title: Genetic associations with severe COVID-19

abstract: Identification of host genetic factors that predispose individuals to severe COVID-19 is important, not only for understanding the disease and guiding the development of treatments, but also for risk prediction when combined to form a polygenic risk score (PRS). Using population controls, Pairo-Castineira et al. identified 12 SNPs (a panel of 8 SNPs and a panel of 6 SNPs, with two SNPs in both panels) associated with severe COVID-19. Using controls with asymptomatic or mild COVID-19, we were able to replicate the association with severe COVID-19 for only three of their SNPs and found marginal evidence for an association for one other. When combined as an 8-SNP PRS and a 6-SNP PRS, we found no evidence of association with severe COVID-19. The difference in our results and the results of Pairo-Castineira et al. might be the choice of controls: population controls vs controls with asymptomatic or mild COVID-19.


title: Muscle Strength and Muscle Mass as Predictors of Hospital Length of Stay in Patients with Moderate to Severe COVID-19: A Prospective Observational Study

abstract:
ImportanceStrength and muscle mass are predictors of relevant clinical outcomes in critically ill patients, but in hospitalized patients with COVID-19 remains to be determined.

ObjectiveTo investigate whether muscle strength or muscle mass are predictive of hospital length of stay (LOS) in patients with moderate to severe COVID-19.

DesignProspective observational study.

SettingClinical Hospital of the School of Medicine of the University of Sao Paulo.

ParticipantsOne hundred ninety-six patients were evaluated. Ten patients did not test positive for SARS-CoV-2 during hospitalization and were excluded from the analyses. The sample comprised patients of both sexes (50% male) with a mean age (SD) of 59 ({+/-}15) years, body mass index of 29.5 ({+/-}6.9) kg/m2. The prevalence of current smoking patients was 24.7%, and more prevalent coexisting conditions were hypertension (67.7%), obesity (40.9%), and type 2 diabetes (36.0%). Mean (SD) LOS was 8.6 days (7.7); 17.0% of the patients required intensive care; 3.8% used invasive mechanical ventilation; and 6.6% died during the hospitalization period.

Main outcomeThe outcome was LOS, defined as time from hospital admission to medical discharge.

ResultsThe crude Hazard Ratio (HR) for LOS was greatest for handgrip strength comparing the strongest vs. other patients (1.54 [95%CI: 1.12 - 2.12; p = 0.008]). Evidence of an association between increased handgrip strength and shorter hospital stay was also identified when handgrip strength was standardized according to the sex-specific mean and standard deviation (1.23 [95%CI: 1.06 - 1.19; p = 0.008]). The magnitude of these associations remained consistent and statistically significant after adjusting for other covariates. Mean LOS was shorter for the strongest patients (7.5 {+/-} 6.1 days) vs. others (9.2 {+/-} 8.4 days). Evidence of associations were also present for vastus lateralis cross-sectional area. The crude HR identified shorter hospital stay for patients with greater sex-specific standardized values (1.17 [95%CI: 1.01 - 1.36; p = 0.037]); however, we found increased uncertainty in the estimate with the addition of other covariates (1.18 [95%CI: 0.97 - 1.43; p = 0.092]). Evidence was also obtained associating longer hospital stays for patients with the lowest values for vastus lateralis cross-sectional area (0.69 [95%CI: 0.50 - 0.95; p = 0.025). Mean LOS for the patients with the lowest muscle cross-sectional area was longer (10.8 {+/-} 8.8 days) vs. others (7.7 {+/-} 7.2 days).

Conclusions and RelevanceMuscle strength and mass assessed upon hospital admission are predictors of LOS in patients with moderate to severe COVID-19, which stresses the value of muscle health in prognosis of this disease.

FundingThe authors acknowledge the support by the Brazilian National Council for Scientific and Technological Development (CNPq - grant 301571/2017-1). H.R. and B.G. are supported by grants from the Conselho Nacional de Pesquisa e Desenvolvimento (CNPq 428242/2018-9; 301571/2017-1; 301914/2017-6). B.G. is also supported by a grant from the Sao Paulo Research Foundation (FAPESP 2017/13552-2).

Key pointsO_ST_ABSQuestionC_ST_ABSDo muscle strength and muscle mass predict hospital length of stay (LOS) in patients with moderate to severe COVID-19 patients?

FindingsIn this prospective observational study that included 186 hospitalized patients with moderate to severe COVID-19, we observed that LOS was shorter among patients in the highest tertile of strength (assessed by handgrip) vs. those in the mid/lowest tertiles (crude Hazard Ratio [HR]: 1.54, 95%CI: 1.12-2.12). In addition, LOS was longer among patients in the lowest tertile of muscle cross-sectional area (assessed by ultrasound imaging) vs. those in the mid/highest tertiles (HR: 0.69, 95%CI: 0.50 - 0.95).

MeaningMuscle strength and mass assessed on hospital admission are predictors of LOS in patients with moderate to severe COVID-19, suggesting that muscle health may be protective in this disease.

category: epidemiology


title: Mitigating the identity and health threat of COVID-19: Perspectives of Middle-Class South Asians living in the UK

abstract: The recognition and representation of BAME community as "high risk" of Covid-19 in the UK presents both a health and an identity threat to this ethnic group. This study employed thematic analysis to explore response to these threats as related by a sample of thirteen middle class members of the South Asian community. This work advances both health and identity psychological theory by recognising the affinity between expressions of health efficacy and identity. Our findings identify South Asian intragroup stigmatisation and commonalities that have implications for the promotion of health behaviour and health communications for minority groups.

category: public and global health


title: Detection of cross-reactive IgA in saliva against SARS-CoV-2 Spike1 subunit

abstract: Abundant secretory IgA (sIgA) in mucus, breast milk, and saliva provides immunity that prevents infection of mucosal surfaces. sIgA in pre-pandemic breast milk samples have been reported to cross-react with SARS-CoV-2, but whether it also occurs in saliva and, if so, whether it cross-reacts with SARS-CoV-2, has remained unknown. We aimed to clarify whether sIgA in saliva cross-reacts with SARS-CoV-2 spike 1 subunit in individuals who have not been infected with this virus. The study included 137 (male, n = 101; female, n = 36; mean age, 38.7 [24-65] years) of dentists and doctors in the Kanagawa Dental University Hospital. Saliva and blood samples were analyzed by PCR and immunochromatography for IgG and IgM, respectively. We then identified patients with saliva samples that were confirmed as PCR- and IgM-negative for COVID-19. Proportions of SARS-CoV-2 cross-reactive IgA-positive individuals were determined by enzyme-linked immunosorbent assay using a biotin-labeled spike S1-mFc recombinant protein covering the receptor-binding domain of SARS-CoV-2. The proportion of SARS-CoV-2 cross-reactive IgA-positive individuals was 46.7%, and this correlated negatively with age (r = -0.218, p = 0.01). The proportion of IgA-positive individuals [≥] 50 y was significantly lower than that of patients aged [≤] 49 y (p = 0.008). sIgA was purified from the saliva of all patients, and the salivary sIgA was found to suppress the binding of SARS-CoV-2 spike protein to the ACE-2 receptor. We found SARS-CoV-2 cross-reactive sIgA in the saliva of some participants who had never been infected with the virus, suggesting that sIgA helps prevent SARS-CoV-2 infection.

category: dentistry and oral medicine


title: Estimating the strength of selection for new SARS-CoV-2 variants

abstract: Controlling the SARS-CoV-2 pandemic becomes increasingly challenging as the virus adapts to human hosts through the continual emergence of more transmissible variants. Simply observing that a variant is increasing in frequency is relatively straightforward, but more sophisticated methodology is needed to determine whether a new variant is a global threat and the magnitude of its selective advantage. We present three methods for quantifying the strength of selection for new and emerging variants of SARS-CoV-2 relative to the background of contemporaneous variants. These methods range from a detailed model of dynamics within one country to a broad analysis across all countries, and they include alternative explanations such as migration and drift. We find evidence for strong selection favoring the D614G spike mutation and B.1.1.7 (Alpha), weaker selection favoring B.1.351 (Beta), and no advantage of R.1 after it spreads beyond Japan. Cutting back data to earlier time horizons reveals large uncertainty very soon after emergence, but that estimates of selection stabilize after several weeks. Our results also show substantial heterogeneity among countries, demonstrating the need for a truly global perspective on the molecular epidemiology of SARS-CoV-2.


title: Short-term antibody response and tolerability of one dose of BNT162b2 vaccine in patients receiving hemodialysis

abstract:
BackgroundPatients receiving in-center hemodialysis (HD) are at high risk of exposure to SARS-CoV-2 with high mortality, and response to vaccination is uncertain.

MethodsWe obtained serial plasma from 58 HD patients and 32 health-care workers (HCW) before and after vaccination with one dose of the BNT162b2 mRNA vaccine; as well as convalescent plasma from 11 HD patients who survived COVID-19. Anti-RBD (region binding domain of the SARS-CoV-2 Spike protein) IgG and IgM levels were measured by ELISA. Groups were stratified by evidence of prior SARS-CoV-2 infection.

ResultsIn HD patients without prior SARS-CoV-2, antiRBD levels were significantly lower at 4 and 8 weeks after vaccination, compared to in HCWs after 3 weeks (p<0.001), and to convalescent plasma (p=0.002). Anti-RBD IgG was non-detectable in 29/46 (63%) of HD, compared to 1/16 (6%) of HCWs (p<0.0001). No patient with non-detectable levels at 4 weeks developed antiRBD by 8 weeks. In HD patients with prior SARS-CoV-2, mean 8-week anti-RBD IgG levels were similar to controls at 3 weeks (p=0.16), and to convalescent plasma (p=0.45). No patients reported symptoms 7 days after vaccination on a standardized questionnaire.

InterpretationWhile the BNT162b2 vaccine was well-tolerated in hemodialysis patients, a single dose failed to elicit a humoral immune response in the majority of SARS-CoV-2 naive patients even after prolonged observation. In those with prior SARS-CoV-2 infection, the humoral response after vaccination was delayed. Whether HD patients develop T-cell responses requires further study. Until then, we advise the second dose be administered to all HD patients at the recommended 3-week time interval, and that rigorous SARS-CoV-2 infection prevention and control measures be continued in dialysis units until vaccine efficacy is proven.

category: nephrology


title: Frequency and neural correlates related to psychosis in motor neurone disease

abstract: Psychosis is a challenging feature of the syndromes motor neurone disease (MND), frontotemporal dementia and their overlap. Clinically evident psychosis affects 5-10% of patients, and more in those with C9orf72 expansions. However, subthreshold psychosis features may be overlooked in the context of overriding concern for physical impairment. This prospective study aimed to establish the prevalence and severity of psychosis features in a population-representative sample of MND, and to identify the neural correlates of psychosis by structural magnetic resonance imaging. A three-tiered system was applied to recruit people with MND, with cognitive and psychosis screening (Tier 1: N=111 with the Edinburgh ALS Cognitive and Behavioural Screen), in-depth neuropsychiatric assessment (Tier 2: N-=60) and imaging (Tier 3: N=30). Age-, education- and sex-matched healthy controls were recruited to Tier 2 (N=30) and Tier 3 (N=20). Overt psychosis was identified in 10% of the Tier 1 cohort, whilst 46% showed milder and diverse neuropsychiatric change. Grey matter correlates of psychosis included atrophy of the cingulate cortex and the hippocampus. White matter correlates included compromised integrity along frontotemporal and temporal-parietal association pathways, especially those connecting the anterior temporal lobe. These grey and white matter changes in MND represent vulnerability to psychosis and are qualitatively similar to volumetric and white matter abnormalities observed in other primary psychotic disorders. Neuropsychiatric features are common, even though overt psychosis is identified in a minority of people with motor neurone disease.

category: neurology


title: Reasons for non-attendance to cervical cancer screening and acceptability of HPV self-sampling among Bruneian women: A cross-sectional study.

abstract:
ObjectiveUptake for cervical cancer screening remains well below the 80% target as recommended by Bruneis National Cervical Cancer Prevention and Control plan. We conducted a pilot study to determine the reasons for non-attendance and explore their acceptance of human papillomavirus (HPV) self-sampling as an alternative to the Pap test.

MethodsA cross-sectional study was conducted at a primary healthcare center in Brunei, from January to December 2019. We recruited screening non-attendees, defined as women who were eligible for Pap test but who either never, or did not have one within the recommended screening interval of 3 years. This recruitment was done conveniently among women attending outpatient care and/or child health services at the primary healthcare center. Participants were first asked to complete a self-administered paper-based questionnaire on their reasons for screening non-attendance, and then invited for HPV self-sampling. Among those who agreed to participate in HPV self-sampling, they were asked to complete a second questionnaire on the self-sampling procedure and their samples were tested for high-risk HPV (hr-HPV). Results were analyzed using descriptive and inferential statistics.

ResultWe enrolled 174 screening non-attendees, out of which 97 (55.7%) also participated in HPV self-sampling. The main reasons for not attending Pap test screening were fear of bad results (16.1%, n = 28); embarrassment (14.9%, n = 26) and lack of time due to home commitments (10.3%, n = 18). When compared to those who agreed to participate in HPV self-sampling, those who declined were significantly older (p = 0.002) and less likely to agree that they are susceptible to cervical cancer (p = 0.023). They preferred to receive Pap test-related information from healthcare workers (59.0%, n = 155), social messaging platforms (28.7%, n = 51) and social media (26.4%, n = 47). HPV self-sampling kits were positively received among the 97 participants, where > 90% agreed on its ease and convenience. Nine (9.3%) tested positive for hr-HPV, out of which eight were non-16/18 HPV genotypes.

ConclusionOur findings suggest that promoting awareness on cervical cancer, clarifying any misconceptions of Pap test results, and highlighting that the disease is preventable and that early detection through screening can facilitate successful treatment would help increase screening uptake among Bruneian non-attendees. Response to HPV self-sampling was highly positive, suggesting the possibility of implementing this strategy in the local setting. Our high detection of non-16/18 HPV genotypes suggest high prevalence of other hr-HPV genotypes in Brunei. Larger studies should be conducted to further validate our findings.


title: Accessibility, inclusivity, and implementation of COVID-19 clinical management guidelines early in the pandemic: a global survey

abstract:
BackgroundWith a rapidly changing evidence base, high-quality clinical management guidelines (CMGs) are key tools for aiding clinical decision making and increasing access to best available evidence-based care. A rapid review of COVID-19 CMGs found that most lacked methodological rigour, overlooked many at-risk populations, and had variations in treatment recommendations. Furthermore, social science literature highlights the complexity of implementing guidelines in local contexts where they were not developed and the resulting potential to compound health inequities. The aim of this study was to evaluate access to, inclusivity of, and implementation of Covid-19 CMGs in different settings.

MethodsA cross-sectional survey of clinicians worldwide from 15 June to 20 July 2020, to explore access to and implementation of Covid-19 CMGs and treatment and supportive care recommendations provided. Data on accessibility, inclusivity, and implementation of CMGs. were analyzed by geographic location.

ResultsSeventy-six clinicians, from 27 countries responded, 82% from high-income countries, 17% from low-middle income countries. Most respondents reported access to Covid-19 CMG and confidence in implementation of these. However, many respondents, particularly from LMICs reported barriers to implementation, including limited access to treatments and equipment. Only 20% of respondents reported having access to CMGs covering care for children, 25% for pregnant women and 50% for older adults (>65 years). Themes emerging were for CMGs to include recommendations for different at-risk populations, and settings, include supportive care guidance, be readily updated as evidence emerges, and CMG implementation supported by training, and access to treatments recommended.

ConclusionOur findings highlight important gaps in Covid-19 CMG development and implementation challenges during a pandemic, particularly affecting different at-risk populations and lower resourced settings. The findings highlight a need for a new, harmonized evidence-based, that is inclusive and adaptable for different context, incorporating implementation support, to improve access in evidence-based care recommendations during an emergency.

category: infectious diseases


title: Systematic review of the scrub typhus treatment landscape: Assessing the feasibility of an individual participant-level data (IPD) platform

abstract:
BackgroundScrub typhus is an acute febrile illness caused by intracellular bacteria from the genus Orientia. It is estimated that one billion people are at risk, with one million cases annually mainly affecting rural areas in Asia-Oceania. Relative to its burden, scrub typhus is understudied, and treatment recommendations vary with poor evidence base. These knowledge gaps could be addressed by establishing an individual participant-level data (IPD) platform, which would enable pooled, more detailed and statistically powered analyses to be conducted. This study aims to assess the characteristics of scrub typhus treatment studies and explore the feasibility and potential value of developing a scrub typhus IPD platform to address unanswered research questions.

Methodology/Principal FindingsWe conducted a systematic literature review looking for prospective scrub typhus clinical treatment studies published from 1998 to 2020. Six electronic databases (Ovid Embase, Ovid Medline, Ovid Global Health, Cochrane Library, Scopus, Global Index Medicus), ClinicalTrials.gov, and WHO ICTRP were searched. We extracted data on study design, treatment tested, patient characteristics, diagnostic methods, geographical location, outcome measures, and statistical methodology.

Among 3,100 articles screened, 127 were included in the analysis. 12,079 participants from 12 countries were enrolled in the identified studies. ELISA, PCR, and eschar presence were the most commonly used diagnostic methods. Doxycycline, azithromycin, and chloramphenicol were the most commonly administered antibiotics. Mortality, complications, adverse events, and clinical response were assessed in most studies. There was substantial heterogeneity in the diagnostic methods used, treatment administered (including dosing and duration), and outcome assessed across studies. There were few interventional studies and limited data collected on specific groups such as children and pregnant women.

Conclusions/SignificanceThere were a limited number of interventional trials, highlighting that scrub typhus remains a neglected disease. The heterogeneous nature of the available data reflects the absence of consensus in treatment and research methodologies and poses a significant barrier to aggregating information across available published data without access to the underlying IPD. There is likely to be a substantial amount of data available to address knowledge gaps. Therefore, there is value for an IPD platform that will facilitate pooling and harmonisation of currently scattered data and enable in-depth investigation of priority research questions that can, ultimately, inform clinical practice and improve health outcomes for scrub typhus patients.

Author summaryScrub typhus is a febrile illness most commonly found in rural tropical areas. It is caused by a Gram-\negative bacteria belonging to the family Rickettsiaceae and transmitted by mites when they feed on vertebrates. There is an estimate of one million cases annually, with an estimated one billion people at risk, mostly in Asia-Oceania. But relative to the scale of the problem, scrub typhus is largely understudied. Evidence-based treatment recommendations by policymakers vary or are non-existent. We searched databases and registries for prospective scrub typhus clinical treatment studies published from 1998 to 2020 and reviewed them. Data from clinical trials and particularly for specific groups, such as pregnant women and children, were minimal. The methods used to measure treatment efficacy were heterogeneous, making it difficult to directly compare or conduct a meta-analysis based on aggregated data. One way to improve the current level of evidence would be by pooling and analysing individual participant-level data (IPD), i.e. the raw data from individual participants in completed studies. This review demonstrated that there is scope for developing a database for individual participant data to enable more detailed analyses. IPD meta-analyses could be a way to address knowledge gaps such as optimum dosing for children.


title: Interim Report: Safety And Immunogenicity Of An Inactivated Vaccine Against Sars-Cov-2 In Healthy Chilean Adults In A Phase 3 Clinical Trial

abstract:
BackgroundThe ongoing COVID-19 pandemic has had a significant impact worldwide, with an incommensurable social and economic burden. The rapid development of safe and protective vaccines against this disease is a global priority. CoronaVac is a vaccine prototype based on inactivated SARS-CoV-2, which has shown promising safety and immunogenicity profiles in pre-clinical studies and phase 1/2 trials in China. To this day, four phase 3 clinical trials are ongoing with CoronaVac in Brazil, Indonesia, Turkey, and Chile. This article reports the safety and immunogenicity results obtained in a subgroup of participants aged 18 years and older enrolled in the phase 3 Clinical Trial held in Chile.

MethodsThis is a multicenter phase 3 clinical trial. Healthcare workers aged 18 years and older were randomly assigned to receive two doses of CoronaVac or placebo separated by two weeks (0-14). We report preliminary safety results obtained for a subset of 434 participants, and antibody and cell-mediated immunity results obtained in a subset of participants assigned to the immunogenicity arm. The primary and secondary aims of the study include the evaluation of safety parameters and immunogenicity against SARS-CoV-2 after immunization, respectively. This trial is registered at clinicaltrials.gov (NCT04651790).

FindingsThe recruitment of participants occurred between November 27th, 2020, until January 9th, 2021. 434 participants were enrolled, 397 were 18-59 years old, and 37 were [≥]60 years old. Of these, 270 were immunized with CoronaVac, and the remaining 164 participants were inoculated with the corresponding placebo. The primary adverse reaction was pain at the injection site, with a higher incidence in the vaccine arm (55.6%) than in the placebo arm (40.0%). Moreover, the incidence of pain at the injection site in the 18-59 years old group was 58.4% as compared to 32.0% in the [≥]60 years old group. The seroconversion rate for specific anti-S1-RBD IgG was 47.8% for the 18-59 years old group 14 days post immunization (p.i.) and 95.6% 28 and 42 days p.i. For the [≥]60 years old group, the seroconversion rate was 18.1%, 100%, and 87.5% at 14, 28, and 42 days p.i., respectively. Importantly, we observed a 95.7% seroconversion rate in neutralizing antibodies for the 18-59 years old group 28 and 42 days p.i. The [≥]60 years old group exhibited seroconversion rates of 90.0% and 100% at 28 and 42 days p.i. Interestingly, we did not observe a significant seroconversion rate of anti-N-SARS-CoV-2 IgG for the 18-59 years old group. For the participants [≥]60 years old, a modest rate of seroconversion at 42 days p.i. was observed (37.5%). We observed a significant induction of a T cell response characterized by the secretion of IFN-{gamma} upon stimulation with Mega Pools of peptides derived from SARS-CoV-2 proteins. No significant differences between the two age groups were observed for cell-mediated immunity.

InterpretationImmunization with CoronaVac in a 0-14 schedule in adults of 18 years and older in the Chilean population is safe and induces specific IgG production against the S1-RBD with neutralizing capacity, as well as the activation of T cells secreting IFN-{gamma}, upon recognition of SARS-CoV-2 antigens.

FundingMinistry of Health of the Chilean Government; Confederation of Production and Commerce, Chile; Consortium of Universities for Vaccines and Therapies against COVID-19, Chile; Millennium Institute on Immunology and Immunotherapy.


title: Qualitatively distinct modes of Sputnik V vaccine-neutralization escape by SARS-CoV-2 Spike variants

abstract: The novel pandemic betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected at least 120 million people since its identification as the cause of a December 2019 viral pneumonia outbreak in Wuhan, China. Despite the unprecedented pace of vaccine development, with six vaccines already in use worldwide, the emergence of SARS-CoV-2  variants of concern (VOC) across diverse geographic locales suggests herd immunity may fail to eliminate the virus. All three officially designated VOC carry Spike (S) polymorphisms thought to enable escape from neutralizing antibodies elicited during initial waves of the pandemic. Here, we characterize the biological consequences of the ensemble of S mutations present in VOC lineages B.1.1.7 (501Y.V1) and B.1.351 (501Y.V2). Using a replication-competent EGFP-reporter vesicular stomatitis virus (VSV) system, rcVSV-CoV2-S, which encodes S from SARS coronavirus 2 in place of VSV-G, and coupled with a clonal HEK-293T ACE2 TMPRSS2 cell line optimized for highly efficient S-mediated infection, we determined that 8 out of 12 (75%) of serum samples from 12 recipients of the Russian Sputnik V Ad26 / Ad5 vaccine showed dose response curve slopes indicative of failure to neutralize rcVSV-CoV2-S: B.1.351. The same set of sera efficiently neutralized S from B.1.1.7 and showed only moderately reduced activity against S carrying the E484K substitution alone. Taken together, our data suggest that control of emergent SARS-CoV-2 variants may benefit from updated vaccines.


title: Real-time PCR assays for detection and quantification of early P. falciparum gametocyte stages

abstract:
IntroductionThe use of reverse transcription, quantitative qRT-PCR assays for detection and quantification of late gametocyte stages has revealed the high transmission capacity of the human malaria parasite, Plasmodium falciparum. A full understanding how the parasite adjusts its transmission in response to varying in-host environmental conditions during natural infections requires simultaneous quantification of early and late gametocytes. Here, we describe qRT-PCR assays that are specific for detection and quantification of early-stage gametocytes of P. falciparum.

MethodsThe assays are based on expression of known early gametocyte genes (pfpeg4, pfg27, pfge1, pfge3 and pfgexp5). The specificity of the qRT-PCR assays was tested using purified stage II and stage V gametocytes. These validated assays were used with qRT-PCR assays targeting late stage (pfs25) and all-stage (pfs16) gametocyte-specific transcripts to quantify gametocytes in natural P. falciparum infections and in a controlled human clinical infection study.

ResultsThe relative expression of pfpeg4, pfg27 and pfge3, but not of pfge1 and pfgexp5, was significantly higher in purified stage II compared to stage V gametocytes, indicating early gametocyte specificity. In natural infections, 71.2% of individuals had both early and late gametocyte transcripts (pfpeg4/pfg27 plus pfs25), 12.6% harboured only early gametocytes transcripts (pfpeg4/pfg27), and 15.2% had only late gametocytes transcripts (pfs25). In natural infections, the limit of detection was equivalent to 190 and 390 gametocytes/mL blood for pfpeg4 and pfg27, respectively. In infected volunteers, transcripts of pfpeg4 and pfg27 were detected shortly after the onset of blood stage infection, demonstrating the specificity of the assays.

ConclusionThe pfpeg4 and pfg27 qRT-PCR assays can be used specifically to quantify circulating immature gametocytes. Quantification of early gametocytes will improve understanding of epidemiological processes that modulate P. falciparum transmission and enhance the evaluation of transmission blocking interventions.


title: Microsampling for monitoring gentamicin in neonates.

abstract:
Gentamicin is recommended as first-line treatment of neonatal sepsis. The use of gentamicin is associated with toxicity which complicates neonatal dosing and necessitates therapeutic drug monitoring (TDM).

In a proof-of-concept investigation, we sought to compare (1) gentamicin concentrations obtained using volumetric absorptive microsampling (VAMS) to standard TDM plasma samples, and (2) the time taken to report results obtained using VAMS compared to standard TDM by the local hospital chemical pathology service.

The difference between gentamicin concentrations obtained from plasma collected for routine clinical care and calculated plasma concentrations, based on samples collected in whole blood using VAMS, was -18.0% and -0.4% for two patients. The research laboratory reported results within the time taken for the routine chemical pathology laboratory to report results. This proof-of-concept study demonstrates that the use of microsampling for TDM by pathology services can fulfil the requirements of providing an accurate gentamicin concentration in a timely manner.

category: intensive care and critical care medicine


title: Pandemic effect on body composition. Single center analysis of 2.771 cases.

abstract:
BackgroundThe COVID-19 pandemic has led to a dramatic increase in the levels of sedentary lifestyle and unhealthy dietary habits. A worsening in populational obesity levels and body composition (BC) is strongly awaited but so far not documented.

ObjectiveTo compare BC profile measured by bioelectrical impedance analysis (BIA) between pre-pandemic (P1-03/15th/2017 to 03/16th/2020) and pandemic (P2-3/17th/2020 to 3/10th/2021) period of time.

Materials and MethodsBIA were grouped according to the time it was performed. Two comparisons were done: an independent sample comparison (ISC) and a paired sample comparison (PSC) considering patients with at least one BIA in P1 and P2. Age, height, gender, weight, body mass index (BMI), body fat mass (BFM), free fat mass (FFM), skeletal muscle mass (SMM), percentage of body fat (PBF), visceral fat area (VFA) were compared. Statistical significance level was defined for a p value<0.05.

Results and DiscussionA total of 3.358 BIA were performed, and 2.771 and 112 were selected for IS and PS, respectively. In ISC, despite an unchanged weight, BFM, FFM, PBF and VFA increased and SSM decreased on P2(p<0.015 for all). A multivariated linear regression model using PBF as dependent variable showed P2 as an independent predictor ({beta}=0.38 95%CI 0.19 to 0.56). In the PSC, PBF also increased from P1 to P2 (p=0.015). To our knowledge this is the first documentation of worsening BC after pandemic. Health authorities should be alert for this phenomenon and their clinical consequences in the days to come.

category: endocrinology


title: Estimates and determinants of SARS-CoV-2 seroprevalence and infection fatality ratio using latent class analysis: the population-based Tirschenreuth study in the hardest-hit German county in spring 2020

abstract:
SARS-CoV-2 infection fatality ratios (IFR) remain controversially discussed with implications for political measures, but the number of registered infections depends on testing strategies and deduced case fatality ratios (CFR) are poor proxies for IFR. The German county of Tirschenreuth suffered a severe SARS-CoV-2 outbreak in spring 2020 with particularly high CFR.

To estimate seroprevalence, dark figure, and IFR for the Tirschenreuth population aged [≥]14 years in June/July 2020 with misclassification error control, we conducted a population-based study, including home visits for elderly, and analyzed 4203 participants for SARS-CoV-2 antibodies via three antibody tests (64% of our random sample). Latent class analysis yielded 8.6% standardized county-wide seroprevalence, dark figure factor 5.0, and 2.5% overall IFR. Seroprevalence was two-fold higher among medical workers and one third among current smokers with similar proportions of registered infections. While seroprevalence did not show an age-trend, the dark figure was 12.2 in the young versus 1.7 for [≥]85-year-old. Age-specific IFRs were <0.5% below 60 years of age, 1.0% for age 60-69, 13.2% for age 70+, confirming a previously reported age-model for IFR. Senior care homes accounted for 45% of COVID-19-related deaths, reflected by an IFR of 7.5% among individuals aged 70+ and an overall IFR of 1.4% when excluding senior care home residents from our computation.

Our data underscore senior care home infections as key determinant of IFR additionally to age, insufficient targeted testing in the young, and the need for further investigations on behavioral or molecular causes of the fewer infections among current smokers.


title: A Vaccination Simulator for COVID-19: Effective and Sterilizing Immunization Cases.

abstract: Accurate modeling provides a means by which a complex problem can be examined for informed decision-making. We present a particle-based SEIR epidemic simulator as a tool to assess the impact of vaccination strategies on viral propagation and to model both sterilizing and effective immunization outcomes. The simulator includes modules to support contact tracing of the interactions amongst individuals as well as epidemiological testing of the general population. The simulator particles are distinguished by age, thus enabling a more accurate representation of the rates of infection and mortality in accordance with differential demographic susceptibilities and medical outcomes. Moreover, thanks to the age differentiation of particles, the vaccination can be simulated based on the age group descending order or randomly across all age groups. The simulator can be calibrated by region of interest and variable vaccination strategies (i.e. random or prioritized by age) so as to enable locality-sensitive virus mitigation policy measures and resource allocation. The results described, based on the experience of the province of Lecco, Italy, indicate that the tool can be used to evaluate vaccination strategies in a way that incorporates local circumstances of viral propagation and demographic susceptibilities. Further, the simulator accounts for modeling the distinction between sterilizing immunization, in which immunized people are no longer contagious, and that of effective immunization, in which symptoms and mortality outcomes are diminished but individuals can still transmit the virus. The sterilizing-age-based vaccination scenario results in the least number of deaths compared to other scenarios. Furthermore, the results show that the vaccination of the most vulnerable portion of the population should be prioritized for the effective immunization case. As the vaccination rate increases, the mortality gap between the scenarios shrinks.


title: Advance requests for MAiD in dementia: Policy recommendations emerging from a mixed-methods study of the views of the Canadian public and MAiD practitioners

abstract:
BackgroundThe Canadian public has repeatedly expressed its desire for advance requests for Medical Assistance in Dying (MAiD) after dementia diagnosis, yet MAiD practitioners willingness to accede to such advance requests is unknown. This study explores the extent and nature of any gap between the publics desire for, and practitioners willingness to provide MAiD, and identifies policies to ameliorate such a gap.

MethodsTwo complementary mixed-method surveys gathered data from convenience samples of 83 Canadian adults and 103 MAiD practitioners. The public survey asked participants which of five specific circumstances commonly encountered in dementia they would include in their advance requests. The practitioner survey queried the validation level participants would require before providing MAiD in each specific circumstance. Participants reasons were probed using thematic analysis of open-ended questions.

ResultsOn average, 77% of public participants indicated they definitely or probably would include each of the five specific circumstances in their advance requests for MAiD. As validation level decreased from patient consent to patient assent, family assent, or advance request alone, the magnitude of the gap between the publics desire and practitioners willingness increased. The practitioners qualitative data contained many practical insights from which emerged seven policy recommendations to ameliorate this gap and increase the likelihood of honouring patient requests.

InterpretationThe study provides evidence of a gap between public desire for, and practitioner willingness to provide MAiD in dementia. The policy recommendations are relevant to consideration of legislation for advance requests for MAiD.

category: medical ethics


title: Visuospatial neglect: Recovery & Functional outcome after 6 months.

abstract:
Background/ObjectiveThis study aims to investigate how complex visuospatial neglect behavioural phenotypes predict long-term outcomes, both in terms of neglect recovery and broader functional outcomes.

MethodsThis study presents a secondary cohort study of acute and 6 month follow up data from 400 stroke survivors who completed the Oxford Cognitive Screens Cancellation Task. At follow-up, patients also completed the Stroke Impact Scale questionnaire. These data were analysed to identify whether any specific combination of neglect symptoms is more likely to result in long-lasting neglect or higher levels of functional impairment, therefore warranting more targeted rehabilitation.

ResultsOverall, 98/142(69%) neglect cases recovered by follow-up and there was no significant difference in the persistence of egocentric/allocentric (X2(1)=0.66, p=0.418) or left/right neglect (X2(2)=0.781, p= 0.677). Egocentric neglect was found to follow a proportional recovery pattern with all patients demonstrating a similar level of improvement over time. Conversely, allocentric neglect followed a non-proportional recovery pattern with chronic neglect patients exhibiting a slower rate of improvement than those who recovered. A multiple regression analysis revealed that the initial severity of acute allocentric, but not egocentric, neglect impairment acted as a significant predictor of poor long-term functional outcomes (F(9,383)=3.96, p<0.001, R2=0.066).

ConclusionsOur findings call for systematic neuropsychological assessment of both egocentric and allocentric neglect following stroke, as the occurrence and severity of these conditions may help predict recovery outcomes.


title: Whole-Body Muscle MRI Characteristics of LAMA2 Gene Mutation Congenital Muscular Dystrophy Children

abstract:
Merosin-deficient or LAMA2-related congenital muscular dystrophy (CMD) belongs to a group of muscle diseases with an overlapping diagnostic spectrum. MRI plays an important role in the diagnosis and disease-tracking of muscle diseases. Whole-body MRI is ideal for describing patterns of muscle involvement. Our purpose is to analyze the pattern of muscle involvement in merosin-deficient CMD children employing whole-body muscle MRI. Ten children with merosin-deficient CMD underwent whole-body muscle MRI. We used a control group of other hereditary muscle diseases, which included 13 children. Overall, 37 muscles were graded for fatty infiltration using Mercuri scale modified by Fischer et al 2008. The results showed a fairly consistent pattern of muscle fatty infiltration in index group, which differed from that in control group. There was a highly statistically significant difference between the two groups in regard to the fatty infiltration of the neck, serratus anterior, rotator cuff, deltoid, forearm, gluteus maximus, gluteus medius, gastrocnemius and soleus muscles. Additionally, results showed relative sparing of the brachialis, biceps brachii, gracilis, sartorius, semitendinosus and extensor muscles of the ankle in index group. There is evidence to suggest that whole-body muscle MRI can become a useful contributor to the differential diagnosis of merosin deficient CMD.

Study HighlightsO_LIWhole-body muscle MRI is a useful contributor to the differential diagnosis of merosin-deficient (LAMA2-related) congenital muscular dystrophy.
C_LIO_LIThe study demonstrated the presence of a fairly characteristic pattern of whole-body muscle MRI in children with merosin-deficient CMD in terms of sensitivity and specificity.
C_LIO_LIThe study may be considered as a preliminary step of arriving at an MRI classification system for children with merosin-deficient CMD.
C_LI


title: Comparing the results of the application of moving and stationary sinusoidal gratings in the functionally assisted treatment of meridional amblyopia

abstract:
BackgroundThe first approach to a frequency-selective visual training in amblyopia had been proposed in the sixties by the physiologist Fergus Campbell. During the stimulation, his grating was moving very slowly, i.e., only once a minute around its axis. Therefore, the CAM-stimulator was based exclusively on the proposed influence of spatial frequency selectivity, however there was no significant contribution of the temporal frequency of the stimulus. Accordingly, we are convinced that this was one of the main reasons for the failure of Campbells approach after the evaluation by a multiple of placebo-controlled studies. The aim of the present work, therefore, was to investigate in the influence of visual exercises, which contained moving gratings as compared to such of stationary gratings implemented into computer games on the development of visual acuity. Especially we were interested in the effects of such type of visual exercises, termed Focal Ambient Visual Acuity Stimulation (FAVAS), on the visual acuity development in patients with meridional amblyopia. We assume, in particular, that such a ring-shaped stimulus can reach all angular positions equally, and thus excite the most ametropic meridians, as compared to the least ametropic meridians, in a particular way.

MethodsOverall, we investigated in two groups of patients with meridional amblyopia who had been selected according to the age structure and to their type of disturbance. Using a cross-over design, the first group was alternately exercised 10 days with the moving followed by 10 days with the stationary grating stimulus, and the second group was alternately exercised 10 days with the stationary followed by 10 days with the moving grating stimulus, i.e. in reverse order. For the treatment, a sinusoidally modulated drifting grating had been implemented as a background stimulus into simple computer games. These games served for the attraction of attention of the children. For the present study these exercises were applied in the following two versions. The first version contained a concentrically outward-moving ring-shaped sinusoidal grating behind of the computer games during the process of visual stimulation. The grating was fixed at a spatial frequency of 0.3 cyc/deg with the time frequency of 1 cyc/sec, which gave an angular velocity of 3.33 deg/sec. The second version of the program contained the same grating, but in a non-moving stationary presentation. In order to additionally distinguish between the envisaged meridional stimulus effects, we examined our patients with regard to their corrected visual acuity using a directionally sensitive set of optical characters developed at the Kharkevich Institute. The monocular corrected visual acuity was tested in all patients at 4 meridians: 0 {degrees}, 45 {degrees}, 90 {degrees} and 135 {degrees}. Additionally, in all patients of the first group and all patients of the second group, the binocular visual acuity was examined too.

ResultsIn the measurements of the corrected visual acuity along four meridians, a statistically significant improvement was found with alignment of the directional optical characters close to the meridian with maximal ametropia, and the minimal improvement in the orientation perpendicular thereto. In the patients of the both groups, the corrected visual acuity had significantly increased as a result of the treatment performed in the stage with a series of exercises with the moving sinusoidal grating. After the stage of treatment using the stationary grating, however, there was found no statistically significant improvement.

ConclusionsExercises using FAVAS computer games that contained a moving sinusoidal grating resulted in a statistically significant positive dynamics of visual acuity development in the most ametropic meridian as compared to the least ametropic meridian. No statistically significant improvement was observed after exercises with the stationary grating.

category: ophthalmology


title: Body Clock: Matching Personalized Multimorbidity and Fast Aging Using Information Entropy

abstract: With aging, most older adults are at risk of having more than two diseases, conventionally defined as multimorbidity. We determined body organ disease number (BODN) as a new multimorbidity index. We measured the degree to which each disease level, from mild to severe, predicts longitudinal BODN uncoupled from chronological age. We determined Body Clock using global disease levels burden from all systems predicting longitudinal BODN for each individual, which is a proxy of the personalized rate of biological aging. Change in Body Clock predicts late-life age-related outcomes and can be used for geriatric clinics and clinical trials for precision medicine.

category: geriatric medicine


title: Multilevel and Quasi Monte Carlo methods for the calculation of the Expected Value of Partial Perfect Information

abstract: The expected value of partial perfect information (EVPPI) provides an upper bound on the value of collecting further evidence on a set of inputs to a cost-effectiveness decision model. Standard Monte Carlo (MC) estimation of EVPPI is computationally expensive as it requires nested simulation. Alternatives based on regression approximations to the model have been developed, but are not practicable when the number of uncertain parameters of interest is large and when parameter estimates are highly correlated. The error associated with the regression approximation is difficult to determine, while MC allows the bias and precision to be controlled. In this paper, we explore the potential of Quasi Monte-Carlo (QMC) and Multilevel Monte-Carlo (MLMC) estimation to reduce computational cost of estimating EVPPI by reducing the variance compared with MC, while preserving accuracy. In this paper, we develop methods to apply QMC and MLMC to EVPPI, addressing particular challenges that arise where Markov Chain Monte Carlo (MCMC) has been used to estimate input parameter distributions. We illustrate the methods using a two examples: a simplified decision tree model for treatments for depression, and a complex Markov model for treatments to prevent stroke in atrial fibrillation, both of which use MCMC inputs. We compare the performance of QMC and MLMC with MC and the approximation techniques of Generalised Additive Model regression (GAM), Gaussian process regression (GP), and Integrated Nested Laplace Approximations (INLA-GP). We found QMC and MLMC to offer substantial computational savings when parameter sets are large and correlated, and when the EVPPI is large. We also find GP and INLA-GP to be biased in those situations, while GAM cannot estimate EVPPI for large parameter sets.

category: health economics


title: Risk heterogeneity in compartmental HIV transmission models of ART as prevention in Sub-Saharan Africa: A scoping review

abstract:
BackgroundTransmission models provide complementary evidence to clinical trials about the potential population-level incidence reduction attributable to ART (ART prevention impact). Different modelling assumptions about risk heterogeneity may influence projected ART prevention impacts. We sought to review representations of risk heterogeneity in compartmental HIV transmission models applied to project ART prevention impacts in Sub-Saharan Africa.

MethodsWe systematically reviewed studies published before January 2020 that used non-linear compartmental models of sexual HIV transmission to simulate ART prevention impacts in Sub-Saharan Africa. We summarized data on model structure/assumptions (factors) related to risk and intervention heterogeneity, and explored multivariate ecological associations of ART prevention impacts with modelled factors.

ResultsOf 1384 search hits, 94 studies were included. 64 studies considered sexual activity stratification and 39 modelled at least one key population. 21 studies modelled faster/slower ART cascade transitions (HIV diagnosis, ART initiation, or cessation) by risk group, including 8 with faster and 4 with slower cascade transitions among key populations versus the wider population. In ecological analysis of 125 scenarios from 40 studies (subset without combination intervention), scenarios with risk heterogeneity that included turnover of higher risk groups were associated with smaller ART prevention benefits. Modelled differences in ART cascade across risk groups also influenced the projected ART benefits, including: ART prioritized to key populations was associated with larger ART prevention benefits. Of note, zero of these 125 scenarios considered lower ART coverage among key populations.

ConclusionAmong compartmental transmission models applied to project ART prevention impacts in Sub-Saharan Africa, representations of risk heterogeneity and projected impacts varied considerably. Inclusion/exclusion of risk heterogeneity with turnover, and intervention heterogeneity across risk groups could influence the projected impacts of ART scale-up. These findings highlight a need to capture risk heterogeneity with turnover and cascade heterogenetiy when projecting ART prevention impacts.

category: hiv aids


title: Comprehensive assessment of humoral response after Pfizer BNT162b2 mRNA Covid-19 vaccination: a three-case series

abstract:
BackgroundSince universal vaccination is a pillar against coronavirus disease 2019 (COVID-19), monitoring anti-SARS-CoV-2 neutralizing antibodies is essential for deciphering post-vaccination immune response.

MethodsThree healthcare workers received 30 g BNT162b2 mRNA Covid-19 Vaccine, followed by a second identical dose, 21 days afterwards. Venous blood was drawn at baseline and at serial intervals, up to 63 days afterwards, for assessing total immunoglobulins (Ig) anti-RBD (receptor binding domain), IgG anti-S1/S2, IgG anti-RBD, IgM anti-RBD, IgM anti-N/S1 and IgA anti-S1.

ResultsAll subjects were SARS-CoV-2 seronegative at baseline. Total Ig anti-RBD, IgG anti-S1/S2 and IgG anti-RBD levels increased between 91-368 folds until 21 days after the first vaccine dose, then reached a plateau. The levels raised further after the second dose (by [~]30-, [~]8- and [~]8-fold, respectively), peaking at day 35, but then slightly declining and stabilizing [~]50 days after the first dose. IgA anti-S1 levels increased between 7-11 days after the first dose, slightly declined before the second dose, after which levels augmented by [~]24-fold from baseline. The anti-RBD and anti-N/S1 IgM kinetics were similar to that of anti-S1 IgA, though displaying substantially weaker increases and modest peaks, only 4 to 7-fold higher than baseline. Highly significant inter-correlation was noted between total Ig anti-RBD, anti-S1/S2 and anti-RBD IgG (all r=0.99), whilst other anti-SARS-CoV-2 antibodies displayed lower, though still significant, correlations. Serum spike protein concentration was undetectable at all time points.

ConclusionsBNT162b2 mRNA vaccination generates a robust humoral immune response, especially involving IgG and IgA, magnified by the second vaccine dose.


title: Urine metabolome of tuberculosis patients receiving intensive phase of treatment show diurnal variations.

abstract:
Diurnal variation in biofluid metabolome as observed in a healthy human may alter in perturbed conditions. Biofluids like urine are rich in molecular constituents including metabolites, and infectious disease conditions like tuberculosis (TB) may influence diurnal differences for which limited reports are available in the literature. In this study, we present an optimized gas chromatography coupled to a quadrupole mass spectrometry (GC-MS) method to analyze processed and trimethylsilyl (TMS) derivatized urine metabolites. Urine samples were collected at four time points (0, 6, 12 and 24 hours) of study subjects [n=15; mean age 37 (24-70) in years] including controls [n=7; mean age 29.3 (24-35) years] and culture-confirmed active TB patients [ATB; n=8; mean age 43.7 (25-70) years] receiving treatment in the intensive phase. Global urine metabolite profiling was carried out using the optimized GC-MS method. Higher urine analyte diversity was observed in ATB patients (74) than in controls (36) during the day. Diurnal variations of the parent anti-TB drugs and their breakdown products (pyrazinamide, pyrazinoic acid, 5-hydroxy pyrazinoic acid, isonicotinic acid and alpha amino butyric acid) were observed with maximum abundance at 6 h. Interestingly, urine of ATB subjects at 6 h showed the highest metabolic diversity, whereas it was at 12 h in controls. Many analytes including glycine and alanine amino-acids showed diurnal variation in ATB and controls. These changes could be attributed to the altered host metabolic activities due to disease, treatment-associated decrease in total body bacterial burden and gut microbiota dysbiosis. And the optimized spiked-in internal standard, urine sample volume and GC-MS method could be used for global urine metabolome analysis in healthy and different perturbed conditions.

"For Table of Contents Only"

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title: Using PARIHS framework to design a community-based COVID-19 intervention in rural Ghana

abstract: This study utilized the Promoting Action on Research Implementation in Health Services (PARIHS) framework to guide the design of the evidence-based practice - COVID Preparedness & Outbreak Prevention Plan (CoCoPOPP) for rural communities in Ghana. Through a participatory academic-community team discussion, interactive dissemination, review of evidence about community-based interventions during Ebola, HIV/AIDS, and Influenza outbreaks via snowball sampling, continuous discourse within the design team, feedback from other local stakeholders and national experts, the evidence-based intervention was developed consistent with the PARIHS framework. By applying the three core elements of the PARIHS framework (that is, evidence, context and facilitation), the study developed orientation, logistic needs and planning as well as social mobilization. The components also included participants recruitment and training, communication, research and M&E plan, execution and technical assistance and facilitation with three overall aims: (1) meet a pressing health need during the COVID-19 pandemic in local underserved settings, (2) ensure that the strategy is informed by high-quality evidence from similar interventions in past outbreaks and (3) evaluate and learn from research on interventions to garner data for organizational use and to share insights on pandemic management and control with the Ghanaian government, wider global health and education community. Hence, CoCoPOPP can be implemented across other rural communities in Ghana and beyond, particularly in other Sub-Saharan African countries with similar cultural settings.


title: Situation of COVID-19 in Brazil: An analysis via growth models as implemented in the ModInterv system for monitoring the pandemic

abstract: In this work we analyze the cumulative curves of deaths attributed to COVID-19 in the 26 Brazilian States and the Federal District up until August 21, 2020. Mathematical growth models implemented by the application ModInterv COVID-19, which can be accessed via internet browser or via a mobile app, were used to investigate at which stage the epidemic is in each of the Brazilian federal units. The analysis revealed that almost all states in the Northern and Northeastern regions were already in the saturation phase, meaning that the epidemic was relatively under control, whereas in all Southern states and in most states in the Midwest the epidemic was still accelerating or showed only a slight deceleration. The Southeastern region presented a great diversity of epidemic stages, with each state being found at a different stage, ranging from acceleration to saturation. It is argued that understanding this heterogeneous geographical distribution of the epidemic is relevant for public health authorities, as it may help in devising more effective strategies against the COVID-19 pandemic in a continental country like Brazil.


title: Dynamics of amygdala connectivity in bipolar disorders: A longitudinal study across mood states

abstract: Alterations in activity and connectivity of brain circuits implicated in emotion processing and emotion regulation have been observed during resting-state for different clinical phases of bipolar disorders (BD), but longitudinal investigations across different mood states in the same patients are still rare. Furthermore, measuring dynamics of functional connectivity patterns offers a powerful method to explore changes in the brains intrinsic functional organization across mood states. We used a novel co-activation pattern (CAP) analysis to explore the dynamics of amygdala connectivity at rest in a cohort of 20 BD patients prospectively followed-up and scanned across distinct mood states: euthymia (20 patients; 39 sessions), depression (12 patients; 18 sessions), or mania/hypomania (14 patients; 18 sessions). We compared them to 41 healthy controls scanned once or twice (55 sessions). We characterized temporal aspects of dynamic fluctuations in amygdala connectivity over the whole brain as a function of current mood. We identified 6 distinct networks describing amygdala connectivity, among which an interoceptive-sensorimotor CAP exhibited more frequent occurrences during hypomania compared to other mood states, and predicted more severe symptoms of irritability and motor agitation. In contrast, a limbic CAP comprising the hippocampus and ventral tegmental area exhibited fewer occurrences during both depression and hypomania compared to euthymia. Our results reveal distinctive interactions between amygdala and distributed brain networks in different mood states, and foster research on interoception systems especially during the manic phase. Our study also demonstrates the benefits of assessing brain dynamics in BD.

category: psychiatry and clinical psychology


title: Evaluating the impact of Hazelwood mine fire event on students' educational development with Bayesian interrupted time-series hierarchical meta-regression

abstract:
BackgroundClimate disasters such as wildfires, floods and droughts can introduce significant interruptions and trauma to impacted communities. Children and young people can be disproportionately affected with additional educational disruptions. However, evaluating the impact of disasters is challenging due to difficulties in establishing studies and recruitment post-disasters.

ObjectivesWith the increasing threat of climate change, we aimed to (1) establish a new analytical framework to evaluate the impact of climate disasters on academic achievement and (2) evaluate the impact of the 2014 Hazelwood mine fire (a six-week fire event in Australia).

MethodsBayesian hierarchical meta-regression was developed to evaluate the impact of the mine fire using only aggregated school-level data from the standardised National Assessment Program-Literacy and Numeracy (NAPLAN) test. NAPLAN results and school characteristics (2008-2018) from 69 primary/secondary schools with different levels of mine fire-related smoke exposure were used to estimate the impact of the event. Using an interrupted time series design, the model estimated immediate effects and post-interruption trend differences with full Bayesian statistical inference.

ResultsMajor academic interruptions across NAPLAN domains were evident in high exposure schools in the year post-mine fire (greatest interruption in Writing: 11.09 [95%CI: 3.16-18.93], lowest interruption in Reading: 8.34 [95%CI: 1.07-15.51]). The interruption was comparable to a four to five-month delay in educational attainment and had not fully recovered after several years.

DiscussionConsiderable academic delays were found as a result of a mine fire, highlighting the need to provide educational and community-based supports in response to future events. Importantly, this work provides a statistical method using readily available aggregated data to assess the educational impacts in response to other climate disasters.

Graphical abstract

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category: occupational and environmental health


title: Retrospective feasibility study of Mycobacterium tuberculosis modified lipoprotein as a potential biomarker for TB detection in children

abstract:
BackgroundCurrent TB diagnostic methods available have been developed for adults and development efforts have neglected the differences in disease and sampling that occur between adults and children. Diagnostic challenges are even greater in HIV co-infected children and infants.

Methods and resultsWe established a sandwich ELISA assay to detect Mycobacterium tuberculosis modified lipoprotein (TLP) ex vivo in plasma. The study population contains plasma samples from 21 patients with active TB and 24 control samples with no TB, collected in the International Maternal Pediatric Adolescent AIDS Clinical Trails (IMPAACT) P1041 study. Retrospective analysis was performed and the result demonstrate that TLP level is associated with TB disease.

ConclusionsPlasma levels of TLP associate with active TB disease in HIV positive subjects and can be used as an indicator for TB detection in children.


title: Estimated durations of asymptomatic, symptomatic, and care-seeking phases of tuberculosis disease

abstract: Ratios of bacteriologically-positive tuberculosis prevalence to notification rates are used to characterise typical durations of tuberculosis disease, but have not accounted for asymptomatic periods prior to care-seeking. We developed novel statistical models to estimate progression from initial bacteriological-positivity including smear conversion, symptom onset and initial care-seeking and fitted them to tuberculosis prevalence survey and notification data (one subnational and 11 national datasets) within a Bayesian framework. Asymptomatic tuberculosis duration was in the range 4 - 8 months for African countries; three countries in Asia showed longer durations of > 1 year. Care-seeking typically began half-way between symptom onset and notification. Our method also estimated smear progression rates and case-detection ratios. We found evidence for higher case-detection ratios and much shorter durations of tuberculosis for people living with HIV. To eradicate tuberculosis transmission, greater gains may be achieved by proactively screening people without symptoms through active case finding interventions.


title: Comparison of post-COVID depression and major depressive disorder

abstract:
BackgroundDuring the COVID-19 pandemic rates of depressive symptoms are markedly elevated, particularly among survivors of infection. Understanding whether such symptoms are distinct among those with prior SARS-CoV-2 infection, or simply a nonspecific reflection of elevated stress, could help target interventions.

MethodWe analyzed data from multiple waves of a 50-state survey that included questions about COVID-19 infection as well as the Patient Health Questionnaire examining depressive and anxious symptoms. We utilized multiple logistic regression to examine whether sociodemographic features associated with depression liability differed for those with or without prior COVID-19, and then whether depressive symptoms differed among those with or without prior COVID-19.

ResultsAmong 91,791 respondents, in regression models, age, gender, race, education, and income all exhibited an interaction with prior COVID-19 in risk for moderate or greater depressive symptoms (p<0.0001 in all cases), indicating differential risk in the two subgroups. Among those with such symptoms, levels of motoric symptoms and suicidality were significantly greater among those with prior COVID-19 illness. Depression risk increased with greater interval following acute infection.

DiscussionOur results suggest that major depressive symptoms observed among individuals with prior COVID-19 illness may not reflect typical depressive episodes, and merit more focused neurobiological investigation.


title: Controlling the pandemic during the SARS-CoV-2 vaccination rollout: a modeling study

abstract: There is a consensus that mass vaccination against SARS-CoV-2 will ultimately end the COVID-19 pandemic. However, it is not clear when and which control measures can be relaxed during the rollout of vaccination programmes. We investigate relaxation scenarios using an age-structured transmission model that has been fitted to age-specific seroprevalence data, hospital admissions, and projected vaccination coverage for Portugal. Our analyses suggest that the pressing need to restart socioeconomic activities could lead to new pandemic waves, and that substantial control efforts prove necessary throughout 2021. Using knowledge on control measures introduced in 2020, we anticipate that relaxing measures completely or to the extent as in autumn 2020 could launch a wave starting in April 2021. Additional waves could be prevented altogether if measures are relaxed as in summer 2020 or in a step-wise manner throughout 2021. We discuss at which point control of COVID-19 would be achieved for each scenario.


title: Background rates of hospitalizations and emergency department visits for selected thromboembolic and coagulation disorders in Ontario, Canada, 2015 to 2020, to inform COVID-19 vaccine safety surveillance

abstract:
ObjectiveThe objective of this study was to estimate background rates of selected thromboembolic and coagulation disorders in Ontario, Canada.

DesignPopulation-based retrospective observational study using linked health administrative databases. Records of hospitalizations and emergency department visits were searched to identify cases using diagnostic codes from the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Canada (ICD-10-CA).

ParticipantsAll Ontario residents.

Primary outcome measuresIncidence rates of stroke, deep vein thrombosis, pulmonary embolism, idiopathic thrombocytopenia, disseminated intravascular coagulation, and cerebral venous thrombosis during five pre-pandemic years (2015-2019, annually, averaged, and monthly average) and 2020.

ResultsThe average annual population was 14 million with 51% female. The mean annual rates during 2015-2019 were 127.1/100,000 population (95% confidence interval [CI], 126.2, 127.9) for ischemic stroke, 22.0/100,000 (95%CI, 21.6, 22.3) for intracerebral haemorrhage, 9.4 (95%CI, 9.2, 9.7) for subarachnoid haemorrhage, 86.8/100,000 (95%CI, 86.1, 87.5) for deep vein thrombosis, 63.7/100,000 (95%CI, 63.1, 64.3) for pulmonary embolism, 6.1/100,000 (95%CI, 5.9, 6.3) for idiopathic thrombocytopenia, 1.6/100,000 (95%CI, 1.5, 1.7) for disseminated intravascular coagulation, and 1.5/100,000 (95%CI, 1.4, 1.6) for cerebral venous thrombosis. Rates were lower in 2020 than during the pre-pandemic years for ischemic stroke, deep vein thrombosis, and idiopathic thrombocytopenia. Rates were generally consistent over time, except for pulmonary embolism, which increased from 57.1 to 68.5 per 100,000 between 2015 and 2019. Rates were higher for females than males for subarachnoid haemorrhage, pulmonary embolism, and cerebral venous thrombosis, and vice versa for ischemic stroke and intracerebral haemorrhage. Rates increased with age for most of these conditions, but idiopathic thrombocytopenia demonstrated a bimodal distribution with incidence peaks at 0-19 years and [≥]60 years.

ConclusionsOur estimated background rates help to contextualize observed events of these potential adverse events of special interest and to detect potential safety signals related to COVID-19 vaccines.

Strengths and limitations of this study[tpltrtarr] Recent background rates of selected thromboembolic and coagulation disorders that are potential adverse events special interest related to COVID-19 vaccine are estimated.
[tpltrtarr]Background rates during five pre-pandemic (2015-2019) years and 2020 will provide context for these events to identify vaccine safety signals.
[tpltrtarr]We used recorded diagnostic codes in administrative data without information on clinical and/or diagnostic confirmation, and the validity of these data are imperfect, which may result in under or overestimation.


title: Overcoming Underrepresentation in Clinical Datasets for Accurate Subpopulation-specific Prognosis

abstract: Many clinical datasets are intrinsically imbalanced, dominated by overwhelming majority groups. Off-the-shelf machine learning models that optimize the prognosis of majority patient types (e.g., healthy class) may cause substantial errors on the minority prediction class (e.g., disease class) and demographic subgroups (e.g., Black or young patients). For example, our work found that missed death cases are 3.14 times higher than missed survival cases in a mortality prediction model. In the typical one-machine-learning-model-fits-all paradigm, racial and age disparities are likely to exist, but unreported. What makes it worse is the deceptive nature of widely used whole-population metrics, such as AUC-ROC. We show that some metrics fail to reflect serious prediction deficiencies. To mitigate representational biases, we design a double prioritized (DP) bias correction technique. Our method trains customized models for specific ethnicity or age groups, a substantial departure from the one-model-predicts-all convention. We report our findings on four prognosis tasks over two imbalanced clinical datasets. DP reduces relative disparities among race and age groups, 5.6% to 86.8% better than the 8 existing sampling solutions being compared, in terms of the minority class' recall.

category: health informatics


title: Subpopulation-specific Machine Learning Prognosis for Underrepresented Patients with Double Prioritized Bias Correction


title: Shared genetic etiology between cortical brain morphology and tobacco, alcohol, and cannabis use

abstract: Genome-wide association studies (GWAS) have independently identified hundreds of genomic regions associated with brain morphology and substance use. However, the genetic overlap between brain structure and substance use has not been characterized. Here we leverage GWAS summary data of 71 brain imaging measures and alcohol, tobacco, and cannabis use to investigate their genetic overlap using LD score regression. We also used genomic structural equation modeling to model a  substance use common genetic factor and examined its genetic overlap with brain structure. After accounting for multiple testing, we identified eight significant negative genetic correlations, including between alcoholic drinks per week and average cortical thickness and intracranial volume with the age of smoking initiation; and five positive genetic correlations, including between insula surface area and lifetime cannabis use, and between the common factor with pericalcarine surface area. Our findings highlight a shared genetic etiology between variation in cortical brain morphology and substance use.

category: addiction medicine


title: Tobacco Smoking and Associated Factors among In-school Adolescents in Vietnam in 2013 and 2019

abstract: Tobacco smoking is one of the most dangerous risk behaviors, leading to many adverse human health consequences. The aims of this study is to estimate the prevalence of tobacco smoking and related factor among adolescents aged 13-17 years in Vietnam. The data were from two rounds of the Vietnam Global School-based Student Health Survey (GSHS) that is the nationally representative survey conducted in 2013 and 2019. The logistic regressions were carried out to identify factors associated with tobacco smoking among study participants. We found the prevalence of current smoking (water pipe and cigarettes) reduced significantly from 5.4% (95% CI: 4.0-7.2) in 2013 to 2.8% (95% CI: 2.2-3.6) in 2019. In 2019, 2.6% of students used electronic cigarette products in the last 30 days. Factors associated with higher odds of current smoking status included study year, gender, parental monitoring, loneliness, suicide attempt, sexual intercourse, truancy, alcohol drinking. Similar patterns were found in e-cigarette use. Smoking among adolescents in Vietnam reduced between 2013 and 2019. Further follow-up studies are needed to confirm the causal factors of the reduction and e-cigarettes use.


title: Determining the cutoff points of the 5C scale for assessment of COVID-19 vaccines psychological antecedents among the Arab population: A multinational study

abstract:
BackgroundOne of the newly faced challenges during the COVID-19 is vaccine hesitancy (VH). The validated 5C scale, that assesses five psychological antecedents of vaccination, could be effective in exploring COVID-19 VH. This study aimed to determine a statistically valid cutoff points for the 5C sub-scales among the Arab population.

MethodsA cross-sectional study was conducted among 446 subjects from three Arab countries (Egypt, United Arab Emirates UAE, and Jordan). Information regarding sociodemographics, clinical history, COVID-19 infection and vaccination history, and 5C scale were collected online. The 5C scores were analyzed to define the cutoff points using the receiver operating characteristic curve (ROC) and to verify the capability of the questionnaire to differentiate whether responders are hesitant or non-hesitant to accept vaccination. ROC curve analysis was conducted setting for previous vaccine administration as a response, with the predictors being the main five domains of the 5C questionnaire. The mean score of each sub-scale was compared with COVID-19 vaccine intake

ResultsThe mean age of the studied population was 37{+/-}11, 42.9% were males, 44.8% from Egypt, 21.1% from Jordan, and 33.6% from UAE. Statistically significant differences between vaccinated and unvaccinated participants, respectively, weredetetd in the median score of confidence [6.0(1.3) versus 4.7(2.0)], complacency [(2.7(2.0) versus 3.0(2.0), constraints [1.7(1.7) versus 3.7(2.3)], and collective responsibility [6.7(1.7) versus 5.7(1.7)]. The area under the curve of the five scales was 0.72, 0.60, 0.76, 0.66, 0.66 for confidence, complacency, constraints, calculation, and collective responsibility at cutoff values of 5.7, 4.7, 6.0, 6.3, and 6.2, respectively.

Conclusionthe Arabic validated version of the 5C scale has a good discriminatory power to predict COVID-19 vaccines antecedent.


title: Multiverse to inform neurological research: an example using recovery outcome of neglect.

abstract:
ObjectiveMultiverse analysis provides an ideal tool for understanding how inherent, yet ultimately arbitrary methodological choices impact the conclusions of individual studies. With this investigation we aimed to demonstrate the utility of multiverse analysis for evaluating generalisability and identifying potential sources of bias within studies employing neurological populations.

MethodMultiverse analysis was used to evaluate the robustness of the relationship between post-stroke visuospatial neglect and poor long term recovery outcome within a sample of 1113 (age =72.5, 45.1% female) stroke survivors. A total of 25,600 t-test comparisons were run across 400 different patient groups defined using various combinations of valid inclusion criteria based on lesion location, stroke type, assessment time, neglect impairment definition, and scoring criteria across 16 standardised outcome measures.

ResultsOverall, 33.9% of conducted comparisons yielded significant results. 99.9% of these significant results fell below the null specification curve, indicating a highly robust relationship between neglect and poor recovery outcome. However, the strength of this effect was not constant across all comparison groups. Comparisons which included <100 participants, pre-selected patients based on lesion type, or failed to account for allocentric neglect impairment were found to yield average effect sizes which differed substantially. Similarly, average effect sizes differed across various outcome measures with the strongest average effect in comparisons involving an activities of daily living measure and the weakest in comparisons employing a depression subscale.

ConclusionsThis investigation demonstrates the utility of multiverse analysis techniques for evaluating effect robustness and identifying potential sources of bias within neurological research.


title: The female protective effect against autism spectrum disorder

abstract: Autism spectrum disorder (ASD) is diagnosed 3-4 times more frequently in males than in females. Genetic studies of rare variants support a female protective effect (FPE) against ASD. However, sex differences in common, inherited genetic risk for ASD are less studied. Leveraging the nationally representative Danish iPSYCH resource, we found siblings of female ASD cases had higher rates of ASD than siblings of male ASD cases (P < 0.01). In the Simons Simplex and SPARK collections, mothers of ASD cases carried more polygenic risk for ASD than fathers of ASD cases (P = 7.0  10-7). Male unaffected siblings under-inherited polygenic risk (P = 0.03); female unaffected siblings did not. Further, female ASD cases without a high-impact de novo variant over-inherited nearly three-fold the polygenic risk of male cases with a high-impact de novo (P = 0.02). Our findings support a FPE against ASD that includes common, inherited genetic variation.

category: genetic and genomic medicine


title: Clinical efficacy of Early Administration of Convalescent Plasma among COVID-19 Cases in Egypt

abstract:
ImportanceEarly and effective treatment of COVID-19 is vital for control of SARS-CoV-2 infection

ObjectivesThe primary objective of the study was to assess the degree of clinical improvement in severe and critically ill COVID-19 patients, treated early with early CPT.

DesignsAn interventional, single-arm, non-randomized clinical trial conducted in Egypt from April 15 to July 21, 2020.

SettingsThis was a multi-centre study conducted in 3 hospitals in Egypt.

Participantsa total of 94 COVID-19 laboratory-confirmed patients using qRT-PCR were enrolled in the study.

InterventionAll patients were administered with two plasma units (each unit is 200cc). The volume of donated plasma was 800cc.

Main Outcome and MeasuresPrimary measure was the degree of clinical improvement among the COVID-19 patients who received CPT within seven days

ResultsA total of 94 patients were enrolled who received CPT either within seven days or after seven days of hospitalization. 82 were severely ill, 12 were critically ill. The average age remained 58 years ({+/-}SD 15.1 years). Male were 69% and 49% patients got cured while 51% died with CFR 51%. 75% deaths were above 45years of age. The symptoms were dyspnoea (55%), fever (52%), cough (46%), and loss of taste and smell (21%), and cyanosis (15%). The most common co-morbidities among the <40 years remained Diabetes Mellitus (21%) and Asthma (14%). Among 40-60 years Hypertension (56%), Diabetes Mellitus (39%) and among >60 years age group Hypertension (57%) and Chronic Heart Disease (24%) were reported. CPT within seven days remained significant as compared with the CPT after seven days with the number of days to cure (p=0.007) and ICU stay (P=0.008) among severely ill cured cases.

Conclusion and RelevanceAmong patients with COVID-19 and severe or critical illness, the use of CPT along with routine standard therapy resulted in a statistically significant improvement when administered within seven days of hospital admission. However, plasma transfusion, irrespective of days to transfusion may not help treat critically ill patients. The overall mean time to cure in severely ill patients was 15 days if CPT provided within seven days with 65% cure rate.

Trial RegistrationClinical Intervention identifier: MOHP_COVID-19_Ver1.1


title: RELATIONSHIP OF LIVER ENZYME LEVELS WITH THE CLINICAL COURSE OF COVID-19

abstract:
IntroductionCovid 19 infection, which can affect many systems in the human body, can cause organ dysfunction. High liver serum enzymes can be found in covid-19 patients, and many factors cause this stop. Patients with high levels of liver enzymes that require invasive mechanical ventilation during their follow-up were examined, and it was aimed to determine whether it was among the predictive indicators of mortality.

MATERIAL AND METHODSPatients infected with covid 19 who were hospitalized in the intensive care unit between March 30 and December 1, 2020 according to the criteria of hospitalization in the intensive care unit, clinical trials such as age, gender, length of stay, additional diseases, liver enzyme levels and whether invasive mechanical ventilation is required their characteristics were recorded and analyzed retrospectively and compared.

RESULTSData were collected from 111 patients whose liver enzyme levels were measured from 131 patients included in the study. It was found that aspartate transaminase, alanine aminotransferase, and gamma-glutamyl transferase levels were statistically higher in the invasive mechanical ventilation group compared to the patients who did not undergo invasive mechanical ventilation.

CONCLUSIONAlanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase levels were statistically higher in COVID19-infected patients who were treated in intensive care and undergoing invasive mechanical ventilation. These enzymes are easily accessible and are shown among predictive values in mortality.


title: Prospective evaluation of ID NOW COVID-19 assay used as point-of-care test in an Emergency Department

abstract:
BackgroundRapid testing for COVID-19 has been clearly identified as an essential component of the strategy to control the SARS-CoV-2 epidemic, worldwide. The ID NOW COVID-19 assay is a simple, user-friendly, rapid molecular biology test based on nicking and extension amplification reaction (NEAR).

ObjectivesThe aim of this study was to evaluate the ID NOW COVID-19 assay when used as a point-of-care test (POCT) in our Emergency Department (ED).

Type of studyThis prospective study enrolled 395 consecutive patients; paired nasopharyngeal swabs were collected from each study participant. The first swab was tested with the ID NOW COVID-19 assay at the point-of-care by ED nurses. The second swab was diluted in viral transport medium (VTM) and sent to the clinical microbiology department for analysis by both the RT-PCR Simplexa test COVID-19 Direct assay as the study reference method, and the ID NOW COVID-19 assay performed in the laboratory.

ResultsNasopharyngeal swabs directly tested with the ID NOW COVID-19 assay yielded a sensitivity, specificity, PPV and NPV of 98.0%, 97.5%, 96.2% and 98.7%, respectively, in comparison with the RT-PCR study reference assay. When the ID NOW COVID-19 assay was performed in the laboratory using the VTM samples, the sensitivity decreased to 62.5% and the NPV to 79.7%. Three false negative test results were reported with the ID NOW COVID-19 assay when performed using undiluted swabs directly in the ED; these results were obtained from patients with elevated CT values (>30).

ConclusionWe demonstrated that the ID NOW COVID-19 assay, performed as a point of care test in the ED using dry swabs, provides a rapid and reliable alternative to laboratory-based RT-PCR methods

category: emergency medicine


title: Maternal and offspring genetic risk score (GRS) analyses of fetal alcohol exposure and ADHD risk in offspring

abstract:
BackgroundStudies investigating the effects of prenatal alcohol exposure on childhood ADHD symptoms using conventional observational designs have reported inconsistent findings, which may be affected by unmeasured confounding and maternal and fetal ability to metabolise alcohol. We used genetic variants from alcohol metabolising genes (alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH)) as proxies for fetal alcohol exposure to investigate their association with offspring ADHD risk around age 7-8.

MethodsWe used data from three longitudinal pregnancy cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC), Generation R study (GenR) and the Norwegian Mother, Father and Child Cohort study (MoBa). Genetic risk scores (GRS) for alcohol use and metabolism using 36 single nucleotide polymorphisms (SNPs) from ADH/ALDH genes were calculated for mothers (NALSPAC=8,196; NMOBA=13,614), fathers (NMOBA=13,935) and offspring (NALSPAC=8,237; NMOBA=14,112; NGENR=2,661). Associations between maternal GRS and offspring ADHD risk were tested in the full sample to avoid collider bias. Offspring GRS analyses were stratified by maternal drinking status. Results: The pooled estimate in maternal GRS analyses adjusted for offspring GRS in ALSPAC and MoBa was OR=0.99, 95%CI 0.97-1.02. The pooled estimate in offspring GRS analyses stratified by maternal drinking status across the cohorts was: ORDRINKING=0.98, 95%CI 0.94-1.02; ORNO DRINKING=0.99, 95%CI 0.97-1.02. These findings remained similar after accounting for maternal genotype data in ALSPAC and maternal and paternal genotype data in MoBa.

ConclusionsWe did not find evidence for a causal effect of fetal alcohol exposure on ADHD risk in offspring. The results may be affected by low power and outcome assessment.

category: epidemiology


title: Predictive modeling of COVID-19 New Confirmed Cases in Algeria using Artificial Neural Network

abstract:
This study investigates the potential of a simple artificial neural network for the prediction of COVID-19 New Confirmed Cases in Algeria (CNCC).

Four different ANN models were built (GRNN, RBFNN, ELM, and MLP). The performance of the predictive models is evaluated based on four numerical parameters, namely root mean squared error (RMSE), mean absolute error (MAE), Nash-Sutcliffe efficiency (NSE), and Pearson correlation coefficient (R). Taylor diagram was also used to examine the similarities and differences between the observed and predicted values obtained from the proposed models.

The results showed the potential of the multi-layer perceptron neural network (MLPNN) which exhibited a high level of accuracy in comparison to the other models.


title: Sex Differences in Brain Structures and Functional Connectivity among Patients with Bipolar I Disorder

abstract:
ObjectivesStudies have demonstrated that sex differences may play a crucial role in the alternations of brain structures in individuals with bipolar disorder, but findings are not consistent. The current study identified sex differences in brain structure and function among a large sample of individuals with bipolar I disorder (BD-I).

MethodsStructural and functional magnetic resonance imaging datasets were acquired from 105 individuals with BD-I (36 men and 69 women) and 210 healthy adults (72 men and 138 women). A general linear regression model was used for voxel-wise analysis of grey matter (GM) and functional connectivity. Age, sex, diagnosis, and sex-by-diagnosis interaction were defined as predictors.

ResultsIn GM, the left caudate (p < .001), left thalamus (p < .001), right caudate (p = .003), right thalamus (p < .001), left anterior cingulate gyrus (p = .015), and left middle/posterior cingulate gyrus (p = .022) exhibited sex-by-diagnosis interaction. Furthermore, by using these six brain regions as seeds, we observed sex-by-diagnosis interaction in the alteration of functional connectivity between the left thalamus and right angular gyrus (p = .019).

ConclusionsOur data revealed a sex-by-diagnosis interaction associated with structure and function of the limbic system in individuals with BD-I. These findings may serve as reference for future studies on the pathophysiology of bipolar disorder.


title: Food Insecurity in Households of People with Autism Spectrum Disorder during the COVID-19 Pandemic

abstract:
ObjectivesTo explore differences in food insecurity for individuals and families of people with autism spectrum disorder (ASD) during the COVID-19 pandemic by individual, family, and neighborhood characteristics.

MethodsWe surveyed a convenience sample of households of people with ASD. We calculated food insecurity using items from the US Census Bureaus Household Pulse Survey..

ResultsOver half of all respondents reported being food insecure (51.8%). Respondents who reported being food insecure were more likely to be minority, have a high school education or less, be on public insurance or uninsured, live in urban/rural communities, and say that their community is not supportive. The majority of respondents did not get free food or groceries (53.2%). Food insecure respondents who got free food was most likely to get them from schools (34.2%).

ConclusionThis is the first study of its kind to explore food security in households of people with ASD. The pandemic has exacerbated existing neighborhood disparities. The federal response to food insecurity caused by the pandemic needs to be further explored especially for preferred and medically necessary foods for people with ASD.

category: public and global health


title: Factors associated with nonessential workplace attendance during the Covid-19 pandemic in the UK in early 2021: evidence from cross-sectional surveys

abstract:
Background and aimsWorking from home where possible is important in reducing spread of Covid-19. In early 2021, a quarter of people in England who believed they could work entirely from home reported attending their workplace. To inform interventions to reduce this, this study examined associated factors.

MethodsData from the ongoing CORSAIR survey series of nationally representative samples of people in the UK aged 16+ years in January-February 2021 were used. The study sample was 1422 respondents who reported that they could work completely from home. The outcome measure was self-reported workplace attendance at least once during the preceding week. Factors of interest were analysed in three blocks: 1) sociodemographic variables, 2) variables relating to respondents circumstances, and 3) psychological variables.

Results26.8% (95%CI=24.5%-29.1%) of respondents reported having attended their workplace at least once in the preceding week. Sociodemographic variables and living circumstances significantly independently predicted non-essential workplace attendance: male gender (OR=1.85,95%CI=1.33-2.58), dependent children in the household (OR=1.65,95%CI=1.17-2.32), financial hardship (OR=1.14,95%CI=1.08-1.21), socio-economic grade C2DE (OR=1.74, 95%CI=1.19-2.53), working in sectors such as health or social care (OR=4.18, 95%CI=2.56-6.81), education and childcare (OR=2.45, 95%CI=1.45-4.14) and key public service (OR=3.78, 95%CI=1.83-7.81), and having been vaccinated (OR=2.08,95%CI=1.33-3.24).

ConclusionsNon-essential workplace attendance in the UK in early 2021 during the Covid-19 pandemic was significantly independently associated with a range of sociodemographic variables and personal circumstances. Having been vaccinated, financial hardship, socio-economic grade C2DE, having a dependent child at home, working in certain key sectors were associated with higher likelihood of workplace attendance.


title: Smoking modulates different secretory subpopulations expressing SARS-CoV-2 entry genes in the nasal and bronchial airways

abstract:
Coronavirus Disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 SARS-CoV-2), which infects host cells with help from the Viral Entry (VE) proteins ACE2, TMPRSS2, and CTSL1-4. Proposed risk factors for viral infection, as well as the rate of disease progression, include age5,6, sex7, chronic obstructive pulmonary disease7,8, cancer9, and cigarette smoking10-13. To investigate whether the proposed risk factors increase viral infection by modulation of the VE genes, we examined gene expression profiles of 796 nasal and 1,673 bronchial samples across four lung cancer screening cohorts containing individuals without COVID-19. Smoking was the only clinical factor reproducibly associated with the expression of any VE gene across cohorts. ACE2 expression was significantly up-regulated with smoking in the bronchus but significantly down-regulated with smoking in the nose. Furthermore, expression of individual VE genes were not correlated between paired nasal and bronchial samples from the same patients. Single-cell RNA-seq of nasal brushings revealed that an ACE2 gene module was detected in a variety of nasal secretory cells with the highest expression in the C15orf48+ secretory cells, while a TMPRSS2 gene module was most highly expressed in nasal keratinizing epithelial cells. In contrast, single-cell RNA-seq of bronchial brushings revealed that ACE2 and

TMPRSS2 gene modules were most enriched in MUC5AC+ bronchial goblet cells. The CTSL gene module was highly expressed in immune populations of both nasal and bronchial brushings. Deconvolution of bulk RNA-seq showed that the proportion of MUC5AC+ goblet cells was increased in current smokers in both the nose and bronchus but proportions of nasal keratinizing epithelial cells, C15orf48+ secretory cells, and immune cells were not associated with smoking status. The complex association between VE gene expression and smoking in the nasal and bronchial epithelium revealed by our results may partially explain conflicting reports on the association between smoking and SARS-CoV-2 infection.

category: respiratory medicine


title: Simultaneous Monitoring of Disease and Microbe Dynamics Through Plasma DNA Sequencing in Pediatric Patients with Acute Lymphoblastic Leukemia

abstract:
Treatment of acute lymphoblastic leukemia (ALL) necessitates continuous risk assessment of leukemic disease burden as well as infections that arise in the setting of immunosuppression and myelosuppression. This study was performed to assess the feasibility of a hybrid capture NGS panel to longitudinally measure molecular leukemic disease clearance and microbial species abundance in 20 pediatric patients with ALL throughout induction chemotherapy. This proof-of-concept helps establish a technical and conceptual framework that we anticipate will be expanded and applied to additional patients with leukemias, as well as extended to additional cancers. Molecular monitoring can help to accelerate the attainment of insights into the temporal biology of host-microbe-leukemia interactions, including how those changes correlate with and alter anticancer therapy efficacy. We also anticipate fewer invasive bone marrow aspirations or biopsies will be required as these methods improve with standardization and are validated for clinical use.

Key PointsO_LIA custom-designed hybridization capture next generation sequencing (NGS) panel noninvasively and quantitatively measures leukemic disease burden and microbial species abundance through serial peripheral blood draws throughout induction chemotherapy.
C_LIO_LISequencing of circulating tumor DNA (ctDNA) alongside microbial cell free DNA (mcfDNA) in the same sample reveals the effectiveness of chemotherapy alongside the immunosuppressive consequences of cytotoxic therapy.
C_LIO_LIEfforts to incorporate ctDNA and mcfDNA NGS monitoring in higher risk patient populations have the potential to uncover mechanisms of response, resistance, and infectious complications that correlate with patient outcomes.
C_LI

category: oncology