title: Localising Vaccination Services: Qualitative Insights on an Orthodox Jewish Collaboration with Public health during the UK coronavirus Vaccine Programme

abstract:
Ethnic and religious minorities have been disproportionately affected by the SARS-CoV-2 pandemic and are less likely to accept coronavirus vaccinations. Orthodox (Haredi) Jewish neighbourhoods in England experienced high incidences of SARS-CoV-2 in 2020-21 and measles outbreaks (2018-19) due to suboptimal childhood vaccination coverage. The objective of our study was to explore how the coronavirus vaccination programme (CVP) was co-delivered between public health services and an Orthodox Jewish health organisation.

Methods included 28 semi-structured interviews conducted virtually with public health professionals, community welfare and religious representatives, and household members. We examined CVP delivery from the perspectives of those involved in organising services and vaccine beneficiaries. Interview data was contextualised within debates of the CVP in Orthodox (Haredi) Jewish print and social media. Thematic analysis generated five considerations: i) Prior immunisation-related collaboration with public health services carved a role for Jewish health organisations to host and promote coronavirus vaccination sessions, distribute appointments, and administer vaccines ii) Public health services maintained responsibility for training, logistics, and maintaining vaccination records; iii) The localised approach to service delivery promoted vaccination in a minority with historically suboptimal levels of coverage; iv) Co-delivery promoted trust in the CVP, though a minority of participants maintained concerns around safety; v) Provision of CVP information and stakeholders response to situated (context-specific) challenges and concerns.

Drawing on this example of CVP co-delivery, we propose that a localised approach to delivering immunisation programmes could address service provision gaps in ways that involve trusted community organisations. Localisation of vaccination services can include communication or implementation strategies, but both approaches involve consideration of investment, engagement and coordination, which are not cost-neutral. Localising vaccination services in collaboration with welfare groups raises opportunities for the on-going CVP and other immunisation programmes, and constitutes an opportunity for ethnic and religious minorities to collaborate in safeguarding community health.


title: Antibody kinetics to SARS-CoV-2 at 13.5 months, by disease severity

abstract:
BackgroundUnderstanding humoral responses and seroprevalence in SARS-CoV-2 infection is essential for guiding vaccination strategies in both infected and uninfected individuals.

MethodsWe determine the kinetics of IgM against the nucleocapsid (N) and IgG against the spike (S) and N proteins of SARS-CoV-2 in a cohort of 860 health professionals (healthy and infected) in northern Barcelona. We model the kinetics of IgG and IgM at nine time points over 13.5 months from infection, using non-linear mixed models by sex and clinical disease severity.

ResultsOf the 781 participants who were followed up, 478 (61.2%) became infected with SARS-CoV-2. Significant differences were found for the three antibodies by disease severity and sex. At day 270 after diagnosis, median IgM(N) levels were already below the positivity threshold in patients with asymptomatic and mild-moderate disease, while IgG(N, S) levels remained positive to days 360 and 270, respectively. Kinetic modelling showed a general rise in both IgM(N) and IgG(N) levels up to day 30, followed by a decay whose rate depended on disease severity. IgG(S) levels increased at day 15 and remained relatively constant over time.

ConclusionsWe describe kinetic models of IgM(N) and IgG(N, S) SARS-CoV-2 antibodies at 13.5 months from infection and disease spectrum. Our analyses delineate differences in the kinetics of IgM and IgG over a year and differences in the levels of IgM and IgG as early as 15 days from symptoms onset in severe cases. These results can inform public health policies around vaccination criteria.

Funded by the regional Ministry of Health of the Generalitat de Catalunya (Call COVID19-PoC SLT16_04; NCT04885478)

category: public and global health


title: Children and adults with mild COVID-19 symptoms develop memory T cell immunity to SARS-CoV-2

abstract:
BackgroundSevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to considerable morbidity/mortality worldwide, but most infections, especially among children, have a mild course. However, it remains largely unknown whether infected children develop cellular immune memory.

MethodsTo determine whether a memory T cell response is being developed as an indicator for long-term immune protection, we performed a longitudinal assessment of the SARS-CoV-2-specific T cell response by IFN-{gamma} ELISPOT and activation marker expression analyses of peripheral blood samples from children and adults with mild-to-moderate COVID-19.

ResultsUpon stimulation of PBMCs with heat-inactivated SARS-CoV-2 or overlapping peptides of spike (S-SARS-CoV-2) and nucleocapsid proteins, we found S-SARS-CoV-2-specific IFN-{gamma} T cell responses in most infected children (83%) and all adults (100%) that were absent in unexposed controls. Frequencies of SARS-CoV-2-specific T cells were higher in infected adults, especially in those with moderate symptoms, compared to infected children. The S-SARS-CoV-2 IFN-{gamma} T cell response correlated with S1-SARS-CoV-2-specific serum IgM, IgG, and IgA antibody concentrations. Predominantly, effector memory CD4+ T cells of a Th1 phenotype were activated upon exposure to SARS-CoV-2 antigens, which persisted for 4-8 weeks after symptom onset. We detected very low frequencies of SARS-CoV-2-reactive CD8+ T cells in these individuals.

ConclusionsOur data indicate that an antigen-specific memory CD4+ T cell response is induced in children and adults with mild SARS-CoV-2 infection. T cell immunity induced after mild COVID-19 could contribute to protection against re-infection.

category: infectious diseases


title: VALIDATION OF A SALIVA-BASED TEST FOR THE MOLECULAR DIAGNOSIS OF SARS-CoV-2 INFECTION

abstract:
BackgroundSince the beginning of the pandemic, clinicians and researchers have been searching for alternative tests to improve screening and diagnosis of SARS-CoV-2 infection (Y. Yang et al., medRxiv 2020; W. Wang et al., 2020.3786; A Senok et al., Infect Drug Resist 2020). Currently, the gold standard for virus identification is the nasopharyngeal (NP) swab (N. Sethuraman et al., JAMA 2020; A.J. Jamal et al Clinical Infect Disease 2021). Saliva samples, however, offer clear practical and logistical advantages (K.K.W To et al, Clinical Microb and Infect; A.L. Wylle et al. N Engl J Med 2020; N. Matic et al, Eur J Clin 2021) but due to lack of collection, transport, and storage solutions, high-throughput saliva-based laboratory tests are difficult to scale up as a screening or diagnostic tool (D. Esser et al., Biomark Insights 2008; E. Kaufman et al., Crit Rev Oral Biol Med2002). With this study, we aimed to validate an intra-laboratory molecular detection method for SARS-CoV-2 on saliva samples collected in a new storage saline solution, comparing the results to NP swabs to determine the difference in sensitivity between the two tests.

MethodsIn this study, 156 patients (cases) and 1005 asymptomatic subjects (controls) were enrolled and tested simultaneously for the detection of the SARS-CoV-2 viral genome by RT-PCR on both NP swab and saliva samples. Saliva samples were collected in a preservative and inhibiting saline solution (Biofarma Srl). Internal method validation was performed to standardize the entire workflow for saliva samples.

ResultsThe identification of SARS-CoV-2 conducted on saliva samples showed a clinical sensitivity of 95.1% and specificity of 97.8% compared to NP swabs. The positive predictive value (PPV) was 81% while the negative predictive value (NPV) was 99.5%. Test concordance was 97.6% (Cohens Kappa=0.86; 95% CI 0.81-0.91). The LoD of the test was 5 viral copies for both samples.

ConclusionsRT-PCR assays conducted on a stored saliva sample achieved similar performance to those on NP swabs and this may provide a very effective tool for population screening and diagnosis. Collection of saliva in a stabilizing solution makes the test more convenient and widely available; furthermore, the denaturing properties of the solution reduce the infective risks belonging to sample manipulation.


title: Vascular flow simulations using SimVascular and OpenFOAM

abstract: Applications of computational fluid dynamics (CFD) techniques to aid in the diagnosis and treatment of cardiovascular disease have entered the research domain in recent years, due to their ability to provide valuable patient-specific information without risks associated with highly invasive procedures. SimVascular [1] [2] is an open-source software which allows streamlined processing and CFD blood flow analysis of medical imaging data. OpenFOAM [3] is a proven open-source software which allows for versatile modeling of various fluid dynamics phenomena. In this study, both SimVascular and OpenFOAM simulations are set up with identical computational mesh, similar numerical schemes, boundary conditions, and material properties, to model blood flow in the coronary artery of a 10 year old patient with Coarctation of the Aorta (CoA) who underwent end-to-side anastomosis. Difference in the flow fields such as flow rate, pressure, vorticity, and wall shear stress between SimVascular and OpenFOAM are analyzed. Similar results are obtained in both simulations up to a certain model time, before the results become drastically different. Both the similarities and differences are documented and discussed.

category: cardiovascular medicine


title: A protocol for the multi-method evaluation of novel externally applied suction-based airway clearance devices in the treatment of foreign body airway obstructions

abstract:
BackgroundForeign body airway obstructions (FBAO, choking) are a significant cause of preventable mortality. Abdominal thrusts, back blows, and chest compressions are traditional interventions; however, suction-based airway clearance devices (anti-choking devices, ACDs) have recently been marketed as an alternative. Of note, there is limited published evidence regarding their efficacy and safety. Our research has two aims: 1) To investigate what situational and patient factors are frequently identified, and which are associated with relief of the FBAO, and survival, in individuals with a FBAO treated with an ACD; and 2) To describe the experience of individuals who have used ACDs in response to a FBAO and identify facilitators and barriers to the use of ACDs compared to traditional interventions.

Methods and analysisAll ACD case reports collected a priori by manufacturers will be analyzed up to July 1st, 2021. Following, a prospective database will be developed using an online reporting system to capture future ACD use from July 1st, 2021 to Dec 31st, 2023. Descriptive statistics will be used to summarize cases, 58 outcomes, and adverse events. Where possible, bivariable and multivariable analysis will be employed to assess for predictors of outcomes (relief of FBAO, survival, and survival with good neurological function). Semi-structured interviews will be conducted with a subset of ACD users to describe in detail their experience using the device. Themes from these interviews will be assessed using the Theoretical Domains Framework.

Ethics and disseminationThis study has ethics approval from the University of New South Wales Human Research Ethics Committee (HC210242). Findings from this multi-year, multi-method study will be published in peer reviewed literature, presented at conferences and contribute to informing future resuscitation guidelines. Data on ACDs are urgently needed as these devices are already being used by parents, caregivers, lay rescuers, and healthcare professionals to respond to choking emergencies.

Strengths and limitations of the study{circ} Foreign body airway obstruction (FBAO) intervention is an area with limited data, largely based on retrospective case series for traditional techniques (e.g., abdominal thrusts, back blows and chest thrusts)
{circ}A multi-phase, multi-year study will be conducted to evaluate a novel intervention (suction-based airway clearance devices, ACDs) that have the potential to improve pre-hospital response to foreign body airway obstructions and survival
{circ}Utilization of retrospective and prospective data, as well as evaluation of the users experience, will help determine the role for airway clearance devices in resuscitation algorithms and future guidelines
{circ}Data will be reliant on self-reporting from users due to the infrequent occurrence of FBAO and few ACDs available to general public
{circ}Previous studies have relied on data collected by manufacturers, which will be improved here by providing users with an independent reporting method

category: emergency medicine


title: Predictors of real-world parents acceptance to vaccinate their children against the COVID-19

abstract:
BackgroundAs the COVID-19 pandemic continues to threaten public health, the vaccination of children against the disease appears to be a key factor to control the pandemic.

ObjectiveTo investigate the prevalence of parents who have vaccinated their children against the COVID-19 and the factors influencing this decision.

MethodsWe conducted a web-based cross-sectional study in Greece during the first week of September 2021. The study questionnaire was distributed through social media and a convenience sample was obtained. Only parents with children aged 12-17 years old could participate in the study. We collected socio-demographic data of parents and we measured their attitudes towards vaccination and COVID-19 pandemic.

ResultsStudy population included 656 parents. Mean age of parents was 45.5 years, while most of them were mothers with a high level of education. Regarding vaccination, 27.1% of parents had their children vaccinated against the COVID-19, while almost all children had a complete vaccination history (98.9%). The most important reasons for decline of COVID-19 vaccination were doubts about the safety and effectiveness of COVID-19 vaccines (45.3%) and fear of side effects (36.6%). Regarding the information about the COVID-19 vaccines, parents showed more trust in family doctors than in scientists and the government. Multivariate regression analysis identified that increased parents age, increased trust in COVID-19 vaccines, and positive attitude of parents towards vaccination had a positive effect on childrens vaccination.

ConclusionsUnderstanding the factors influencing parents decision to vaccinate their children against the COVID-19 is crucial to increase the COVID-19 vaccination coverage rate. Implementation of public health policies is necessary to spread knowledge about COVID-19 vaccines and to regain vaccine confidence.

category: pediatrics


title: Causal effect of C-reactive protein and vitamin D on human cerebral anatomy observed among genetically correlated biomarkers in blood

abstract: Psychiatric disorders such as schizophrenia are commonly associated with structural brain alterations affecting the cortex, which frequently vary with clinically relevant factors including antipsychotic treatment, duration of illness and age of onset. While the underlying variables mediating these structural changes are poorly understood, recent genetic evidence suggests circulating metabolites and other biochemical traits play a causal role in a number of psychiatric disorders which could be mediated by changes in the cerebral cortex. In the current study, we leveraged publicly available genome-wide association study (GWAS) data to explore shared genetic architecture and evidence for causal relationships between a panel of 50 biochemical traits and measures of cortical thickness and surface area at both the global and regional levels. Linkage disequilibrium score regression identified a total of 20 significant and 156 suggestive genetically correlated biochemical-cortical trait pairings, of which six exhibited strong evidence for causality in a latent causal variable model. Interestingly, a negative causal relationship was identified between a unit increase in serum C-reactive protein levels and thickness of the lingual and lateral occipital regions that was also supported by Mendelian randomisation, while circulating vitamin D (25-hydroxyvitamin D) levels exhibited a positive causal effect on temporal pole thickness. Taken together, our findings suggest a subset of biochemical traits exhibit shared genetic architecture and potentially causal relationships with cortical thickness in functionally distinct regions, which may contribute to alteration of cortical structure in psychiatric disorders.

category: psychiatry and clinical psychology


title: Stress-induced changes in inflammatory and atherosclerosis markers during official basketball games in professional coaches

abstract:
ObjectiveTop-level competitive sports coaches repeatedly cope with situations of acute stress in order to succeed and manage high team performance. Occupational stress-induced biochemical and immune system markers are not well studied for this specific group of people. The purpose of this study was to evaluate stress-induced alterations of inflammatory markers and atherosclerosis risk factors during an official basketball game in top-level professional basketball coaches (head and assistant).

MethodsBlood samples and vital signs were obtained from 27 healthy coaches (Greek A1 Mens National Basketball League), 30 minutes before and 30 minutes after the games. We performed a full blood count and measured inflammatory cytokines, atherosclerosis markers and cortisol levels. Data were statistically analysed using two-tailed paired and independent samples t-tests and Pearsons Correlations.

ResultsPost-game neutrophils (NEU) and apolipoprotein B (ApoB) levels were significantly increased while lymphocytes (LYM) were significantly decreased in comparison to pre-game values. Blood pressure (systolic and diastolic) levels were considered as a pre-hypertension state at both measurements. We found significant alterations between head and assistant coaches in diastolic blood pressure and cortisol levels after the game. Cortisol was negatively correlated to inflammatory cytokine levels and positively correlated with ApoB levels.

ConclusionsGame-induced acute psychological stress initiates an aseptic inflammatory response in top-level professional coaches and can be related to the atherosclerosis pathways posing as an acute as well as chronic health threat for top-level coaches who have to deal with long periods of stressful working conditions.

SUMMARY BOXO_ST_ABSWhat are the new findings?C_ST_ABSO_LITop-level basketball games induce an aseptic inflammatory response in professional basketball coaches mainly manifested by increased levels of peripheral blood neutrophils
C_LIO_LIThe response to game conditions also included elevated levels of ApoB after the game that were positively correlated with cortisol levels
C_LIO_LIStressful game conditions over a long season of games could pose as a serious health issue for professional coaches
C_LIO_LIHealth monitoring for professional coaches in top-level competitive sports such as basketball should be implemented more often with particular focus on inflammatory and atherosclerosis markers
C_LI

category: sports medicine


title: The Morbidity Costs of Air Pollution through the Lens of Health Spending in China

abstract:
This study offers one of the first causal evidence on the morbidity costs of fine particulates (PM2.5) for all age cohorts in a developing country, using individual-level healthcare spending data from the basic medical insurance program in Wuhan, China. Our instrumental variable (IV) approach uses thermal inversion to address potential endogeneity in PM2.5 concentrations and shows that PM2.5 imposes a significant impact on medical expenditures. The IV estimate suggests that a 10 g/m3 reduction in monthly average PM2.5 leads to a 2.79% decrease in the value of health spending and a 0.70% decline in the number of transactions in pharmacies and health facilities. The effect is more salient for males, children, and older adults. Moreover, our estimates provide a lower bound of peoples willingness-to-pay, which amounts to CNY 51.85 (or USD 8.38) per capita per year for a 10 g/m3 reduction in PM2.5.

JEL CodesQ51, Q53, I11, I31

Conflict of interestThe authors declare that they have no conflict of interest.

category: health policy


title: Bacterial and Fungal Co-Infections among ICU COVID-19 Hospitalized Patients in a Palestinian Hospital: Incidence and Antimicrobial Stewardship

abstract: Diagnosis of co-infections with multiple pathogens among hospitalized COVID-19 patients can be jointly challenging and very essential for appropriate treatment, shortening hospital stay and preventing antimicrobial resistance. This study proposes to investigate the burden of bacterial and fungal co-infections outcomes on COVID-19 patients. It is a single centre cross-sectional study of hospitalized COVID-19 patients at Beit-Jala hospital in Palestine. The study included 321 hospitalized patients admitted to the ICU between June 2020 and March 2021 aged [≥] 20 years, with a confirmed diagnosis of COVID-19 via RT-PCR conducted on a nasopharyngeal swab. The patients information was gathered using graded data forms from electronic medical reports. The diagnosis of bacterial and fungal infection was proved through the patients clinical presentation and positive blood or sputum culture results. All cases had received empirical antimicrobial therapy before the ICU admission, and different regimens during the ICU stay. The rate of bacterial co-infection was 51.1%, mainly from gram-negative isolates (Enterobacter species and K.pneumoniae). The rate of fungal co-infection caused by A.fumigatus was 48.9%, and the mortality rate was 8.1%. However, it is unclear if it had been attributed to SARS-CoV-2 or coincidental.


title: COVID-19 convalescent plasma and randomized clinical trials: rebuilding confidence by explaining failures and finding signals of efficacy.

abstract: Convalescent plasma (CP) recurs as a frontline treatment in epidemics because it is available as soon as there are survivors. The COVID-19 pandemic represented the first large-scale opportunity to shed light into mechanisms of action, safety and efficacy of CP using modern evidence-based medicine approaches. Studies ranging from observational case series to randomized controlled trials (RCT) have reported highly variable efficacy results for COVID-19 CP (CCP), resulting in uncertainty. Reasons for CCP success and failure may be hidden in study details, which are usually difficult to explain to physicians and the public but provide fertile ground for designing next-generation studies. We analyzed variables associated with efficacy such as clinical settings, disease severity, CCP SARS-CoV-2 antibody levels and function, dose, timing of administration (variously defined as time from onset of symptoms, molecular diagnosis, diagnosis of pneumonia, or hospitalization, or by serostatus), outcomes (defined as hospitalization, requirement for ventilation, clinical improvement or mortality), CCP provenance and time for collection, and criteria for efficacy. Focusing only on the results from the 30 available RCTs we noted that these were more likely to show signals of efficacy, including reductions in mortality, if the plasma neutralizing titer was [≥] 160 and the time to randomization was [≤] 9 days, consistent with passive antibody therapy efficacy requiring dosing with sufficient antibody. The fact that most studies revealed signals of efficacy despite variability in CCP and its use suggest likely therapeutic effects that become apparent despite the data noise. Despite the recent WHO guidelines discouraging CCP usage, the Omicron variant of concern is reminding us the superiority of polyclonal antibody therapies over monoclonal antibodies, and CCP from vaccinated convalescents is likely to be evaluated soon


title: Store-Operated Calcium Entry Controls Innate and Adaptive Immune Cell Function in Inflammatory Bowel Disease

abstract:
ObjectiveInflammatory bowel disease (IBD) is characterized by dysregulated intestinal immune responses and constitutes a major clinical challenge in need of new treatment modalities to improve patient care. Store-operated Ca2+ entry (SOCE) is the predominant Ca2+ influx pathway in T cells and other immune cells, regulating many of their functional properties. It is currently unknown whether the pharmacologic blockade of SOCE represents a suitable drug-target for IBD treatment.

DesignUsing mass and flow cytometry the effects of SOCE inhibition on lamina propria (LP) immune cells of patients with ulcerative colitis (UC) and Crohns disease (CD) were investigated. Primary organoid cultures served to study the impact of SOCE inhibition on the function, differentiation and survival of intestinal epithelial cells (IEC). T cell transfer models of colitis were applied to examine how the genetic or pharmacologic ablation of SOCE affects the clinical course of IBD in mice.

ResultsWe observed that the LP of IBD patients is characterized by an enrichment of innate lymphoid cells (ILC), CD4+ and CD8+ effector- as well as T regulatory cells producing IL-17 and TNF. The pharmacologic inhibition of SOCE attenuated the production of pathogenic cytokines including IL-2, IL-4, IL-6, IL-17, TNF and IFN{gamma} by human colonic T cells and ILC, reduced the production of IL-6 by B cells and the production of IFN{gamma} by myeloid cells, without affecting the viability, differentiation and function of primary IEC. T cell-specific genetic deletion of the SOCE signaling components Orai1, Stim1 or Stim2 revealed that the magnitude of SOCE correlates with the function of T cells and intestinal inflammation in mice. Moreover, the pharmacologic inhibition of SOCE alleviated the clinical course of colitic mice.

ConclusionOur data suggest that SOCE inhibition may serve as a new pharmacologic strategy for treating IBD.

category: gastroenterology


title: Association between work attendance when experiencing fever or cold symptoms and company characteristics and socioeconomic status in the COVID-19 pandemic in Japanese workers: a cross-sectional study

abstract:
ObjectiveThis study investigated the association between attending work while experiencing fever or cold symptoms and workers socioeconomic background and company characteristics during the COVID-19 pandemic.

MethodsA cross-sectional online survey was performed. Of a total of 33,302 participants, 3,676 workers who experienced fever or cold symptoms after April 2020 were included. The odds ratios (ORs) of attending work while sick associated with workers socioeconomic background and company characteristics were evaluated using a multilevel logistic model.

ResultsThe OR of attending work while sick associated with a lack of policy prohibiting workers from working when ill was 2.75 (95%CI: 2.28-3.20, P<0.001).

ConclusionThis study suggests that clear company policies on work and illness can be effective for preventing employees from attending work while sick.

category: occupational and environmental health


title: Validation of a Trans-Ancestry Polygenic Risk Score for Type 2 Diabetes in Diverse Populations

abstract: Type 2 diabetes (T2D) is a worldwide scourge caused by both genetic and environmental risk factors that disproportionately afflicts communities of color. Leveraging existing large-scale genome-wide association studies (GWAS), polygenic risk scores (PRS) have shown promise to complement established clinical risk factors and intervention paradigms, and improve early diagnosis and prevention of T2D. However, to date, T2D PRS have been most widely developed and validated in individuals of European descent. Comprehensive assessment of T2D PRS in non-European populations is critical for an equitable deployment of PRS to clinical practice that benefits global populations. Here we integrate T2D GWAS in European, African American and East Asian populations to construct a trans-ancestry T2D PRS using a newly developed Bayesian polygenic modeling method, and evaluate the PRS in the multi-ethnic eMERGE study, four African American cohorts, and the Taiwan Biobank. The trans-ancestry PRS was significantly associated with T2D status across the ancestral groups examined, and the top 2% of the PRS distribution can identify individuals with an approximately 2.5-4.5 fold of increase in T2D risk, suggesting the potential of using the trans-ancestry PRS as a meaningful index of risk among diverse patients in clinical settings. Our efforts represent the first step towards the implementation of the T2D PRS into routine healthcare.

category: genetic and genomic medicine


title: A population-specific missense variant rs1597000001 in CETP promotes a favorable lipid profile and reduces CETP activity.

abstract: Sequencing of CETP in M[a]ori and Pacific peoples identified a common (MAF [~]2.4%-5.4%) population-specific missense variant (rs1597000001, CETP:c.530C>T p.Pro177Leu) that associates with higher HDL-C levels ([Formula] [95% CI 0.211; 0.260]) and lower LDL-C ([Formula] [95% CI -0.209; -0.058]). In a subsample of the study cohort (n = 11), heterozygous carriers of the population-specific variant had lower plasma CETP activity (P = 0.028). Our study identifies a population-specific missense variant in CETP which lowers CETP activity with an effect on HDL-C that is comparable to Mendelian CETP loss-of-function mutations.


title: Mask Interventions in K12 Schools Can Also Reduce Community Transmission in Fall 2021

abstract: The dominance of the COVID-19 Delta variant has renewed questions about the impact of K12 school policies, including the role of masks, on disease burden.1 A recent study showed masks and testing could reduce infections in students, but failed to address the impact on the community,2 while another showed masking is critical to slow disease spread in communities, but did not consider school openings under Delta.3 We project the impact of school-masking on the community, which can inform policy decisions, and support healthcare system planning. Our findings indicate that the implementation of masking policies in school settings can reduce additional infections post-school opening by 23-36% for fully-open schools, with an additional 11-13% reduction for hybrid schooling, depending on mask quality and fit. Masking policies and hybrid schooling can also reduce peak hospitalization need by 71% and result in the fewest additional deaths post-school opening. We show that given the current vaccination rates within the community, the best option for children and the general population is to employ consistent high-quality masking, and use social distancing where possible.


title: Spike Protein NTD mutation G142D in SARS-CoV-2 Delta VOC lineages is associated with frequent back mutations, increased viral loads, and immune evasion

abstract: The significantly greater infectivity of the SARS-CoV-2 Delta variants of concern (VOC) is hypothesized to be driven by key mutations that result in increased transmissibility, viral load and/or evasion of host immune response. We surveyed the mutational profiles of Delta VOC genomes between September 2020 and mid-August 2021 and identified a previously unreported mutation pattern at amino acid position 142 in the N-terminal domain (NTD) of the spike protein which demonstrated multiple rounds of mutation from G142 to D142 and back. This pattern of frequent back mutations was observed at multiple time points and across Delta VOC sub-lineages. The etiology for these recurrent mutations is unclear but raises the possibility of host-directed editing of the SARS-CoV-2 genome. Within Delta VOC this mutation is associated with higher viral load, further enhanced in the presence of another NTD mutation (T95I) which was also frequently observed in these cases. Protein modeling of both mutations predicts alterations of the surface topography of the NTD by G142D, specifically disturbance of the  super site epitope that binds NTD-directed neutralizing antibodies (NAbs). The appearance of frequent and repeated G142D followed by D142G back mutations is previously unreported in SARS-CoV-2 and may represent viral adaptation to evolving host immunity characterized by increasing frequency of spike NAbs, from both prior infection and vaccine-based immunity. The emergence of alterations of the NTD in and around the main NAb epitope is a concerning development in the ongoing evolution of SARS-CoV-2 which may contribute to increased infectivity, immune evasion and  breakthrough infections characteristic of Delta VOC. Future vaccine and therapy development may benefit by recognizing the emergence of these novel spike NTD mutations and considering their impact on antibody recognition, viral neutralization, infectivity, replication, and viral load.


title: Spread of Gamma (P.1) sub-lineages carrying Spike mutations close to the furin cleavage site and deletions in the N-terminal domain drives ongoing transmission of SARS-CoV-2 in Amazonas, Brazil

abstract: The Amazonas was one of the most heavily affected Brazilian states by the COVID-19 epidemic. Despite a large number of infected people, particularly during the second wave associated with the spread of the Variant of Concern (VOC) Gamma (lineage P.1), SARS-CoV-2 continues to circulate in the Amazonas. To understand how SARS-CoV-2 persisted in a human population with a high immunity barrier, we generated 1,188 SARS-CoV-2 whole-genome sequences from individuals diagnosed in the Amazonas state from 1st January to 6th July 2021, of which 38 were vaccine breakthrough infections. Our study reveals a sharp increase in the relative prevalence of Gamma plus (P.1+) variants, designated as Pango Lineages P.1.3 to P.1.6, harboring two types of additional Spike changes: deletions in the N-terminal (NTD) domain (particularly{Delta} 144 or{Delta} 141-144) associated with resistance to anti-NTD neutralizing antibodies or mutations at the S1/S2 junction (N679K or P681H) that probably enhance the binding affinity to the furin cleavage site, as suggested by our molecular dynamics simulations. As lineages P.1.4 (S:N679K) and P.1.6 (S:P681H) expanded (Re > 1) from March to July 2021, the lineage P.1 declined (Re < 1) and the median Ct value of SARS-CoV-2 positive cases in Amazonas significantly decreases. Still, we found no overrepresentation of P.1+ variants among breakthrough cases of fully vaccinated patients (71%) in comparison to unvaccinated individuals (93%). This evidence supports that the ongoing endemic transmission of SARS-CoV-2 in the Amazonas is driven by the spread of new local Gamma/P.1 sub-lineages that are more transmissible, although not more efficient to evade vaccine-elicited immunity than the parental VOC. Finally, as SARS-CoV-2 continues to spread in human populations with a declining density of susceptible hosts, the risk of selecting new variants with higher infectivity are expected to increase.


title: RISK FACTORS FOR EARLY NATURAL MENOPAUSE: EVIDENCE FROM THE 1958 AND 1970 BRITISH BIRTH COHORTS

abstract: Using data from two generations of British women followed from birth through childhood and into adulthood, we investigate risk factors for the onset of natural menopause before the age of 45 (known as early menopause). We focus on key stages during the life course to understand when risk factors are particularly harmful. We find that earlier cessation of menstruation is influenced by circumstances at birth. Women born in lower social class families, whose mother smoked during the pregnancy or who were short-term breastfed (one month or less) were more likely to undergo menopause before 45. Early menopause is also associated with poorer cognitive ability and smoking in childhood. Adult health behaviour also matters. Smoking is positively correlated with early menopause, while regular exercise (one to several times a week) and moderate frequency of alcohol drinking (one to three times a month) in womens early thirties are associated with a reduced risk of early menopause. The occurrence of gynaecological problems by womens early thirties is also linked to early menopause. We note that some of these factors (e.g. health behaviours) are modifiable and thus the risks may be preventable.

category: epidemiology


title: Effectiveness of Mass Vaccination in Brazil against Severe COVID-19 Cases

abstract:
BackgroundMass vaccination campaigns started in Brazil on January/2021 with CoronaVac followed by ChAdOx1 nCov-19, and BNT162b2 mRNA vaccines. Target populations initially included vulnerable groups such as people older than 80 years, with comorbidities, of indigenous origin, and healthcare workers. Younger age groups were gradually included.

MethodsA national cohort of 66.3 million records was compiled by linking registry-certified COVID-19 vaccination records from the Brazilian National Immunization Program with information on severe COVID-19 cases and deaths. Cases and deaths were aggregated by state and age group. Mixed-effects Poisson models were used to estimate the rate of severe cases and deaths among vaccinated and unvaccinated individuals, and the corresponding estimates of vaccine effectiveness by vaccine platform and age group. The study period is from mid-January to mid-July 2021.

ResultsEstimates of vaccine effectiveness preventing deaths were highest at 97.9% (95% CrI: 93.5-99.8) among 20-39 years old with ChAdOx1 nCov-19, at 82.7% (95% CrI: 80.7-84.6) among 40-59 years old with CoronaVac, and at 89.9% (87.8--91.8) among 40-59 years old with partial immunization of BNT162b2. For all vaccines combined in the full regimen, the effectiveness preventing severe cases among individuals aged 80+ years old was 35.9% (95% CrI: 34.9-36.9) which is lower than that observed for individuals aged 60-79 years (61.0%, 95% CrI: 60.5-61.5).

ConclusionDespite varying effectiveness estimates, Brazils population benefited from vaccination in preventing severe COVID-19 outcomes. Results, however, suggest significant vaccine-specific reductions in effectiveness by age, given by differences between age groups 60-79 years and over 80 years.


title: Scale-free dynamics of Covid-19 in a Brazilian city

abstract: Mathematical models can provide insights into the control of pandemic COVID-19, which remains a global priority. The dynamics of directly-transmitted infectious diseases, such as COVID-19, are usually described by compartmental models where individuals are classified as susceptible, infected and removed. These SIR models typically assume homogenous transmission of infection, even in large populations, a simplification that is convenient but inconsistent with observations. Here we use original data on the dynamics of COVID-19 spread in a Brazilian city to investigate the structure of the transmission network. We find that transmission can be described by a network in which each infectious individual has a small number of susceptible contacts, of the order of 2-5, which is independent of total population size. Compared with standard models of homogenous mixing, this scale-free, fractal infection process gives a better description of COVID-19 dynamics through time. In addition, the contact process explains the geographically localized clusters of disease seen in this Brazilian city. Our scale-free model can help refine criteria for physical and social distancing in order to more effectively mitigate the spread of COVID-19. We propose that scale-free COVID-19 dynamics could be a widespread phenomenon, a topic for further investigation.


title: What pushed Israel out of herd immunity? Modeling COVID-19 spread of Delta and Waning immunity

abstract: Following a successful vaccination campaign at the beginning of 2021 in Israel, where approximately 60% of the population were vaccinated with an mRNA BNT162b2 vaccine, it seemed that Israel had crossed the herd immunity threshold (HIT). Nonetheless, Israel has seen a steady rise in COVID-19 morbidity since June 2021, reaching over 1,000 cases per million by August. This outbreak is attributed to several events that came together: the temporal decline of the vaccines effectiveness (VE); lower effectiveness of the vaccine against the current Delta (B.1.617.2) variant; highly infectiousness of Delta; and temporary halt of mandated NPIs (non-pharmaceutical interventions) or any combination of the above. Using a novel spatial-dynamic model and recent aggregate data from Israel, we examine the extent of the impact of the Delta variant on morbidity and whether it can solely explain the outbreak. We conclude that both Delta infectiousness and waning immunity could have been able to push Israel below the HIT independently, and thus, to mitigate the outbreak effective NPIs are required. Our analysis cautions countries that once vaccines will wane a highly infectious spread is expected, and therefore, the expected decline in the vaccines effectiveness in those countries should be accompanied by another vaccination campaign and effective NPIs.


title: Morphological alternations of intracerebral arterial during middle age: a community cohort study

abstract:
BackgroundAmple evidence has suggested that vascular modifications are associated with aging. To expand previous understanding of age-related vascular changes, we examined the association between aging and cerebrovascular morphologies.

Methods1176 participants aged 35 to 75 years recruited from Shanghai, China were included in this study. Cerebrovascular morphological features comprising arterial branch density, radius, and tortuosity were quantified using three-dimensional magnetic resonance angiography. Linear regression was used to examine the association between age and vasculature features.

ResultsAge was found to be a significant predictor for cerebrovascular morphological alterations after adjusting for vascular risk factors. However, after dividing subjects into subgroups based on their age, aging was found to be significantly correlated with all three morphometric features only in the 45-54 subgroup after adjusting for the other vascular risk factors. Smoking gives rise to a more rapid age-related changes in vascular morphologies, while alcohol consumption could decelerate those age-related alterations.

ConclusionsRapid alternations in all three morphological features assessed have been noticed to be associated with aging in the 45-54 subgroup, suggesting the potential importance of the 5th decade for early preservation method of vascular aging.

FundingNational Natural Science Foundation of China.


title: Early immunologic response to mRNA COVID-19 vaccine in patients receiving biologics and/or immunomodulators.

abstract:
Patients with immune conditions and immune-modifying therapies were excluded from the Covid-19 vaccine trials. Studies have shown conflicting response to different vaccines in persons receiving immune suppressors or biologics. The aim of this study is to evaluate humoral and cellular response to Covid-19 vaccines in patients with Inflammatory Bowel Disease (IBD) using biologic and/or immunomodulatory (IMM) therapies.

MethodsParticipants are adults with IBD receiving biologics or IMM planning to receive a Covid 19 vaccine. Cellular immunity (CD4+ and CD8+ T cell levels) with flow cytometry are measured at baseline and 2 weeks after each vaccine dose. Humoral immunity (antibody titers and neutralizing capacity,VNT%) is analyzed by ELISA at baseline, 2 weeks after each dose, and 6 and 12 months after vaccine. We present the early results of the first 19 subjects. The study is approved by the IRB.

Results19 subjects (18 in biologics and 1 in IMM) who received 2 doses of the Pfizer-BioNTech vaccine are included. Total IgG antibodies increased 21.13 times after the first dose and 90 times after the second dose. VTN% increased 11.92 times after the first dose and 53.79 times after the second dose. When compared with a healthy control cohort, total IgG antibodies and VTN% were lower in the subjects after the first dose. After the second dose, IgG antibodies increased but remained lower than controls, but VTN% were similar to controls. CD4 and CD8 mean levels had an upward trend after vaccination.

ConclusionsNeutralizing capacity response to the vaccine in subjects was similar to a healthy cohort in spite of lower increases in total IgG antibodies. The CD4 and CD8 results observed may support the capacity to mount an effective cellular response in patients on biologics. Larger studies are needed to determine vaccine efficacy in these patients.


title: Safety, Immunogenicity, and Efficacy of COVID-19 Vaccine in Children and Adolescents: A Systematic Review

abstract:
AimTo identify the safety, immunogenicity, and protective efficacy of COVID-19 vaccine in children and adolescents.

MethodsWe conducted a systematic review. Databases including PubMed, Web of Science, WHO COVID-19 database, and CNKI were searched on 23 July 2021. International Clinical Trials Registry Platform (ICTRP) was also searched to collect ongoing trials. We included published researches or ongoing clinical trials related to the safety, immunogenicity, and efficacy of COVID-19 vaccine in children or adolescents (aged [≤]18 years). Meta-analysis was performed if the consistency of the included studies was high. If not, descriptive analyses were performed.

ResultsEight published studies with 2851 children or adolescents and 28 ongoing clinical trials were included. Among eight published studies, two (25.0%) were RCTs, two (25.0%) case series, and four (50.0%) case reports. The results showed selected COVID-19 vaccines had a good safety profile in children and adolescents. Injection site pain, fatigue, headache, and chest pain were the most common adverse events. Some studies reported a few cases of myocarditis and pericarditis. Two RCTs showed that the immune response to BNT162b2 in adolescents aged 12-15 years was non-inferior to that in young people aged 16-25 years, while a stronger immune response was detected with 3g CoronaVac injection. Only one single RCT showed the efficacy of BNT162b2 was 100% (95% CI: 75.3 to 100). Of the 28 ongoing clinical trials, twenty-three are interventional studies. Fifteen countries are conducting interventional clinical trials of COVID-19 vaccines in children and adolescents. Among them, China (10, 43.5%) and United Stated (9, 39.1%) were the top two countries with the most trials. BNT162b2 was the most common vaccine, which is under testing.

ConclusionSome of the COVID-19 vaccines have potential protective effects in children and adolescents, but awareness is needed to monitor possible adverse effects after injection. Clinical trials of the COVID-19 vaccine in children and adolescents with long follow-up, large sample size, and different vaccines are still urgently needed.


title: Characterizing cerebral metabolite profiles in anorexia and bulimia nervosa and their associations with habitual behavior

abstract:
BackgroundAnorexia nervosa (AN) and bulimia nervosa (BN) are associated with altered brain structure and function, as well as increased habitual behavior. This neurobehavioral profile may implicate neurochemical changes in the pathogenesis of these illnesses. Altered glutamate, myo-inositol and N-acetyl aspartate (NAA) concentrations are reported in restrictive AN, yet whether these extend to binge-eating disorders, or relate to habitual traits in affected individuals, remains unknown.

MethodsUsing single-voxel proton magnetic resonance spectroscopy, we measured glutamate, myo-inositol and NAA in 85 women [n=22 AN (binge-eating/purging subtype; AN-BP), n=33 BN, n=30 controls]. Spectra were acquired from the right inferior lateral prefrontal cortex and the right occipital cortex. To index habitual behavior, participants performed an instrumental learning task and completed the Creature of Habit Scale. Exploratory analyses examined associations between metabolites and habitual behavior.

ResultsWomen with AN-BP, but not BN, had reduced myo-inositol and NAA concentrations relative to controls in both voxels. Patient groups had intact performance on the instrumental learning task; however, both groups reported increased routine behaviors compared to controls. Women with BN also reported greater automatic behaviors, and automaticity was related to reduced prefrontal glutamate and NAA in the AN-BP group.

DiscussionFindings extend previous reports of reduced myo-inositol and NAA levels in AN to AN-BP, which may reflect disrupted axonal-glial signaling. Although we found inconsistent support for increased habitual behavior in AN-BP and BN, we identified preliminary associations between prefrontal metabolites and automaticity in AN-BP. These results provide further evidence of unique neurobiological profiles across binge-eating disorders.


title: Pairwise genetic meta-analyses between schizophrenia and substance dependence phenotypes reveals novel association signals

abstract: Almost half of individuals diagnosed with schizophrenia also present with a substance use disorder, however, little is known about potential molecular mechanisms underlying this comorbidity. We used genetic analyses to enhance our understanding of the molecular overlap between these conditions. Our analyses revealed a positive genetic correlation between schizophrenia and the following dependence phenotypes: alcohol (rg = 0.3685, SE = 0.0768, P = 1.61 x 10-06), cannabis use disorder (rg = 0.309, SE = 0.0332, P = 1.19 x 10-20) and nicotine dependence (rg = 0.1177, SE = 0.0436, P = 7.0 x 10-03), as well as lifetime cannabis use (rg = 0.234, SE = 0.0298, P = 3.73 x 10-15) and drinks per week (rg = 0.0688, SE = 0.0217, P = 1.5 x 10-03). We further constructed latent causal variable (LCV) models to test for partial genetic causality and found evidence for a potential causal relationship between alcohol dependence and schizophrenia (GCP = 0.6, SE = 0.22, P = 1.6 x 10-03). This putative causal effect with schizophrenia was not seen using a continuous phenotype of drinks consumed per week, suggesting that distinct molecular mechanisms underlying dependence are involved in the relationship between alcohol and schizophrenia. To localise the specific genetic overlap between schizophrenia and substance use disorders, we conducted a gene-based and gene-set pairwise meta-analysis between schizophrenia and each of the four individual substance dependence phenotypes in up to 790,806 individuals. These bivariate meta-analyses identified 44 associations not observed in the individual GWAS, including five shared genes that play a key role in early central nervous system development. These genes may play an important role in substance dependence in schizophrenia, and, as a result, could represent important targets for future treatment or early intervention, as comorbid substance dependence is associated with poor treatment adherence, greater chronicity and increased mortality.


title: 'Like brushing teeth' - Implementation experiences with opt-in, at-home screening for SARS-CoV-2 among schoolchildren in Germany

abstract:
BackgroundOver the course of the pandemic, many countries have repeatedly closed schools and shifted students to remote learning. However, evidence for negative mental and physiological health consequences of such measures for students is increasing, highlighting the need for evidence-based recommendations on how to safely reopen schools. This study presents experiences when implementing opt-in, at-home SARS-CoV-2 screening using rapid diagnostic tests (RDTs) to facilitate safe face-to-face-teaching during a pandemic.

MethodsWe present data form a prospective study implementing an RDT-based screening program at a primary school in southwest Germany. We conducted qualitative in-depth interviews with participating children, parents, and school stakeholders to elicit implementation experiences and screening perception.

ResultsThe screening intervention was highly accepted and appreciated among participants; no positive RDT was reported over the duration of the study. Self-testing at home before coming to school was feasible, but more positive consequences of screening participation (e.g., easing of mask mandates) besides a personal feeling of safety would be appreciated. Participants preferred home-based RDTs over some other measures, particularly mask mandates. Despite the RDTs being licensed as self-tests in Germany, additional training can help avoid mistakes, and ensuring intervention ownership and improving pre-implementation communication can facilitate buy-in.

ConclusionsAg-RDT-based SARS-CoV-2 screening programs relying on self-testing at home proved feasible and accepted among primary school students, parents, and school staff who participated in this study.

Trial RegistrationDRKS00024845

O_TEXTBOXWhat is known about the subjectO_LIEfforts to reduce COVID-19-associated school disruption are currently being debated globally as a means to reduce the impact of extended school closures on childrens mental and physiological wellbeing.
C_LIO_LIRapid diagnostic tests (RDTs) for SARS-CoV-2 are reliable and can be performed as self-tests at home.
C_LIO_LIAlthough countries have already introduced RDT-based screening programs to facilitate safe face-to-face teaching, little is known about screening acceptance and experiences.
C_LI

What this study addsO_LIStudents, parents, and school staff perceive home-based RDT screening as feasible and less disrupting than other protective measures (e.g., mask mandates)
C_LIO_LIImplementers should communicate early and clearly, and provide a support system for training, troubleshooting, and in case of positive results
C_LIO_LIConcerns remain regarding the fidelity of home-based test performance in cases where students or parents are hesitant, even when testing is compulsory
C_LI

C_TEXTBOX


title: Attitudes towards vaccines and intention to vaccinate against COVID-19: Implications for public health communications in Australia

abstract:
ObjectiveTo examine SARS-CoV-2 vaccine confidence, attitudes and intentions in Australian adults.

MethodsNationwide survey in February-March 2021 of adults representative across sex, age and location. Vaccine uptake and a range of putative drivers of uptake, including vaccine confidence, socioeconomic status, and sources of trust, were examined using logistic and Bayesian regressions for vaccines generally and for SARS-CoV-2 vaccines.

ResultsOverall 1,166 surveys were collected from participants aged 18-90 years (mean 52, SD of 19). Seventy-eight percent reported being likely to receive a vaccine against COVID-19. Higher SARS-CoV-2 vaccine intentions were associated with: increasing age (OR: 1.04 95%CI [1.03-1.044]), being male (OR: 1.37, 95% CI [1.08 - 1.72]), residing in the least disadvantaged area quintile (OR: 2.27 95%CI [1.53 - 3.37]) and a self-perceived high risk of getting COVID-19 (OR: 1.52 95% CI [1.08 - 2.14]). However, 72% of participants did not believe that they were at a high risk of getting COVID-19. Findings regarding vaccines in general were similar except there were no sex differences. For both the SARS-CoV-2 vaccine and vaccines in general, there were no differences in intentions to vaccinate as a function of education level, perceived income level, and rurality. Knowing that the vaccine is safe and effective, and that getting vaccinated will protect others, trusting the company that made it and getting vaccination recommended by a doctor were reported to influence a large proportion of the study cohort to uptake the SARS-CoV-2 vaccine. Seventy-eight percent reported the intent to continue engaging in virus-protecting behaviours (mask wearing, social distancing etc.) post-vaccine.

ConclusionsSeventy-eight percent of Australians are likely to receive a SARS-CoV-2 vaccine. Key influencing factors identified in this study (e.g. knowing that the vaccine is safe and effective, getting a doctors recommendation to get vaccinated) can be used to inform public health messaging to enhance vaccination rates.

Strengths and limitations of this studyO_LIThis research captured a large, representative sample of the adult Australian population across age, sex, location, and socioeconomic status.
C_LIO_LIWe have self-reported Australian uptake intentions and attitudes on general vaccines and COVID-19 vaccine, and intent to continue engaging in virus-protecting behaviours (mask wearing, social distancing etc.) post SARS-CoV-2 vaccine.
C_LIO_LIWe examine a range of drivers and factors that may influence intent to get the SARS-CoV-2 vaccine uptake, including vaccine confidence, demographics and socioeconomic status.
C_LIO_LIThe survey is based on established behavioural theories, and is the Australian arm of the international iCARE survey which to date has collected global comparative information from over 90,000 respondents in 140 countries.
C_LIO_LIOur survey was only available in English, which may have led to an underrepresentation of ethnic groups, and participation was voluntary, so our sample may be prone to selection bias from those with more interest or engagement in COVID-19.
C_LI


title: Selective ensemble methods for deep learning segmentation of major vessels in invasive coronary angiography

abstract: AO_SCPLOWBSTRACTC_SCPLOWInvasive coronary angiography is a primary imaging modality that visualizes the lumen area of coronary arteries for the diagnosis of coronary artery diseases and guidance for interventional devices. In the current practice of quantitative coronary analysis (QCA), semi-automatic segmentation tools require labor-intensive and time-consuming manual correction; this limits their application in the catheterization room. For a more automated QCA, it is necessary to minimize operator intervention through robust segmentation methods with improved predictability. In this study, we introduced two selective ensemble methods that integrated the weighted ensemble approach with per-image quality estimation. In our selective ensemble methods, the segmentation outcomes from five base models with different loss functions were ranked by mask morphology or estimated dice similarity coefficient (DSC). The final output was determined by imposing different weights according to the ranking. The ranking criteria based on mask morphology were determined empirically to avoid frequent types of segmentation errors, whereas the estimation of DSCs was performed by comparing the pseudo-ground truth generated from a meta-learner. In the assessment with 7,426 frames from 2,924 patients, the selective ensemble methods improved segmentation performance with DSCs of up to 93.11% and provided a better delineation of lumen boundaries near the coronary lesion with local DSCs of up to 94.04%, outperforming all individual models and hard voting ensembles. The probability of mask disconnection at the most narrowed region could be minimized to <1%. The robustness of the proposed methods was evident in the external validation. Inference time for major vessel segmentation was approximately one-third, indicating that our selective ensemble methods may allow the real-time application of QCA-based diagnostic methods in routine clinical settings.

category: radiology and imaging


title: Transjugular Intrahepatic Portosystemic Shunt and Locoregional Therapies in Patients Undergoing Orthotopic Liver Transplantation: A Protocol for a Retrospective, Linked United Network for Organ Sharing Cohort

abstract:
IntroductionOrthotopic Liver Transplantation (OLT) is the potential curative treatment option for patients with end-stage liver disease (ESLD) or hepatocellular carcinoma (HCC) within organ procurement and transplantation network (OPTN) criteria. However, these groups of patients may require bridging interventions, including Transjugular Intrahepatic Portosystemic Shunt (TIPS) or Locoregional Therapies (LRTs), given the nationwide organ shortage and increasing waitlist time. The perioperative and long-term post-OLT survival and clinical outcomes require further investigation to evaluate the clinical utility and therapeutic advantages of these bridging interventions, if any. We propose a large retrospective database analysis that will evaluate both perioperative and long-term effects of these OLT-related interventions.

Methods and analysisThree datasets from the United Network for Organ Sharing (UNOS) database will be included and linked to estimate the causal effect of 1) Transjugular Intrahepatic Portosystemic Shunts and 2) Locoregional therapies in patients undergoing OLT, the latter among patients with HCC. Only therapy naive adult patients, without multivisceral transplants, and without living donor transplants will be included. The primary outcome will be overall survival. Secondary outcomes will include perioperative clinical outcomes, post-operative survival, and postoperative clinical outcomes. The inverse probability of treatment weighted models with Cox regression will be utilized to analyze survival outcomes, logistic regression for categorical outcomes, and ordinary least squares regression for continuous outcomes. A sensitivity analysis will be conducted to assess the appropriateness of a complete-case analysis for the primary outcome and ensure the robustness of the findings.

Ethics and DisseminationThis study protocol was reviewed by the Emory University School of Medicine Institutional Review Board (IRB), and ethical approval was waived due to the retrospective analysis of the originally anonymized database. The results will be disseminated in peer-reviewed journals and presented at relevant conferences. It was not appropriate or possible to involve patients or the public in the design, or conduct, or reporting, or dissemination plans of our research.

STRENGTHS AND LIMITATIONS OF THIS STUDYO_ST_ABSStrengthsC_ST_ABSThe proposed study:

O_LIWill be the first study evaluating the causal effect of TIPS in OLT candidates and of locoregional therapies in OLT candidates with HCC
C_LIO_LIWill be the first study to link UNOS datasets to investigate the estimands, thereby providing insight into the clinical impact of TIPS and LRTs at various stages in the clinical pathway.
C_LI

LimitationsThe proposed study:

O_LIWill be a retrospective study and thus subject to poor or inadequate reporting in the registry, though propensity score matching will be done
C_LIO_LIMay be subject to unmeasured confounding and sensitive to model misspecification
C_LIO_LIMay lack the necessary sample size and subsequently be underpowered to estimate the target estimands
C_LI


title: Accuracy of Conflict-of-Interest Disclosures of Physician-Authors Publishing in High-Impact U.S. Medical Journals: A Comparison of the Journal of the American Medical Association and the New England Journal of Medicine

abstract:
ObjectiveTo assess the accuracy of self-reported financial conflict-of-interest (COI) disclosures in the New England Journal of Medicine (NEJM) and Journal of the American Medical Association (JAMA) within the requisite disclosure period prior to article submission.

DesignCross-sectional investigation.

Data SourcesOriginal clinical-trial research articles published in NEJM (n = 206) or JAMA (n = 188) from January 1 to December 31, 2017; self-reported COI disclosure forms submitted to NEJM or JAMA with the authors published articles; Open Payments website (from database inception; latest search: August 2019).

Main outcome measuresFinancial data reported to Open Payments from 2014 to 2016 (time period that included all subjects requisite disclosure windows) were compared to self-reported disclosure forms submitted to the journals. Payments were defined as those not associated with a research study or formal research funding. Payment types were categorized as "disclosed," "undisclosed," "indeterminate," or "unrelated."

ResultsThirty-one articles from NEJM and 31 articles from JAMA met inclusion criteria. The physician-authors (n = 118) received a combined total of $7.48 million. Of the 106 authors (89.8%) who received payments, 86 (81.1%) received undisclosed payments. The top 23 most highly compensated received $6.32 million, of which $3.00 million (47.6%) was undisclosed. Disclosure rates were the equivalent between the top 23 and the entire sample.

ConclusionsHigh payment amounts, as well as high proportions of undisclosed financial compensation, regardless of amount received, comprised potential COIs for two influential US medical journals. Further research is needed to explain why such high proportions of general payments were undisclosed and whether journals that rely on self-reported COI disclosure need to reconsider their policies.

category: medical ethics


title: A Cross-Sectional Examination of Conflict-of-Interest Disclosures of Physician-Authors Publishing in High-Impact US Medical Journals


title: Intraoperative microseizure detection using a high-density micro-electrocorticography electrode array

abstract: One-third of epilepsy patients suffer from medication-resistant seizures. While surgery to remove epileptogenic tissue helps some patients, 30-70% of patients continue to experience seizures following resection. Surgical outcomes may be improved with more accurate localization of epileptogenic tissue. We have previously developed novel thin-film, subdural electrode arrays with hundreds of microelectrodes over a 100-1,000 mm2 area to enable high-resolution mapping of neural activity. Here we used these high-density arrays to study microscale properties of human epileptiform activity. We performed intraoperative micro-electrocorticographic recordings within epileptic cortex (the site of seizure onset and early spread) in nine patients with epilepsy. In two of these patients, we obtained recordings from cortical areas distal to the epileptic cortex. Additionally, we recorded from two non-epileptic patients with movement disorders undergoing deep brain stimulator implantation as non-epileptic tissue controls. A board-certified epileptologist identified microseizures, which resembled electrographic seizures normally observed with clinical macroelectrodes. Epileptic cortex exhibited a significantly higher microseizure rate (2.01 events/min) than non-epileptic cortex (0.01 events/min; permutation test, P=0.0068). Using spatial averaging to simulate recordings from larger electrode contacts, we found that the number of detected microseizures decreased rapidly with increasing contact diameter and decreasing contact density. In cases in which microseizures were spatially distributed across multiple channels, the approximate onset region was identified. Our results suggest that micro-electrocorticographic electrode arrays with a high density of contacts and large coverage are essential for capturing microseizures in epilepsy patients and may be beneficial for localizing epileptogenic tissue to plan surgery or target brain stimulation.

category: neurology


title: Relationships between barley consumption and gut microbiome characteristics in a healthy Japanese population: a cross-sectional study

abstract:
ObjectiveBarley contains abundant soluble {beta}-glucan fibres, which have established health benefits. In addition, the health benefits conferred by the gut microbiota have attracted considerable interest. However, few studies have focused on the barley intake and microbiota of the Japanese population. In this study, we aimed to identify the relationship between the barley consumption and gut microbiota composition of the Japanese population.

Research Methods & ProceduresA total of 236 participants were recruited in Japan, and 94 participants with no complication of diabetes, hypertension, and dyslipidemia were selected for the study. We analysed faecal samples from the participants, their medical check-up results, and responses to questionnaires about dietary habits. The participants were grouped according to their median barley intake. Then, we assessed the relative abundance of 50 microbial genera throughout the group and selected 20 that differed at P < 0.1 (Mann-Whitney U-test). We also analysed the networks and clustering of the 20 selected genera.

ResultsAccording to their relative abundance, Bifidobacterium, Anaerostipes, and Butyricicoccus were candidate characteristic microbiota of the group that consumed large amounts of barley (P < 0.05). Furthermore, network and cluster analyses revealed that barley directly correlated with Bifidobacterium and Butyricicoccus.

ConclusionsBarley consumption generates changes in the intestinal microbiota of the Japanese population. We found that Bifidobacterium, Anaerostipes, and Butyricicoccus abundance was positively associated with barley consumption. This study showed that barley is important for gut microbiota and relates to Japanese traditional food like natto.

category: nutrition


title: Association between Positive Airway Pressure Adherence and Healthcare Costs

abstract:
BackgroundThe impact of positive airway pressure (PAP) therapy for obstructive sleep apnea (OSA) on healthcare costs is uncertain.

Research QuestionAre three-year healthcare costs associated with PAP adherence in participants from the Tele-OSA clinical trial?

Study Design and MethodsParticipants with OSA and prescribed PAP in the Tele-OSA study were stratified into three PAP adherence groups based on usage patterns over three years: (a) high (consistently [≥] 4 hours/night); (b) moderate (2-3.9 hours/night or inconsistently [≥] 4 hours/night); (c) low (<2 hours/night). Using data from three months of the Tele-OSA trial and 33 months of post-trial follow-up, average healthcare costs (2020 US dollars) in six-month intervals were derived from electronic health records and analyzed using multivariable generalized linear models.

ResultsOf 543 participants, 25% were categorized as having high adherence, 22% moderate adherence, and 52% low adherence to PAP therapy. Average (standard deviation) PAP use was 6.5 (1.0) hours, 3.7 (1.2) hours, and 0.5 (0.5) hours for the high, moderate, and low adherence groups, respectively. The high adherence group had the lowest average [standard error] covariate-adjusted six-month healthcare costs ($3,162 [$240]) compared with the moderate ($3,658 [$369]) and low ($4,016 [$315]) adherence groups. Significant cost savings were observed between the high and low adherence groups ($854 [95% CI $158, $1,551]); savings between moderate and low adherence were non-significant ($359 [95% CI -$459, $1,176]).

InterpretationIn participants with OSA, better PAP adherence was associated with significantly lower healthcare costs over three years. Findings support the importance of strategies to enhance long-term PAP adherence.

category: health economics


title: Resilience Assessment of healthcare facilities within urban context: Learning from a non-profit hospital in Tehran, Iran

abstract: Tehrans healthcare system is under increasing strain due to population expansion and a lack of disaster preparedness measures. The purpose of this paper is to analyze hospital resilience in an urban setting to identify areas for improvement to keep the studied hospital operational during a crisis. In this study, the Urban Resilience Index (URI) in Amir-Alam hospital was assessed using a customized version of the City Resilience Profiling Tool (CRPT) established by the United Nations Office for Disaster Risk Reduction (UNISDR). The 36 indicators were analyzed in 5 components. The result has revealed that the hospitals urban resilience score was calculated to be 51.75 out of 100, indicating medium resilience, while, regarding the critical indicators, the score was 20.25 out of 60, which is not acceptable. The physical, organizational, and spatial attributes of the Amir-Alam hospital are among the least resilient, but the functional and dynamic characteristics are reasonably decent.

category: health systems and quality improvement


title: Potential Impacts of Mass Nutritional Supplementation on Dynamics of Measles: A Simulation Study

abstract:
The bidirectional interaction between undernutrition and infection can be devastating to child health. Nutritional deficiencies stunt growth, impair immunity, increase susceptibility to both infection and more severe outcomes from common infections. Simultaneously, infections compound undernutrition by increasing metabolic demand, reducing food intake, and impairing nutrient absorption. Treatment of acute malnutrition (wasting) can reverse at least some of its deleterious effects and reduce susceptibility to, and transmission of, infectious diseases. Nutrition-specific approaches may be packaged with other interventions, including immunization, to support overall child health. To understand how mass nutritional supplementation, treatment of wasting, and vaccination affect the dynamics of a vaccine-preventable infection, we developed a population-level, compartmental model of measles transmission of children aged 6-23 months old, stratified by nutrition status. We simulated a range of scenarios to assess the potential reductions in measles infection and mortality associated with targeted therapeutic feeding for children who are wasted and with a mass supplementation intervention. Nutrition interventions were assumed to reduce susceptibility to measles-related death and to increase engagement with the health sector, leading to increased vaccination rates. We found that if all wasted children receive therapeutic feeding, and if this leads to an increase in measles vaccination uptake, up to 12%, 20%, and 23% reductions in measles infections, measles-attributable mortality, and overall mortality among wasted children, respectively, could be averted. Combination of wasting treatment and mass supplementation coverage followed by an increase in vaccination coverage of non-wasted children from a baseline of 75% to 85%, leads to a 64-66% reduction in measles infection and mortality and 27% reduction in overall mortality among wasted children, compared with the wasting treatment alone. Our work highlights the synergistic benefits that may be achieved by leveraging mass nutritional supplementation as a touch point with the health system, to increase rates of vaccination in order to improve child survival beyond what would be expected from the additive benefits of each intervention.

Significance StatementThe pathways by which undernutrition and infection interact have not been fully disentangled. Undernourished children may be more susceptible to infection and at increased risk for infectious disease complications. Infection also can interfere with nutrition intake or retention. Nutrition-based interventions may have indirect benefits on reducing infectious disease burden by reducing susceptibility through multiple routes. One of these is enhancing engagement with the health sector, thereby leading to adoption of other essential services such as vaccination. Here we quantify the association between undernutrition and a vaccine-preventable disease by developing a mathematical model of measles transmission which accounts for childhood nutritional and vaccination statuses. Our results show that mass nutritional supplementation has a strong effect in reducing the burden of measles and undernutrition, compared with wasting treatment only. Our work may elevate the potential role of nutritional supplementation in infection prevention, and encourage more targeted data collection around the effectiveness of packaged care in optimizing child development and growth.

category: infectious diseases


title: A comparative study of Bacterial culture isolates, site of infections and drug resistance pattern between COVID and non COVID patients admitted in a tertiary care hospital : A Pilot study

abstract:
IntroductionSARS-CoV2 which is a corona virus also predisposes patient to secondary bacterial infection by various mechanisms like-damaging the respiratory epithelium, profoundly affecting the innate and adaptive immunity, antagonising Interferon responses that enhance bacterial adherence, colonisation and invasion to respiratory tissue. In addition, prolonged hospital stay, invasive therapeutic devices, widespread use of empiric antibiotics and most importantly use of immune-suppressants like Steroid or Tocilizumab further increases the chances of bacterial infection. As opposed to this concept-physical distancing, frequent hand washing and use of gloves and protective gear by the healthcare workers also diminishes the chance of secondary bacterial infection. The present study is done to delineate the bacteriological profile, infection site predisposition or to gain knowledge on antibiotic sensitivity pattern.

MethodRetrospective data will be analyzed from June 2020, when the first COVID wave came to June 2021, corresponding to second COVID wave. The present study is a pilot study before collecting and analyzing the whole data Only those samples which were positive for bacterial isolates were randomly selected and the COVID status and drug resistance patterns were checked.

Results and discussionThe most common organism found was Klebsiella. Acinetobacter was also found in few patients. But most striking finding was that COVID positive patients showed higher incidence of antibiotic resistance with Acinetobacter. Though E Coli was also found commonly in COVID positive patients, they were not drug resistant.

ConclusionMDR infections are common in COVID patients. Acinetobacter and Klebsiella are prone to develope MDR infections. While E.Coli is also common in COVID patients, chance of drug resistance is less among them.


title: Robust induction of B cell and T cell responses by a third dose of inactivated SARS-CoV-2 vaccine

abstract: SARS-CoV-2 inactivated vaccines have shown remarkable efficacy in clinical trials, especially in reducing severe illness and casualty. However, the waning of humoral immunity over time has raised concern over the durability of immune memory following vaccination. Thus, we conducted a non-randomized trial among the healthcare professionals (HCWs) to investigate the long-term sustainability of SARS-CoV-2-specific B cells and T cells stimulated by inactivated vaccines and the potential need for a third booster dose. Although neutralizing antibodies elicited by the standard two-dose vaccination schedule dropped from a peak of 29.3 AU/ml to 8.8 AU/ml 5 months after the second vaccination, spike-specific memory B and T cells were still detectable, forming the basis for a quick recall response. As expected, the faded humoral immune response was vigorously elevated to 63.6 AU/ml by 7.2 folds 1 week after the third dose along with abundant spike-specific circulating follicular helper T cells in parallel. Meanwhile, spike-specific CD4+ and CD8+ T cells were also robustly elevated by 5.9 and 2.7 folds respectively. Robust expansion of memory pools by the third dose potentiated greater durability of protective immune responses. Another key finding in this trial was that HCWs with low serological response to 2 doses were not truly "non-responders" but fully equipped with immune memory that could be quickly recalled by a third dose even 5 months after the second vaccination. Collectively, these data provide insights into the generation of long-term immunological memory by the inactivated vaccine, which could be rapidly recalled and further boosted by a third dose.


title: Olfactory Bulb and Amygdala Gene Expression Changes in Subjects Dying with COVID-19

abstract: In this study we conducted RNA sequencing on two brain regions (olfactory bulb and amygdala) from subjects who died from COVID-19 or who died of other causes. We found several-fold more transcriptional changes in the olfactory bulb than in the amygdala, consistent with our own work and that of others indicating that the olfactory bulb may be the initial and most common brain region infected. To some extent our results converge with pseudotime analysis towards common processes shared between the brain regions, possibly induced by the systemic immune reaction following SARS-CoV-2 infection. Changes in amygdala emphasized upregulation of interferon-related neuroinflammation genes, as well as downregulation of synaptic and other neuronal genes, and may represent the substrate of reported acute and subacute COVID-19 neurological effects. Additionally, and only in olfactory bulb, we observed an increase in angiogenesis and platelet activation genes, possibly associated with microvascular damages induced by neuroinflammation. Through coexpression analysis we identified two key genes (CAMK2B for the synaptic neuronal network and COL1A2 for the angiogenesis/platelet network) that might be interesting potential targets to reverse the effects induced by SARS-CoV-2 infection. Finally, in olfactory bulb we detected an upregulation of olfactory and taste genes, possibly as a compensatory response to functional deafferentation caused by viral entry into primary olfactory sensory neurons. In conclusion, we were able to identify transcriptional profiles and key genes involved in neuroinflammation, neuronal reaction and olfaction induced by direct CNS infection and/or the systemic immune response to SARS-CoV-2 infection.


title: High Response Rate to Antidepressants in the Management of Paroxysmal Hypertension (Pseudopheochromocytoma)

abstract:
There is no widely recognized preventive treatment for patients with paroxysmal hypertension ("pseudopheochromocytoma") who suffer recurrent and often severe paroxysmal elevation of blood pressure, repeated emergency room visits and hospitalizations. In this case series we assessed the effectiveness of treatment with an antidepressant in preventing recurrent paroxysms. A secondary exploratory objective was to examine the psychological profile of patients and its relationship to response to treatment. The charts of 52 patients who reported having experienced at least 3 symptomatic episodes were selected; and and for whom treatment data were included. Treatment with an antidepressant was offered to, and follow-up data were available in 37..

Two patients refused treatment, 6 were unable to tolerate an effective dose, 3 were lost to follow-up, and 1 was non-compliant with the medication. Of the remaining 25 evaluable patients, 92% (23/25) responded, with 80% (21/25) achieving complete and persisting cessation of paroxysms, and 8% (2/25), a reduction in frequency. Importantly, an antidepressant was effective in nearly all patients who reported that they were not suffering from anxiety or depression. The data were insufficient to determine superiority of any one antidepressant versus another. We conclude that treatment with an antidepressant is effective in preventing hypertensive paroxysms in a high proportion of patients with paroxysmal hypertension. Given the absence of any other pharmacologic intervention capable of preventing recurrent paroxysms, the similarly high response rate observed in previous reports, and the relatively safe profile of antidepressant agents, the findings support more widespread use of an antidepressant in patients with this disorder to prevent years of continued hypertensive paroxysms and their consequences.

category: cardiovascular medicine


title: The role of social support in achieving weight loss in adults in the Caribbean aiming to achieve remission of type 2 diabetes: A cross-case analysis.

abstract:
BackgroundRemission of type 2 diabetes through weight loss is possible in a high proportion of persons with a recent diagnosis, but a major challenge is achieving sufficient weight loss.

ObjectivesIn the first study of this type in the Caribbean, we investigated factors associated with successful weight loss in adults in a diabetes remission intervention. We hypothesized that differences in social support may have influenced differences in weight loss achieved by participants in the Barbados Diabetes Reversal Study (BDRS).

MethodsA comparative case study was conducted. Quantitative data for the primary outcome measure of weight reduction (the participants baseline and 8-month weights) were assessed to identify the 6 participants with the highest and 6 participants with the lowest weight loss. The 8-week (low-calorie diet phase) and 8-month (weight maintenance phase) interview transcripts for each participant were then analysed via qualitative thematic analysis to explore factors related to social support.

ResultsInformal and formal support were identified for both categories of participants. Cases were similar with respect to their sources of support however dissimilarities were found in (1) the depth of support received; (2) access to supportive environments and (3) diversity of social supportive networks. Participants in the top weight loss group reported consistency in the levels of support received over the low-calorie diet and weight maintenance phases of the study while the converse was true for those of the bottom weight loss group.

ConclusionStudy findings suggest that individuals aiming at type 2 diabetes remission benefit from strong social support networks. These networks provide tangible assistance and facilitate the sharing and discussion of strategies for weight reduction. Future studies should facilitate in-depth understanding of how formal and informal supportive networks can aid sustained dietary diabetes remission and long-term weight maintenance.

category: endocrinology


title: The Role of Physical Environmental Characteristics and Intellectual Disability in Conduct Problem Trajectories Across Childhood: A Population-Based Cohort Study

abstract:
BackgroundThe paucity of research investigating the role of the physical environment in the developmental progression of conduct problems and the potential moderating effects of intellectual disability (ID) is surprising, given the clinical relevance of elucidating environmental determinants of disruptive behaviours.

AimsTo use data from a large UK cohort study to assess associations between physical environmental exposures, ID, and conduct problem trajectories.

MethodThe sample included 8,168 Millennium Cohort Study children (1.9% with ID). Multilevel growth curve modelling was used to examine the role of physical environment characteristics in the developmental trajectories of conduct problems after adjustments for ID status.

ResultsExposure to external environmental domains was not associated with differences in childrens conduct problems across development. Alternatively, internal aspects of the household environment: spatial density (b = 0.40, p<.001) and damp problems (b = 0.14, p<.001) were both significantly associated with increased trajectories. Various individual and familial covariates were positively associated with conduct problems over time, including: presence of ID (b = 0.96, p<.001), autism spectrum disorder (b = 1.18, p<.001), male sex (b = 0.26, p<.001), poverty (b = 0.19, p<.001), maternal depression (b = 0.65, p<.001), and non-nuclear family structure (b = 0.35, p<.001). Positive ID status appeared to moderate the effects of internal household spatial density, reporting a non-linear negative association with spatial density and conduct problems across development (b = -1.08, p<.01).

ConclusionsOur findings highlight the potential harmful consequences of poor internal residential conditions on childrens development of disruptive behaviours.


title: Efficacy of vaccination against severe COVID-19 in relation to Delta variant and time since second dose: the REACT-SCOT case-control study

abstract:
BackgroundThe objectives of this study were to investigate whether vaccine efficacy against severe COVID-19 has decreased since Delta became the predominant variant; (2) whether efficacy wanes with time since second dose.

MethodsEfficacy was estimated in a matched case-control study that includes all diagnosed cases of COVID-19 in Scotland up to 19 August 2021. The main outcome measure was severe COVID-19, defined as cases with entry to critical care or fatal outcome.

FindingsEfficacy of vaccination against severe COVID-19 decreased in May 2021 coinciding with the replacement of the B.1.1.7 (Alpha) by the B.1.617.2 (Delta) variant in Scotland, but this decrease was reversed over the next month. In the most recent time window, the efficacy of two doses was 91% (95 percent CI 87% to 94%) for the AstraZeneca product and 92% (95 percent CI 88% to 95%) for mRNA (Pfizer or Moderna) products. Efficacy of the AstraZeneca product against severe COVID-19 declined with time since second dose to 69% (95 percent CI 52% to 80%) at 20 weeks from second dose. Efficacy of mRNA vaccines declined in the first ten weeks from second dose but more slowly thereafter to 93% (95 percent CI 88% to 96%) at 20 weeks from second dose.

InterpretationThese results are reassuring with respect to concerns that efficacy against severe COVID-19 might have fallen since the Delta variant became predominant, or that efficacy of mRNA vaccines wanes with increasing time since second dose. However it is now clear that efficacy of the AstraZeneca vaccine against severe COVID-19 wanes substantially by 20 weeks from second dose, suggesting that delivery of booster doses should initially focus on those who received this type of vaccine.

FundingNo specific funding was received for this work. HC is supported by an endowed chair from the AXA Research Foundation.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSSeveral reports have suggested that efficacy of COVID-19 vaccines has fallen since the Delta variant became predominant, or that efficacy wanes with time since second dose. The starting point for this study was the evidence of waning efficacy cited by the CDC, the FDA and more recently the UK Joint Committee on Vaccination and Immunisation in support of their recent recommendations for delivery of booster doses for the general population.

Added value of this studyThis study shows that efficacy of both AstraZeneca and mRNA vaccines against severe COVID-19 (fatal or requiring critical care) remains high (around 90%) in the most recent time window, but that efficacy of the AstraZeneca vaccine wanes to about 70% by 20 weeks from second dose. In contrast efficacy of the mRNA vaccines wanes rapidly at first but stabilises at about 90% by 20 weeks from second dose.

Implications of all the available evidenceThese results suggest that booster doses of vaccine are not needed for those who have received two doses of mRNA vaccine, except for vulnerable individuals who may require a third primary dose.


title: Interrogating COVID-19 Vaccine Hesitancy in the Philippines with a Nationwide Open-Access Online Survey

abstract: To mitigate the unprecedented health, social, and economic damage of COVID-19, the Philippines is undertaking a nationwide vaccination program to mitigate the effects of the global pandemic. In this study, we interrogated COVID-19 vaccine hesitancy in the country by deploying a nationwide open-access online survey, two months before the rollout of the national vaccination program. The Health Belief Model (HBM) posits that people are likely to adopt disease prevention behaviors and to accept medical interventions like vaccines if there is sufficient motivation and cues to action. A majority of our 7,193 respondents (62.5%) indicated that they were willing to be vaccinated against COVID-19. Moreover, multivariable analysis revealed that HBM constructs were associated with vaccination intention in the Philippines. Perceptions of high susceptibility, high severity, and significant benefits were all good predictors for vaccination intent. We also found that external cues to action were important. Large majorities of our respondents would only receive the COVID-19 vaccines after many others had received it (72.8%) or after politicians had received it (68.2%). Finally, our study revealed that most (21%) were willing to pay an amount of PHP1,000 [USD20] for the COVID-19 vaccines with an average willing-to-pay amount of PHP1,892 [USD38].

category: public and global health


title: Identification of rare loss of function variation regulating body fat distribution

abstract: Biological and translational insights from large-scale, array-based genetic studies of fat distribution, a key determinant of metabolic health, have been limited by the difficulty in linking identified predominantly non-coding variants to specific gene targets. Rare coding variant analyses provide greater confidence that a specific gene is involved, but do not necessarily indicate whether gain or loss of function would be of most therapeutic benefit. Here we use a dual approach that combines the power of genome-wide analysis of array-based rare, non-synonymous variants in 184,246 individuals of UK Biobank with exome-sequence-based rare loss of function gene burden testing. The data indicates that loss-of-function (LoF) of four genes (PLIN1, INSR, ACVR1C and PDE3B) is associated with a beneficial impact on WHRadjBMI and increased gluteofemoral fat mass, whereas PLIN4 LoF adversely affects these parameters. This study robustly implicates these genes in the regulation of fat distribution, providing new and in some cases somewhat counter-intuitive insight into the potential consequences of targeting these molecules therapeutically.


title: SARS-CoV-2 anti-spike IgG antibody responses after second dose of ChAdOx1 or BNT162b2 in the UK general population

abstract: We investigated anti-spike IgG antibody responses and correlates of protection following second doses of ChAdOx1 or BNT162b2 SARS-CoV-2 vaccines in the UK general population. In 222,493 individuals, we found significant boosting of anti-spike IgG by second doses of both vaccines in all ages and using different dosing intervals, including the 3-week interval for BNT162b2. After second vaccination, BNT162b2 generated higher peak levels than ChAdOX1. Older individuals and males had lower peak levels with BNT162b2 but not ChAdOx1, while declines were similar across ages and sexes with ChAdOX1 or BNT162b2. Prior infection significantly increased antibody peak level and half-life with both vaccines. Anti-spike IgG levels were associated with protection from infection after vaccination and, to an even greater degree, after prior infection. At least 67% protection against infection was estimated to last for 2-3 months after two ChAdOx1 doses and 5-8 months after two BNT162b2 doses in those without prior infection, and 1-2 years for those unvaccinated after natural infection. A third booster dose may be needed, prioritised to ChAdOx1 recipients and those more clinically vulnerable.


title: SARS-CoV-2 anti-spike IgG antibody responses after second dose of ChAdOx1 or BNT162b2 and correlates of protection in the UK general population


title: Live wildlife trade in markets - a scoping review to inform risk assessment of emerging infectious diseases

abstract: Wet markets are important for food security in many regions worldwide but have come under scrutiny due to their potential role in the emergence of infectious diseases. The sale of live wildlife has been highlighted as a particular risk, and the World Health Organisation has called for the banning of live, wild-caught mammalian species in markets unless risk assessment and effective regulations are in place. Following PRISMA guidelines, we conducted a global scoping review of peer-reviewed information about the sale of live, terrestrial wildlife in markets that are likely to sell fresh food, and collated data about the characteristics of such markets, activities involving live wildlife, the species sold, their purpose, and animal, human, and environmental health risks that were identified. Of the 59 peer-reviewed records within scope, only 25% (n = 14) focussed on disease risks; the rest focused on the impact of wildlife sale on conservation. Although there were some global patterns (for example, the types of markets and purpose of sale of wildlife), there was wide diversity and huge epistemic uncertainty in all aspects associated with live, terrestrial wildlife sale in markets such that the feasibility of accurate assessment of the risk of emerging infectious disease associated with live wildlife trade in markets is limited. Given the value of both wet markets and wildlife trade and the need to support food affordability and accessibility, conservation, public health, and the social and economic aspects of livelihoods of often vulnerable people, there are major information gaps that need to be addressed to develop evidence-based policy in this environment. This review identifies these gaps and provides a foundation from which information for risk assessments can be collected.


title: Robust clinical detection of SARS-CoV-2 variants by RT-PCR/MALDI-TOF multi-target approach

abstract: The COVID-19 pandemic sparked rapid development of SARS-CoV-2 diagnostics. However, emerging variants pose the risk for target dropout and false-negative results secondary to primer/probe binding site (PBS) mismatches. The Agena MassARRAY(R) SARS-CoV-2 Panel combines RT-PCR and MALDI-TOF mass-spectrometry to probe for five targets across N and ORF1ab genes, which provides a robust platform to accommodate PBS mismatches in divergent viruses. Herein, we utilize a deidentified dataset of 1,262 SARS-CoV-2-positive specimens from Mount Sinai Health System (New York City) from December 2020 through April 2021 to evaluate target results and corresponding sequencing data. Overall, the level of PBS mismatches was greater in specimens with target dropout. Of specimens with N3 target dropout, 57% harbored an A28095T substitution that is highly-specific for the alpha (B.1.1.7) variant of concern. These data highlight the benefit of redundancy in target design and the potential for target performance to illuminate the dynamics of circulating SARS-CoV-2 variants.