, resting-state, task-based connectivity, psychophysiological interaction.

Study SelectionGuidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses were followed, Publications were included if they reported stereotactic coordinates of functional brain connectivity results on individuals with substance use problems without a comorbid major mental illness or organic impairment.

Data Extraction and SynthesisSpatially convergent brain regions across functional connectivity studies on subjects with substance use problems were analyzed using Activation Likelihood Estimation meta-analysis.

Altered connectivity with regions of the brain reward system was performed carried out through voxelwise seed-based meta-analyses. Subanalyses were performed to examine mediating factors such as severity of illness, connectivity modalities and types of substances.

Main Outcomes and MeasuresIdentification of deficits in functional brain connectivity with the reward system across studies on substance use problems.

ResultsNinety-six studies using a seed-based connectivity approach were included, representing 5757 subjects with substance use problems. In subjects with substance use problems, the ventromedial prefrontal cortex exhibited hyperconnectivity with the ventral striatum, and hypoconnectivity with the amygdala and hippocampus. Executive striatum showed hyperconnectivity with motor thalamus and dorsolateral prefrontal cortex, and hypoconnectivity with anterior cingulate cortex and anterior insula. Finally, the limbic striatum was found to be hyperconnected to the orbitofrontal cortex, and hypoconnected to the precuneus, compared to healthy subjects.

Conclusions and RelevanceThe current study provided meta-analytical evidence of deficient functional connectivity between brain regions of the reward system and cortico-striato-thalamocortical loops in addiction, in line with current influential neurobiological models. These results are consistent with deficits in motivation and habit formation occurring in addiction, and they also highlight alterations in brain regions involved in socio-emotional processing and attention salience.

KEY POINTSO_ST_ABSQuestionC_ST_ABSWhat functional brain connectivities with the brain reward system are reliably disrupted across studies on substance use problems?

FindingsSubjects with substance use problems exhibited deficient connectivity between the ventromedial prefrontal cortex and subcortical structures including the ventral striatum, amygdala, and hippocampus. Executive striatum showed hyperconnectivity with motor thalamus and dorsolateral prefrontal cortex, and hypoconnectivity with anterior cingulate cortex and anterior insula. Altered connectivity between limbic striatum and core regions of the default mode network was also observed.

MeaningDeficient functional brain connectivity along the cortico-striato-thalamocortical loops may reflect deficits in habit formation, socio-emotional and salience processing in addiction.


title: Comparing men who have sex with men and inject drugs and people who inject drugs who are men and have sex with men in San Francisco: Implications for HIV and hepatitis C virus prevention

abstract:
BackgroundMen who have sex with men (MSM) and people who inject drugs (PWID) carry a disproportionate burden of HIV and hepatitis C virus (HCV) infections. We compared the demographic and risk profiles of MSM who inject drugs (MSM-IDU, i.e., men reached through affiliation with MSM) and PWID who are men and have sex with men (PWID-MSM, i.e., men reached through affiliation with PWID).

MethodsWe used data from the most recent waves of the National HIV Behavioural Surveillance among MSM (2017) and PWID (2018) in San Francisco. Participants were recruited through venue-based (MSM) and peer-referral (PWID) sampling and completed standardised questionnaires. We compared the characteristics of MSM-IDU and PWID-MSM using bivariate tests.

ResultsOf 504 participants completing the MSM survey, 6.2% reported past-year injection drug use (MSM-IDU). Among 311 male participants completing the PWID survey, 19.0% reported past-year sex with a male (PWID-MSM). Relative to MSM-IDU, more PWID-MSM were older, identified as bisexual, had lower income, a history of incarceration and were homeless. MSM-IDU had more male sexual partners (median: 10 vs 3) and fewer injected daily (29.0% vs 64.4%) than PWID-MSM. While more PWID-MSM sought sterile equipment from a syringe program (86.4% vs 35.5%), fewer reported using PrEP (15.0% vs 42.9%).

ConclusionThe sociodemographic, risk behaviour, and prevention access profiles of MSM-IDU and PWID-MSM in San Francisco suggest that they represent distinct populations who may require tailored HIV and HCV prevention strategies. MSM- and PWID-focused prevention programs should provide combined sexual health and harm reduction messages and services.


title: Emotional Distress, Stress, Anxiety and the Impact of the COVID-19 Pandemic on Early Career Women in Healthcare Sciences Research

abstract:
ObjectivesThe main objective of this study was to report stress and anxiety levels during the early period of the pandemic on early career women researchers in health sciences research and determine the factors associated with increased stress and anxiety.

MethodsA 50-item self-administered internet questionnaire was developed using a mix of Likert-type scales and open-ended response questions. The survey was distributed via email and social media platforms June 10-August 3, 2020. Anxiety and stress associated with the demands of being in health sciences research as well as personal/family demands were assessed through validated measures (Patient Reported Outcomes Measurement Information System (PROMIS)-Anxiety Short Form and Perceived Stress Scale (PSS)) and open-ended responses.

ResultsOne hundred and fifty-one early career women in healthcare sciences research completed the survey. The mean respondent age was 37.3{+/-}5.2 years, all had a college degree or higher, 50.3% holding a PhD and 35.8%, M.D. Of the 151 respondents, 128 reported their race/ethnicity and the majority were Caucasian (74.0%). One-third (31.2%) reported being  very much concerned about reaching their research productivity goals, and 30.1% were  very much concerned about academic promotion and tenure. Fifty percent reported a  moderate PROMIS anxiety score and 72.1% reported a  moderate PSS score. For the open-ended responses, 65.6% reported a worry about their professional goals as a result of the COVID-19 pandemic. Major concerns revolved around finances, childcare and job security.

ConclusionsThroughout the pandemic, early career women investigators have reported high overall stress, anxiety and worries.

category: medical education


title: Early-Life Circumstances and Racial Disparities in Cognition among US Older Adults

abstract:
ImportanceExisting studies concentrate on exploring mid-life to late-life risk factors on racial disparities in cognition. Given the critical role of neurocognitive development in early life, understanding contributions of early-life circumstances has important implications for early-stage interventions.

ObjectiveTo evaluate the association between early-life circumstances and racial disparities in cognition, and to determine their overall and respective contributions.

Design, Setting, and ParticipantsWe assembled three analytic samples from the Health and Retirement Study (HRS) (1995-2018), a nationally representative longitudinal survey of Americans 50 years or older. 17,092 participants, with 13,907 identifying as non-Hispanic White (White) and 3,185 as non-Hispanic Black (Black), were included in the Core sample. The Trauma and PGS samples respectively included 6,533 participants (5,696 White, 837 Black) and 5,532 participants (4,893 White, 639 Black).

Main Outcomes and MeasuresThe main outcomes were cognitive score and cognitive impairment, as assessed by the Telephone Interview for Cognitive Status (TICS). We used the Blinder-Oaxaca Decomposition (BOD) to evaluate disparities in cognitive outcomes between White and Black participants attributable to differences in early-life circumstances.

ResultsAmong all White and Black participants at initial survey, their respective average age were 58.1 (95% CI, 58.0-58.3) years and 55.8 (95% CI, 55.5-56.0) years; their respective average cognitive score were 17.3 (95% CI, 17.2-17.3) points and 14.6 (95% CI, 14.4-14.7) points; and their respective proportion with cognitive impairment were 7.2 (95% CI, 6.8-7.6) percentage points (pp) and 22.9 (95% CI, 21.5-24.4) pp. Across three analytic samples, overall differences in early-life circumstances respectively explained 23.5%-40.4% and 33.8%-65.3% of the racial gaps in cognitive score and proportion of cognitive impairment between White and Black participants. Difference in educational attainment contributed the most. In the Trauma sample, for example, years of education explained 3.1 (95% CI, 1.9-4.3) pp or 18.6% of the racial gap in proportion of cognitive impairment using the baseline assessment, and 3.3 (95% CI, 2.0-4.5) pp or 26.9% using the latest assessment. Additional early-life contributors included educational environments (e.g., ownership of books, parental education, time spent with mothers) and socioeconomic status (e.g., financial difficulty). However, childhood trauma and selected genetic factors were not significant contributors.

Conclusions and RelevanceLess favorable early-life circumstances are associated with clinically meaningful and statistically significant racial gaps in cognition.

Key PointsO_ST_ABSQuestionsC_ST_ABSHow much do differences in early-life circumstances explain late-life disparities in cognitive outcomes between non-Hispanic Black (Black) and non-Hispanic White (White) older adults? What are the key early-life contributors to these racial disparities?

FindingsEarly-life circumstances contribute substantially to racial disparities in cognitive outcomes over age 50. Educational attainment and early-life educational environment are the most important contributors, even after accounting for a rich set of other early-life socioeconomic, demographic, health, traumatic, and genetic factors.

MeaningExposure to less favorable early-life circumstances for Black than White adults was associated with large racial gaps in cognitive outcomes.

category: neurology


title: Identification of a shared, common haplotype cosegregating with an SGCB c.544A>C mutation in Indian patients affected with sarcoglycanopathy

abstract:
BackgroundSarcoglycanopathies (SG) is the most frequent form of autosomal recessive limb-girdle muscular dystrophies (LGMD) leading to progressive muscle wasting and weakness, predominantly characterized by limb-girdle weakness. LGMDR4 is caused by mutations in SGCB encoding for the beta-sarcoglycan proteins. In this study, we describe a shared, common haplotype cosegregating in 14 SG cases from 13 unrelated families with the likely pathogenic homozygous mutation c.544A>C (p.Thr182Pro) in SGCB.

MethodsThe genotypes of five selected markers (rs10009426, rs6824707, rs2271046, rs35414474 and rs17611952) surrounding the c.544A>C (p.Thr182Pro) were extracted from the variant call format (VCF) generated from whole-exome sequencing (WES) of 14 cases and 14 related family members as controls. The linkage data file was constructed and linkage disequilibrium (LD) plots were generated using HaploView to visualize patterns of LD. Further, haplotype reconstructions based on the 6 markers were conducted using PLINK1.9. using the expectation-maximization (EM) algorithm, an iterative method to find maximum likelihood. Subsequently, the R programming language was used to determine and compare plots of the haplotype frequencies and percentages for both groups to infer the risk haplotypes.

ResultsFour strong LD blocks were identified in control group: rs10009426 to rs6824707 (0.27{square}kb), rs6824707 to rs2271046 (41.6 kb), rs10009426 to rs2271046 (41.8 kb) and rs35414474 to rs17611952 (0.17 kb) which were absent in the case group. Similarly, a total of nine haplotypes were estimated in cases and controls of which haplotype H1= G, A, T, G, G, T showed significant statistical difference in the frequency between cases and controls. H1 is also observed to cosegregate with c.544A>C (p.Thr182Pro) in the pedigrees of all the cases.

ConclusionThe identification of c.544A>C (p.Thr182Pro) mutation in 14 cases from India indicates a probable event of founder effect. Further, the H1 haplotype, cosegregating with this mutation, convincingly sheds light on the recent developments in population genetics allowing insights into demographic and population history. This haplotype can also be used as a genetic marker to screen individuals with genetic susceptibility as carriers and provide genetically informed risk stratification and management in the prevention of SG.


title: Real-life protection provided by vaccination, booster doses and previous infection against covid-19 infection, hospitalisation or death over time in the Czech Republic: a whole country retrospective view

abstract:
SO_SCPLOWUMMARYC_SCPLOWO_ST_ABSBackgroundC_ST_ABSEvidence is accumulating that the effectiveness of covid-19 vaccines against infection wanes, reaching relatively low values after 6 months. Published studies demonstrating this effect based their findings on a limited range of vaccines or subset of populations, and did not include booster vaccine doses or immunity obtained due to covid-19 infection. Here we evaluate effectiveness of covid-19 vaccines, booster doses or previous infection against covid-19 infection, hospital admission or death for the whole population in the Czech Republic.

MethodsData used in this study cover the whole population of the Czech Republic reported as infected and/or vaccinated between the first detected case on March 1, 2020 and November 20, 2021 (for reinfections), or December 26, 2020 and November 20, 2021 (for vaccinations), including hospital admissions and deaths. Vaccinations by all vaccines approved in the EU were included in this study. Anonymous, individual-level data including dates of vaccination, infection, hospital admission and death were provided by the the Institute of Health Information and Statistics of the Czech Republic. The risks of reinfection, breakthrough infection after vaccination, hospital admission and death were calculated using hazard ratios from a Cox regression adjusted for sex, age, vaccine type and vaccination status.

FindingsThe vaccine effectiveness against any PCR-confirmed infection declined from 87% (95% CI 86-87) at 0-2 months after the second dose to 53% (95% CI 52-54) at 7-8 months for Comirnaty, from 90% (95% CI 89-91) at 0-2 monthsto 65% (95% CI 63-67) at 7-8 months for Spikevax, and from 83% (95% CI 80-85) at 0-2 months to 55% at (95% CI 54-56) 5-6 months for the Vaxzevria. For Janssen Covid-19 Vaccine we found no significant decline but the estimates are less certain. The vaccine effectiveness against hospital admissions and deaths decayed at a significantly lower rate with about 15%, resp. 10% decline during the first 6-8 months. The administration of a booster dose returns the protection to or above the estimates in the first two months after dose 2. In unvaccinated but previously SARS-CoV-2-positive individuals the protection against PCR-confirmed SARS-CoV-2 infection declined from close to 97% (95% CI 97-97) after 2 months through 90% at 6 months down to 72% (95% CI 65-78) at 18 months.

InterpretationOur results confirm the waning of vaccination-induced immunity against infection and a smaller decline in the protection against hospital admission and death. A booster dose is shown to restore the vaccine effectiveness back to the levels seen soon after the completion of the basic vaccination schedule. The post-infection immunity decreases over time, too.

FundingNo external funding was used to conduct this study.

RO_SCPLOWESEARCHC_SCPLOWO_SCPCAP C_SCPCAPO_SCPLOWINC_SCPLOWO_SCPCAP C_SCPCAPO_SCPLOWCONTEXTC_SCPLOWO_ST_ABSEvidence before this studyC_ST_ABSAccumulating evidence from several countries indicates that the effectiveness of covid-19 vaccines against infection declines in time, from about 80-90% shortly after completing the vaccination to about 50-60% and even less after 6 months. Published studies also suggest a significant boosting in vaccine effectiveness against infection about one week after the third vaccine dose. However, these observations come from different and often limited data sets. Moreover, the existing studies do not compare the decline in vaccine effectiveness with a decline in infection-based immunity in unvaccinated individuals.

Added value of this studyIn our study, we bring together data on infections, vaccinations (including booster doses), hospital admissions and deaths to estimate how the protection due to vaccination or previous SARS-CoV-2 infection declines with time, for the whole population of the Czech Republic. Our findings show an overall decrease in vaccine effectiveness over time and a large increase after the administration of a booster dose. At the same time we show a fairly stable and high post-infection immunity over the study period. We hope this evidence will contribute to a better understanding of the changing impact of vaccines and previous infection in complex, real-world environments, which is crucial for the development of more effective and more easily communicated public health policies.

Implications of all the available evidenceOur results strongly support a timely and widespread application of booster vaccine doses since their application appears to restore the vaccine-induced protection to the levels attained soon after completing the original vaccination scheme, including the high protection against mild disease or asymptomatic infection.


title: Genome-wide Association Study identifies two novel loci for Gilles de la Tourette Syndrome

abstract: Tourette Syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture, characterized by multiple motor tics and at least one vocal tic persisting for more than one year. We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6,133 TS individuals and 13,565 ancestry-matched controls. We identified a genome-wide significant locus on chromosome 5q15 and one array-wide significant locus on chromosome 2q24.2. Integration of eQTL, Hi-C and GWAS data implicated the NR2F1 gene and associated lncRNAs within the 5q15 locus, and the RBMS1 gene within the 2q24.2 locus. Polygenic risk scoring using previous GWAS results demonstrated statistically significant ability to predict TS status in the novel cohort. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring on brain volume data identified statistically significant associations with right and left putamen volumes. Our work presents novel insights in the neurobiology of TS opening up new directions for future studies.


title: Human serum from SARS-CoV-2 vaccinated and COVID-19 patients shows reduced binding to the RBD of SARS-CoV-2 Omicron variant in comparison to the original Wuhan strain and the Beta and Delta variants

abstract:
The COVID-19 pandemic is caused by the betacoronavirus SARS-CoV-2. In November 2021, the Omicron variant was discovered and classified as a variant of concern (VOC). Omicron shows substantially more mutations in the spike protein than any previous variant, mostly in the receptor binding domain (RBD). We analyzed the binding of the Omicron RBD to the human ACE2 receptor (hACE2) and the ability of human sera from COVID-19 patients or vaccinees in comparison to Wuhan, Beta or Delta RBDs variants.

All RBDs were produced in insect cells. RBD binding to hACE2 was analyzed by ELISA and microscale thermophoresis (MST). Similarly, sera from 27 COVID-19 patients, 58 fully vaccinated individuals and 16 booster recipients were titrated by ELISA on the fixed RBDs from the original Wuhan strain, Beta, Delta and Omicron VOC.

Surprisingly, the Omicron RBD showed a weaker binding to ACE2 compared to Beta and Delta, arguing that improved ACE2 binding is not a likely driver of Omicron evolution. Serum antibody titers were significantly lower against Omicron RBD compared to the original Wuhan strain. However, a difference of 2.5 times was observed in RBD binding while in other studies the neutralization of Omicron SARS-CoV-2 was reduced by a magnitude of 10x and more. These results indicate an immune escape focused on neutralizing antibodies.

The reduced binding of sera to Omicron RBD adds evidence that current vaccination protocols may be less efficient against the Omicron variant.

category: infectious diseases


title: Human serum from SARS-CoV-2 vaccinated and COVID-19 patients shows reduced binding to the RBD of SARS-CoV-2 Omicron variant


title: Resources Required for Implementation of SARS-CoV-2 Screening in Massachusetts K-12 Public Schools in Winter/Spring 2021

abstract:
ImportanceCDC guidance emphasizes the importance of in-person education for students in grades kindergarten to 12 (K-12) during the COVID-19 pandemic. CDC encourage weekly SARS-CoV-2 testing of asymptomatic, unvaccinated students and staff ("screening") to reduce infection risk and provide data about in-school SARS-CoV-2 prevalence where community incidence is high. The financial costs of screening assays have been described, but the human resource requirements at the school and district level to implement a SARS-CoV-2 screening program are not well known.

ObjectiveTo quantify the resources required to implement a screening program in K-12 schools.

Design, Setting, and ParticipantsA consortium of Massachusetts public K-12 schools was formed to implement and evaluate a range of SARS-CoV-2 screening approaches. Participating districts were surveyed weekly about their programs, including: type of assay used, individual vs. pooled screening, approaches to return of results and deconvolution (identification of positive individual specimens) of positive pools, number and type of personnel implementing the screening program, and hours spent on program implementation.

Main Outcomes and MeasuresCosts, resource utilization

ResultsIn 21 participating districts, over 21 weeks from January to June 2021, the positivity rate was 0.0%-0.21% among students and 0.0%-0.13% among educators/staff, and 4 out of 21 (19%) districts had at least one classroom transition to remote learning at any point due to a positive case. The average weekly cost to implement a screening program, including assay and personnel costs, was $17.00 per person tested; this was $46.68 for individual screenings and $15.61 for pooled screenings. The total weekly costs by district ranged from $1,644-$93,486, and districts screened between 58 and 3,675 people per week. The reported number of personnel working per week ranged from 1-5 to >50, and the total number of hours worked by all personnel ranged from 5-10 to >50.

Conclusion and RelevanceThe human resources required to implement SARS-CoV-2 screening in Massachusetts public K-12 schools were substantial. Where screening is recommended for the 2021-22 school year due to high COVID-19 incidence (e.g., where vaccination uptake is low and/or more infectious variants predominate), understanding the human resources required to implement screening will assist districts policymakers in planning.


title: Outcomes Associated with Expanded Take-Home Eligibility for Outpatient Treatment with Medications for Opioid Use Disorder: A Mixed-Methods Analysis

abstract:
BackgroundAccess to medications for opioid use disorder (MOUD) in the U.S. is highly restricted. In March 2020, to reduce transmission of COVID-19, SAMHSA issued emergency regulations allowing up to two weeks of take-home doses for most patients.

ObjectivesWe evaluated the benefits and unintended consequences of these new regulations expanding take-home eligibility to inform MOUD policy post-pandemic

MethodsWe conducted a mixed-methods evaluation of an opioid treatment program in San Francisco caring for a diverse, low-income urban population. We assessed clinic-level intake, retention, and take-home prescribing; individual-level acute care utilization and mortality; and patient/provider perceptions of benefits, harms and challenges of the new regulations.

ResultsClinic volume, intake and retention were largely unchanged after implementation of the new regulations, though the average monthly proportion of individuals receiving take-homes significantly increased from 31% to 47% (p<0.001). Among 506 established patients ([≥]90 days of care), the 10-month mortality was 2.7% among those who never received take-homes versus 3.2% among those newly started (p=0.79) and 0.8% among those with increases in take-homes (p=0.24). Individuals who never received take-homes had higher rates of emergency department visits (47.0%) and hospitalizations (19.7%) versus those with new starts (ED visits 29.2%, p<0.001; hospitalizations 14.3%, p=0.19) or increases in take-homes (ED visits 17.5%, p<0.001; hospitalizations 10.0%, p=0.02). Both patients and providers reported increased treatment flexibility, leading to increased engagement and stabilization.

ConclusionsGiven the benefit and lack of appreciable harms, policymakers should consider extending expanded MOUD take-home eligibility after COVID-19, with careful monitoring for unintended outcomes.


title: High correlation between binding IgG (anti-RBD/S) and neutralizing antibodies against SARS-CoV-2 six months after vaccination

abstract: Vaccination is considered the most important measure to control the COVID-19 pandemic. Extensive follow-up studies with distinct vaccines and populations are able to promote robust and reliable data to better understand the effectiveness of this pharmacologic strategy. In this sense, we present data regarding binding and neutralizing antibodies throughout time, from vaccinated and previously infected (PI) health care workers (HCW) in Portugal. We analyzed serum samples of 132 HCW, vaccinated and with previous SARS-CoV-2 infection. Samples were collected before vaccination (baseline, M1), at second dose vaccine uptake (M2), and 25-70 days (M3) and 150-210 days (M4) after the second dose for vaccinated individuals. The IgG (anti-RBD/S) antibody geometric mean titer found on vaccinated HCW at M2 (814.7 AU/ml; 95% CI 649.8-1021.5) were significantly higher than those found on PI HCW at recruitment (M1) (252.6 AU/ml; 95% CI 108.7 - 587.1), and the neutralizing antibodies (nAb) were similar between these groups, 93.2 UI/ml (95% CI 73.2-118.5) vs. 84.1 UI/ml (95% CI 40.4-155.9), respectively. We detected about 10-fold higher IgG (anti-RBD/S) antibodies titers in M3 when compared with M2, with a slightly but significant decrease in titers from 36 days after the second dose vaccine uptake. The increase of nAb titers were correlated with IgG (anti-RBD/S) antibodies titers, however, contrasting to IgG (anti-RBD/S) antibodies titers, we did not detect a decrease in nAb titer from 36 days after a second vaccine dose uptake. At M4, was observed a decrease of 8-fold in binding IgG (anti-RBD/S) and nAb. No significant differences in antibody titers were observed by sex, age or chronic diseases. Our results suggest that IgG (anti-RBD/S) antibodies titers and nAb titers could be correlated, but ongoing follow up of the cohort, is required to better understand this correlation, and the duration of the immune response.


title: Identifying molecular mediators of the relationship between body mass index and endometrial cancer risk: a Mendelian randomization analysis

abstract:
BackgroundEndometrial cancer is the most common gynaecological cancer in high-income countries. Elevated body mass index (BMI) is an established modifiable risk factor for this condition and is estimated to confer a larger effect on endometrial cancer risk than any other cancer site. However, the molecular mechanisms underpinning this association remain unclear. We used Mendelian randomization (MR) to evaluate the causal role of 14 molecular risk factors (hormonal, metabolic, and inflammatory markers) in endometrial cancer risk. We then evaluated and quantified the potential mediating role of these molecular traits in the relationship between BMI and endometrial cancer.

Methods and FindingsGenetic instruments to proxy 14 molecular risk factors and BMI were constructed by identifying single-nucleotide polymorphisms (SNPs) reliably associated (P < 5.0 x 10-8) with each respective risk factor in previous genome-wide association studies (GWAS). Summary statistics for the association of these SNPs with overall and subtype-specific endometrial cancer risk (12,906 cases and 108,979 controls) were obtained from a GWAS meta-analysis of the Endometrial Cancer Association Consortium (ECAC), Epidemiology of Endometrial Cancer Consortium (E2C2), and UK Biobank. SNPs were combined into multi-allelic models and odds ratios (ORs) and 95% confidence intervals (95% CIs) were generated using inverse-variance weighted random-effects models. The mediating roles of the molecular risk factors in the relationship between BMI and endometrial cancer were then estimated using multivariable MR. In MR analyses, there was strong evidence that BMI (OR per SD increase: 1.88, 95% CI: 1.69 to 2.09, P = 3.87 x 10-31), total testosterone (OR per inverse normal transformed nmol/L increase: 1.64, 95% CI: 1.43 to 1.88, P = 1.71 x 10-12), bioavailable testosterone (OR per inverse normal transformed nmol/L increase: 1.46, 95% CI: 1.29 to 1.65, P = 3.48 x 10-9), fasting insulin (OR per natural log transformed pmol/L increase: 3.93, 95% CI: 2.29 to 6.74, P = 7.18 x 10-7) and sex hormone-binding globulin (SHBG, OR per inverse normal transformed nmol/L increase: 0.71, 95% CI: 0.59 to 0.85, P = 2.07 x 10-4) had a causal effect on endometrial cancer risk. Additionally, there was suggestive evidence that total serum cholesterol (OR per mg/dL increase: 0.90, 95% CI: 0.81 to 1.00, P = 4.01 x 10-2) had an effect on endometrial cancer risk. In mediation analysis using multivariable MR, we found evidence for a mediating role of fasting insulin (19% total effect mediated, 95% CI: 5 to 34%, P = 9.17 x 10-3), bioavailable testosterone (15% mediated, 95% CI: 10 to 20%, P = 1.43 x 10-8), and SHBG (7% mediated, 95% CI: 1 to 12%, P = 1.81 x 10-2) in the relationship between BMI and endometrial cancer risk. The primary limitations of this analysis include the assumption of linear relationships across univariable and multivariable analyses and the restriction of analyses to individuals of European ancestry.

ConclusionsOur comprehensive Mendelian randomization analysis provides insight into potential causal mechanisms linking BMI with endometrial cancer risk and suggests pharmacological targeting of insulinemic and hormonal traits as a potential strategy for the prevention of endometrial cancer.