title: The individual and global impact of copy number variants on complex human traits

abstract: Copy number variations (CNVs) have been involved in multiple genomic disorders but their impact on complex traits remains understudied. We called CNVs in the UK Biobank and performed genome-wide association scans (GWASs) between the copy-number of CNV-proxy probes and 57 continuous traits, revealing 131 signals spanning 47 phenotypes. Our analysis recapitulated well-known associations (1q21 and height), revealed the pleiotropy of recurrent CNVs (26 traits for 16p11.2-BP4-BP5), and suggested new gene functionalities (MARF1 in female reproduction). Forty CNV signals overlapped known GWAS loci (RHD deletion and hematological traits). Conversely, others overlapped Mendelian disorder regions, suggesting variable expressivity and a broad impact of these loci, as illustrated by signals mapping to Rotor syndrome (SLCO1B1/3), renal cysts and diabetes (HNF1B), or Charcot-Marie-Tooth (PMP22) loci. The total CNV burden negatively impacted 35 traits, leading to increased adiposity, liver/kidney damage, and decreased intelligence and physical capacity. Thirty traits remained burden-associated after correcting for CNV-GWAS signals, pointing to a polygenic CNV-architecture. The burden negatively correlated with socio-economic indicators, parental lifespan, and age (survivorship proxy), suggesting that CNVs contribute to decreased longevity. Together, our results showcase how studying CNVs can reveal new biological insights, emphasizing the critical role of this mutational class in shaping complex traits.


title: Data analysis of COVID-19 wave peaks in relation to latitude and temperature for multiple nations

abstract: It was observed that the multiple peaks of coronavirus disease-19 (COVID-19) appeared in different seasons in different countries. There were countries where the COVID-19 peak occurred during extremely low temperatures, such as Norway, Canada and on the other hand there were countries with high-temperature ranges such as Brazil, India, UAE. Most of the high-latitude countries received their outbreak in winter and most of the countries near the equator mark the outbreak during the summer. Most of the biological organisms have their growth dependant on the temperature, and hence we explored that if there is any relation of temperature versus COVID-19 outbreak in the particular country. It was also seen that people are not behaving differently during the peak of the COVID-19 wave, hence it was important to know whether the COVID-19 virus has evolved or the global temperature variation caused these multiple peaks. This work focuses on finding the effect of temperature variation on the COVID-19 outbreak. We used Levenberg-Marquardt technique to find the correlation between the temperature at which COVID-19 outbreak peaks and the latitude of the particular country. We found that between the temperature range of 14 {degrees}C to 20 {degrees}C spread of the COVID-19 is minimal. Based on our results we can also say that the COVID-19 outbreak is seen in lower temperature (0 {degrees}C to 13 {degrees}C) ranges as well as in the higher temperature ranges (21 {degrees}C to 35 {degrees}C). The current data analysis will help the authorities to manage their resources in advance to prepare for any further outbreaks that might occur in the COVID-19 or even in the next pandemic.

category: health informatics


title: An individual-level socioeconomic measure for assessing algorithmic bias in health care settings: A case for HOUSES index

abstract: While artificial intelligence (AI) algorithms hold great potential for improving health and reducing health disparities, biased AI algorithms have a potential to negatively impact the health of under-resourced communities or racial/ethnic minority populations. Our study highlights the major role of socioeconomic status (SES) in AI algorithm bias and (in)completeness of electronic health records (EHRs) data, which is commonly used for algorithm development. Understanding the extent to which SES impacts algorithmic bias and its pathways through which SES operates its impact on algorithmic bias such as differential (in)completeness of EHRs will be important for assessing and mitigating algorithmic bias. Despite its importance, the role of SES in the AI fairness science literature is currently under-recognized and under-studied, largely because objective and scalable individual-level SES measures are frequently unavailable in commonly used data sources such as EHRs. We addressed this challenge by applying a validated individual-level socioeconomic measure that we call the HOUSES index. This tool allows AI researchers to assess algorithmic bias due to SES. Although our study used a cohort with a relatively small sample size, these study results highlight a novel conceptual strategy for quantifying AI bias by SES.


title: Clinical features, demography and predictors of outcomes of SARS-CoV-2 infection in a tertiary care hospital in India-A cohort study

abstract:
BackgroundThe second wave of the COVID-19 pandemic hit India from early April 2021 to June 2021 and more than 400,000 cases per day were reported in the country. We describe the clinical features, demography, treatment trends, baseline laboratory parameters of a cohort of patients admitted at the All India Institute of Medical Sciences, New Delhi with SARS-CoV-2 infection and their association with the outcome.

MethodsThis was a retrospective cohort study describing the clinical, laboratory and treatment patterns of consecutive patients admitted with SARS-CoV-2 infection. Multivariate logistic regression models were fitted to identify the clinical and biochemical predictors of developing hypoxia, deterioration during the hospital stay and death.

FindingsA total of 2080 patients were included in the study. The case fatality rate was 19.5%. Amongst the survivors, the median duration of hospital stay was 8 (5-11) days. Out of 853 (42.3%%) of patients who had COVID-19 Acute respiratory distress syndrome at presentation, 340 (39.9%) died. Patients aged 45-60 years [OR (95% CI): 1.8 (1.2-2.6)p =0.003] and those aged >60 years [OR (95%CI): 3.4 (2.3-5.2), p<0.001] had a higher odds of death as compared to the 18-44 age group. Vaccination reduced the odds of death by 30% [OR (95% CI): 0.7 (0.5-0.9), p=0.036]. Patients with hyper inflammation at baseline as suggested by leucocytosis [OR (95% CI): 2.1 (1.4-3.10), p <0.001], raised d-dimer >500 mg/dL [OR (95% CI): 3.2 (2.2-4.6), p <0.001] and raised C-reactive peptide >0.5 mg/L [OR (95% CI): 3.8 (1.1-13), p=0.037] had higher odds of death. Patients who were admitted in the second week had lower odds of death and those admitted in the third week had higher odds of death.

InterpretationThis is the largest cohort of patients admitted with COVID-19 from India reported to date and has shown that vaccination status and early admission during the inflammatory phase can change the course of illness of these patients. Strategies should be made to improve vaccination rates and early admission of patients with moderate and severe COVID-19 to improve outcomes.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThe COVID-19 pandemic has been ravaging the world since December 2019 and the cases in various regions are being reported in waves. We found that the case fatality rates ranging from 1.4% to 28.3% have been reported in the first wave in India. Older age and the presence of comorbidities are known predictors of mortality. There are no reports regarding the effectiveness of vaccination, correlation of mortality with the timing of admission to the health care facility and inflammatory markers in the  second wave of the COVID-19 pandemic in India.

Added-value of this studyThis study reports the real-world situation where patients get admitted at varying time points of their illness due to the mismatch between the availability of hospital beds and the rising number of COVID-19 patients during the pandemic. It reports the odds of developing severe hypoxia necessitating oxygen therapy and death thus helping identify priority groups for admission.

Implications of all the available evidenceThis study found increased odds of requiring oxygen support or death in patients older than 45 years of age, with comorbidities, and those who had hyper-inflammation with raised C-reactive peptide, d-dimer or leukocytosis. Patients who were admitted in the second week of illness had lower odds of death as compared to those admitted in the third week implying that treatment with corticosteroids in the second week of the illness during the  inflammatory phase could lead to reduced mortality. These findings would help triage patients and provide guidance for developing admission policy during times where hospital beds are scarce. Vaccination was found to reduce the odds of deterioration or death and should be fast-tracked to prevent further  waves of the pandemic.

category: infectious diseases


title: Specificity of SARS-CoV-2 antibody-detection assays against S and N protein among pre-COVID-19 sera from patients with protozoan and helminth parasitic infections

abstract:
BackgroundWe aimed to assess the specificity of SARS-CoV-2 antibody detection assays among people with known tissue-borne parasitic infections.

MethodsWe tested three SARS-CoV-2 antibody-detection assays (cPass SARS-CoV-2 Neutralization Antibody Detection Kit, Abbott SARS-CoV-2 IgG assay, and STANDARD Q COVID-19 IgM/IgG Combo Rapid Test) among 559 pre-COVID-19 sera.

ResultsThe specificity of assays was 95-98% overall. However, lower specificity was observed among sera from patients with protozoan infections of the reticuloendothelial system, such as human African trypanosomiasis (Abbott Architect; 88% [95%CI 75-95]), visceral leishmaniasis (SD RDT IgG; 80% [95%CI 30-99]), and from patients with recent malaria from a holoendemic area of Senegal (ranging from 91% for Abbott Architect and SD RDT IgM to 98-99% for cPass and SD RDT IgG). For specimens from patients with evidence of past or present helminth infection overall, test specificity estimates were all [≥] 96%. Sera collected from patients clinically suspected of parasitic infections that tested negative for these infections yielded a specificity of 98-100%. The majority (>85%) of false-positive results were positive by only one assay.

ConclusionsThe specificity of SARS-CoV-2 serological assays among sera from patients with tissue-borne parasitic infections was below the threshold required for decisions about individual patient care. Specificity is markedly increased by the use of confirmatory testing with a second assay. Finally, the SD RDT IgG proved similarly specific to laboratory-based assays and provides an option in low-resource settings when detection of anti-SARS-CoV-2 IgG is indicated.


title: Geospatial Variability in Excess Death Rates during the COVID-19 Pandemic in Mexico: Examining Socio Demographic and Population Health Characteristics

abstract:
BackgroundMexico has suffered one of the highest COVID-19 mortality rates in the world. In this study we examined how socio demographic and population health characteristics shape the geospatial variability in excess mortality patterns during the COVID-19 pandemic in Mexico.

MethodsWeekly all-cause mortality time series for all 32 Mexican states, from January 4, 2015 to April 10, 2021, were analyzed to estimate the excess mortality rates using Serfling regression models. The association between socio-demographic, health indicators and excess mortality rates were determined using multiple linear regression analyses. Finally, we used functional data analysis to characterize clusters of states with distinct mortality growth rate curves.

ResultsThe overall all-cause excess deaths rate during the COVID-19 pandemic in Mexico until April 10, 2021 was estimated at 39.66 per 10 000 population. The lowest excess death rates were observed in southeastern states including Chiapas (12.72), Oaxaca (13.42) and Quintana Roo (19.41) whereas Mexico City had the highest excess death rate (106.17), followed by Tlaxcala (51.99) and Morelos (45.90). We found a positive association of excess mortality rates with aging index (P value<.0001), marginalization index (P value<.0001), and average household size (P value=0.0003) in the final adjusted model (Model R2=76%). We identified four distinct clusters with qualitatively similar excess mortality curves.

ConclusionCentral states exhibited the highest excess mortality rates whereas the distribution of aging index, marginalization index, and average household size explained the variability in excess mortality rates across Mexico. Our findings can help tailor interventions to mitigate the mortality impact of the pandemic.

Key messageO_LIThis study quantified and examined spatial patterns of excess mortality across states of Mexico, with lower rates of excess mortality in southeastern states and higher rates in central states.
C_LIO_LIMexico City recorded 1 in 5 of all excess deaths in reported in Mexico, which accounted for 19% of total excess deaths across the country.
C_LIO_LIFindinds indicate that aging index, marginalization index, and average household size played a significant role on excess death rates across Mexican states during the COVID-19 pandemic.
C_LIO_LIFour distinct clusters characterized the excess mortality curves across Mexican states.
C_LI

category: epidemiology


title: B and T cell responses after a third dose of SARS-CoV-2 vaccine in Kidney Transplant Recipients

abstract:
BackgroundAccumulating evidence suggests that solid organ transplant recipients, as opposed to the general population, show strongly impaired responsiveness towards standard SARS-CoV-2 mRNA-based vaccination, demanding alternative strategies for protection of this vulnerable group.

MethodsIn line with recent recommendations, a third dose of either heterologous ChAdOx1 (AstraZeneca) or homologous BNT162b2 (BioNTech) was administered to 25 kidney transplant recipients (KTR) without humoral response after 2 doses of BNT162b2, followed by analysis of serological responses and vaccine-specific B- and T-cell immunity.

Results9/25 (36%) KTR under standard immunosuppressive treatment seroconverted until day 27 after the third vaccination, while one patient developed severe COVID-19 infection immediately after vaccination. Cellular analysis seven days after the third dose showed significantly elevated frequencies of viral spike protein receptor binding domain specific B cells in humoral responders as compared to non-responders. Likewise, portions of spike-reactive CD4+ T helper cells were significantly elevated in seroconverting patients. Furthermore, overall frequencies of IL-2+, IL-4+ and polyfunctional CD4+ T cells significantly increased after the third dose, whereas memory/effector differentiation remained unaffected.

ConclusionsOur data suggest that a fraction of transplant recipients benefits from triple vaccination, where seroconversion is associated with quantitative and qualitative changes of cellular immunity. At the same time, the study highlights that modified vaccination approaches for immunosuppressed patients still remain an urgent medical need.

Significance statementProtection of solid organ transplant recipients against SARS-Cov-2 by vaccination remains an unmet need given the low immunogenicity of available vaccines in the presence of immunosuppression. Administration of a third dose to 25 kidney transplant recipients (KTR) resulted in seroconversion in 36% of patients, associated with significant quantitative and functional changes within the spike-antigen-specific B-cell- and CD4+ T-helper cell compartment. Our data support the need for individual humoral monitoring of immunosuppressed individuals after vaccination as well as continued efforts to adapt vaccination protocols for this at-risk group.

category: nephrology


title: The D614G virus mutation enhances anosmia in COVID-19 patients: Evidence from a systematic review and meta-analysis of studies from South Asia

abstract:
The prevalence of chemosensory dysfunction in patients with COVID-19 varies greatly between populations. It is unclear whether such differences are due to factors at the level of the human host, or at the level of the coronavirus, or both. At the host level, the entry proteins which allow virus binding and entry have variants with distinct properties, and the frequency of such variants differs between ethnicities. At the level of the virus, the D614G mutation enhances virus entry to the host cell. Since the two virus strains (D614 and G614) co-existed in the first six months of the pandemic in most populations, it has been difficult to distinguish between contributions of the virus and contributions of the host for anosmia. To answer this question, we conducted a systematic review and meta-analysis of studies in South Asian populations when either the D614 or the G614 virus was dominant. We show that populations infected predominantly with the G614 virus had a much higher prevalence of anosmia (pooled prevalence of 31.8%) compared with the same ethnic populations infected mostly with the D614 virus strain (pooled anosmia prevalence of 5.3%). We conclude that the D614G mutation is a major contributing factor that increases the prevalence of anosmia in COVID-19, and that this enhanced effect on olfaction constitutes a previously unrecognized phenotype of the D614G mutation. The new virus strains that have additional mutations on the background of the D614G mutation can be expected to cause a similarly increased prevalence of chemosensory dysfunctions.

Graphical Abstract

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category: otolaryngology


title: The fomite contribution to the transmission of COVID-19 in the UK: an evolutionary population estimate

abstract: A SEIR model with an added fomite term is used to constrain the contribution of fomites to the spread of COVID-19 under the Spring 2020 lockdown in the UK. Assuming uniform priors on the reproduction number in lockdown and the fomite transmission rate, an upper limit is found on the fomite transmission rate of less than 1 contaminated object in 7 per day per infectious person (95% CL). Basing the prior on the reproduction rate during lockdown instead on the CoMix study results for the reduction in social contacts under lockdown, and assuming the reproduction number scales with the number of social contacts, provides a much more restrictive upper limit on the transmission rate by contaminated objects of fewer than 1 in 30 per day per infectious person (95% CL). Applied to postal deliveries and groceries, the upper limit on the fomite transmission rate corresponds to a probability below 1 in 70 (95% CL) that a contaminated object transmits the infection. Fewer than about half (95% CL) of the total number of deaths during the lockdown are found to arise from fomites, and most likely fewer than a quarter. These findings apply only to fomites with a transmission rate that is unaffected by a lockdown.


title: Emergence of SARS-CoV-2 variant B.1.575.2 containing the E484K mutation in the spike protein in Pamplona (Spain) May-June 2021

abstract:
With the emergence of new SARS-CoV-2 variants and the acquisition of novel mutations in exiting lineages, the need to implement methods capable of monitoring viral dynamics arises. We report the emergence and spread of a new SARS-CoV-2 variant within B.1.575 lineage containing the E484K mutation in the spike protein (named B.1.575.2) in a region of Northern Spain between May and June 2021. SARS-CoV-2 positive samples with cycle threshold value less than or equal to 30 were selected to screen of presumptive variants using the TaqPath COVID-19 RT-PCR kit and TaqMan SARS-CoV-2 Mutation Panel. Confirmation of variants was performed by whole genome sequencing. Of the 200 samples belonging to the B.1.575 lineage, 194 (97%) corresponded to the B.1.575.2 sub-lineage, which was related to the presence of the E484K mutation. Of 197 cases registered in GISAID EpiCoV database as lineage B.1.575.2 194 (99.5%) were identified in Pamplona (Spain).

This report emphasizes the importance of complementing surveillance of SARS-CoV-2 with sequencing for the rapid control of emerging viral variants.


title: The Exposome and its Associations with Broad Mental and Physical Health Measures in Early Adolescence

abstract: Exposures to perinatal, familial, social, and physical environmental stimuli can have substantial effects on human development. Yet the complex network structure of the environment (i.e., exposome) makes it challenging to investigate. Here, we analyze the exposome using data from the Adolescent Brain Cognitive Development Study (ABCD, N = 11,235, mean age = 10.9, 52% male) and replicate key findings in an age and sex matched sample from the Philadelphia Neurodevelopmental Cohort (PNC, N = 4,993). Both these cohorts are large, diverse samples of US adolescents with phenotyping at multiple levels of environmental exposure. In ABCD, applying data-driven iterative factor analyses and bifactor modeling, we reduced dimensionality from n=798 exposures to six exposome subfactors and a general (adverse) exposome factor. These factors revealed quantitative differences among racial and ethnic groups. Exposome factors increased variance explained in mental health by 10-fold (from <4% to >38%), over and above other commonly used sociodemographic factors. The general exposome factor was associated with psychopathology ({beta}=0.28, 95%CI 0.26-0.3) and key health-related outcomes: obesity (OR=1.4, 95%CI 1.3-1.5) and advanced pubertal development (OR=1.3, 95%CI 1.2-1.5). In PNC, using substantially fewer available environmental exposures (n=29), analyses yielded consistent associations of the general exposome factor with psychopathology ({beta} =0.15, 95%CI 0.13-0.17), obesity (OR=1.4, 95%CI 1.3-1.6) and advanced pubertal development (OR=1.3, 95%CI 1-1.6). Findings demonstrate how incorporating the exposome framework can be useful to study the role of environment in human development.

category: pediatrics


title: Diagnostic accuracy of rapid point-of-care tests for diagnosis of current SARS-CoV-2 infections in children: A systematic review and meta-analysis

abstract:
ObjectiveTo systematically assess the diagnostic accuracy of rapid point-of-care tests for diagnosis of current SARS-CoV-2 infections in children under real-life conditions.

DesignSystematic review and meta-analysis.

Data sourcesMEDLINE, Embase, Cochrane Database for Systematic Reviews, INAHTA HTA database, preprint servers (via Europe PMC), ClinicalTrials.gov, WHO ICTRP from 1 January 2020 to 7 May 2021; NICE Evidence Search, NICE Guidance, FIND Website from 1 January 2020 to 24 May 2021.

Review methodsDiagnostic cross-sectional or cohort studies that included paediatric study participants and evaluated rapid point-of care tests for diagnosing current SARS-CoV-2 infections against RT-PCR as the reference standard were eligible for inclusion. QUADAS-2 was used to assess the risk of bias and the applicability of the included studies. Bivariate meta-analyses with random effects were performed. Variability was assessed by subgroup analyses.

Results17 studies with a total of 6355 paediatric study participants were included. All studies compared antigen tests against RT-PCR. Overall, studies evaluated eight antigen tests from six different brands. Only one study was at low risk of bias. The pooled overall diagnostic sensitivity and specificity in paediatric populations was 64.2% (95% CI: 57.4% to 70.5%) and 99.1% (95% CI: 98.2% to 99.5%), respectively. In symptomatic children, the pooled diagnostic sensitivity was 71.8% (95% CI: 63.6% to 78.8%) and the pooled diagnostic specificity was 98.7% (95% CI: 96.6% to 99.5%). The pooled diagnostic sensitivity in asymptomatic children was 56.2% (95% CI: 47.6% to 64.4%) and the pooled diagnostic specificity was 98.6% (95% CI: 97.3% to 99.3%).

ConclusionsThe performance of current antigen tests in paediatric populations under real-life conditions varies broadly. Relevant data was only identified for about 1% of antigen tests with market access in Europe. The results should be interpreted with caution since risk of bias in studies was predominantly judged as unclear due to poor reporting. Further, the most common paediatric use cases (e.g., self-testing in schools or toddlers getting tested by their parents before leaving for kindergarten) have not been addressed in clinical performance studies yet. Policymakers should scrutinise whether the observed low diagnostic sensitivity may impact the planned purpose of antigen tests and are encouraged to require the evaluation of tests in the intended setting prior to the broad implementation of testing programmes.

Systematic review registrationCRD42021236313 (PROSPERO).

SUMMARY BOXESO_ST_ABSWhat is already known on this topic?C_ST_ABSO_LIDuring the current SARS-CoV-2 pandemic, antigen tests are widely used to detect children with current SARS-CoV-2 infection in schools and kindergarten despite an ongoing debate on potential benefits and harms.
C_LIO_LIA recent Cochrane review showed that sensitivity estimates of antigen tests in adult populations vary broadly and are substantially lower as reported by manufacturers; however, test performance in paediatric populations remained unknown.
C_LI

What this study adds?O_LIA systematic literature search and comprehensive author queries allowed to include 17 studies evaluating the diagnostic accuracy of antigen tests in children.
C_LIO_LIBased on the results of the bivariate meta-analysis, the real-life performance of current antigen tests for professional use in paediatric populations is below the minimum performance criteria set by WHO, the US FDA, or the MHRA in the UK.
C_LIO_LIConsidering the unclear risk of bias in most studies due to poor reporting, the performance of antigen tests for professional use in paediatric populations is similar to what has been reported previously for adult populations.
C_LIO_LIThere is an urgent need to evaluate the performance of antigen tests for the most common paediatric use cases since the impact of context-specific factors, e.g., sample collection in toddlers by laypersons or self-testing performed by children, on the diagnostic test accuracy - and most notably on the diagnostic sensitivity - remains unknown.
C_LI

How might it impact clinical practice in the foreseeable future?O_LIThe results presented in this systematic review may support the development and improvement of testing programmes in schools and kindergarten.
C_LIO_LIThe evidence gaps identified in this systematic review demonstrate current research needs in the context of rapid point-of-care testing for SARS-CoV-2 infection in paediatric populations to support evidence-based decision making.
C_LI


title: Mental Health Utilization in Children in the time of COVID-19

abstract:
BackgroundIn early 2020, coronavirus disease 2019 (COVID-19) was declared a public health emergency and a combination of lockdown and social distancing measures were put in place across the globe. Many children, adolescents and adults have experienced adverse mental health effects related to the pandemic and its impact on daily life, although the long-term impact on individuals and health systems is not well understood.

MethodsThis cross-sectional study was based on data from 2018-2021 collected via medical records from our hospital. Admissions were transformed into time-series data, and models were generated to analyze changes in admission rates for mental health emergencies in 2020 and 2021 compared to previous years.

ResultsOf 1906 inpatient encounters among 1543 unique patients seen by the Child and Adolescent Psychiatry Consultation-Liaison service, there was a decrease in overall admissions beginning in March 2020, coinciding with statewide lock down due to the COVID-19 pandemic. In April 2020, admissions were reduced 36% compared to average admissions from 2018-2019. By 2021, overall admissions were significantly higher than for the previous three years. Similarly, the count of suicide attempts was significantly higher in 2021 compared to previous years. The rate of patients admitted to inpatient facilities upon discharge was significantly higher during the COVID-19 pandemic period.

ConclusionAdmissions for mental health emergencies fluctuated during the period associated with the COVID-19 pandemic across an array of diagnoses. Increases in admissions and severity of mental health emergencies during COVID-19 may reflect a detrimental impact of the pandemic on the mental health of children, as well as unmet needs during this time.


title: What has changed in the experiences of people with mental health problems during the COVID-19 pandemic? Findings from follow-up interviews using a coproduced, participatory qualitative approach

abstract:
PurposeWe sought to understand how the experiences of people in the UK with pre-existing mental health conditions had developed during the course of the COVID-19 pandemic.

MethodsIn September-October 2020 we interviewed adults with mental health conditions pre-dating the pandemic, whom we had previously interviewed three months earlier. Participants had been recruited through online advertising and voluntary sector community organisations. Interviews were conducted by telephone or video-conference by researchers with lived experience of mental health difficulties, and explored changes over time in peoples experience of the pandemic.

ResultsWe interviewed 44 people, achieving diversity of demographic characteristics and a range of mental health conditions and service use among our sample. Three overarching themes were derived from interviews. The first theme "Spectrum of adaptation": to difficulties in access to, or the quality of, statutory mental health services, through developing new personal coping strategies or identifying alternative sources of support. The second theme is "Accumulating pressures": from pandemic-related anxieties and sustained disruption to social contact and support, and to mental health treatment. The third theme "Feeling overlooked": A sense of people with pre-existing mental health conditions being overlooked during the pandemic by policy-makers at all levels. The latter was compounded for people from ethnic minority communities or with physical health problems.

ConclusionOur study highlights the need to support marginalised groups who are at risk of increased inequalities, and to maintain crucial mental and physical healthcare and social care for people with existing mental health conditions, notwithstanding challenges of the pandemic.

category: psychiatry and clinical psychology


title: The influence of repeated mild lockdown on mental and physical health during the COVID-19 pandemic: a large-scale longitudinal study in Japan

abstract: The mental and physical effects of repeated lockdowns are unknown. We conducted a longitudinal study of the influence of repeated mild lockdowns during two emergency declarations in Japan, in May 2020 and February 2021. The analyses included 7,893 people who participated in all online surveys. During repeated mild lockdowns, mental and physical symptoms decreased overall, while loneliness increased and social networks decreased. Subgroup analyses revealed that depression and suicidal ideation did not decrease only in the younger age group (aged 18-29) and that younger and middle-aged people (aged 18-49), women, people with a history of treatment for mental illness, and people who were socially disadvantaged in terms of income had higher levels of mental and physical symptoms at all survey times. Additionally, comprehensive extraction of the interaction structure between depression, demographic attributes, and psychosocial variables indicated that loneliness and social networks were most closely associated with depression. These results indicate that repeated lockdowns have cumulative negative effects on interpersonal interaction and loneliness and that susceptible populations, such as young people and those with high levels of loneliness, require special consideration during repetitive lockdown situations.

category: public and global health


title: Assessing the sustainability of an integrated rural sanitation and hygiene approach: A repeated cross-sectional evaluation in 10 countries

abstract:
IntroductionWhile many studies have implemented programs to increase sanitation coverage throughout the world, there are limited rigorous studies on the sustainability of these sanitation programs.

MethodsBetween 2014 and 2018, the rural Sustainable Sanitation and Hygiene for All (SSH4A) approach was implemented by SNV in Sub-Saharan Africa and Asia. Repeated cross-sectional household surveys were administered annually throughout program implementation, and 1-to-2-years following completion of program activities. We characterize to what extent sanitation coverage was sustained 1-2 years after implementation of this SSH4A intervention.

ResultsSurveys were conducted in 12 program areas in 10 countries, with 22,666 households receiving a post-implementation survey. Six of 12 program areas (Bhutan, Ghana, Kenya, both Nepal sites, and Tanzania) had similar coverage levels of basic sanitation 1-to-2-years post-implementation, whereas there were varied levels of slippage in the other program areas (both Ethiopia sites, Indonesia, Mozambique, Uganda, and Zambia), ranging from a drop of 63 percentage points in coverage in Ethiopia to a drop of only 4 percentage points in Indonesia. In countries that experienced losses in the coverage of household sanitation, generally sanitation sharing among neighbors did not increase, whereas open defecation did increase. In each of the areas where slippage occurred, the sanitation coverage levels at the final time point were all still higher than the initial time point before SNV started working in these areas. We found a number of factors to be associated with the sustainability of sanitation coverage, including household socio-economic status, having household members with disabilities, baseline sanitation coverage levels of the program areas, and rate of change of coverage during program activities.

ConclusionsData revealed sustained gains in sanitation coverage in some program areas, yet slippage in other areas. This work may serve to benchmark sustainability of sanitation interventions in Sub-Saharan Africa and Asia.


title: Learning to Automatically Diagnose Multiple Diseases in Pediatric Chest Radiographs Using Deep Convolutional Neural Networks

abstract: Chest radiograph (CXR) interpretation is critical for the diagnosis of various thoracic diseases in pediatric patients. This task, however, is error-prone and requires a high level of understanding of radiologic expertise. Recently, deep convolutional neural networks (D-CNNs) have shown remarkable performance in interpreting CXR in adults. However, there is a lack of evidence indicating that D-CNNs can recognize accurately multiple lung pathologies from pediatric CXR scans. In particular, the development of diagnostic models for the detection of pediatric chest diseases faces significant challenges such as (i) lack of physician-annotated datasets and (ii) class imbalance problems. In this paper, we retrospectively collect a large dataset of 5,017 pediatric CXR scans, for which each is manually labeled by an experienced radiologist for the presence of 10 common pathologies. A D-CNN model is then trained on 3,550 annotated scans to classify multiple pediatric lung pathologies automatically. To address the highclass imbalance issue, we propose to modify and apply "Distribution-Balanced loss" for training D-CNNs which reshapes the standard Binary-Cross Entropy loss (BCE) to efficiently learn harder samples by down-weighting the loss assigned to the majority classes. On an independent test set of 777 studies, the proposed approach yields an area under the receiver operating characteristic (AUC) of 0.709 (95% CI, 0.690-0.729). The sensitivity, specificity, and F1-score at the cutoff value are 0.722 (0.694-0.750), 0.579 (0.563-0.595), and 0.389 (0.373-0.405), respectively. These results significantly outperform previous state-of-the-art methods on most of the target diseases. Moreover, our ablation studies validate the effectiveness of the proposed loss function compared to other standard losses, e.g., BCE and Focal Loss, for this learning task. Overall, we demonstrate the potential of D-CNNs in interpreting pediatric CXRs.

category: radiology and imaging


title: A Novel Convolutional Neural Network for COVID-19 detection and classification using Chest X-Ray images

abstract: The early and rapid diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), the main cause of fatal pandemic coronavirus disease 2019 (COVID-19), with the analysis of patients chest X-ray (CXR) images has life-saving importance for both patients and medical professionals. In this research a very simple novel and robust deep-learning convolutional neural network (CNN) model with less number of trainable-parameters is proposed to assist the radiologists and physicians in the early detection of COVID-19 patients. It also helps to classify patients into COVID-19, pneumonia and normal on the bases of analysis of augmented X-ray images. This augmented dataset contains 4803 COVID-19 from 686 publicly available chest X-ray images along with 5000 normal and 5000 pneumonia samples. These images are divided into 80% training and 20 % validation. The proposed CNN model is trained on training dataset and then tested on validation dataset. This model has a promising performance with a mean accuracy of 92.29%, precision of 99.96%, Specificity of 99.85% along with Sensitivity value of 85.92%. The result can further be improved if more data of expert radiologist is publically available.


title: Association of Naive B Cells with Humoral Response to SARS-CoV-2 Vaccination

abstract: Immunocompromised patients are considered high-risk and prioritized for vaccination against COVID-19. We aimed to analyze B-cell subsets in these patients to identify potential predictors of humoral vaccination response. Patients (n=120) suffering from hematologic malignancies or other causes of immunodeficiency and healthy controls (n=79) received a full vaccination series with an mRNA vaccine. B-cell subsets were analyzed prior to vaccination. Two independent anti-SARS-CoV-2 immunoassays targeting the receptor-binding domain (RBD) or trimeric S protein (TSP) were performed three to four weeks after the second vaccination. Seroconversion occurred in 100% of healthy controls, in contrast to 67% (RBD) and 82% (TSP) of immunocompromised patients, while only 32% (RBD) and 22% (TSP) achieved antibody levels comparable to those of healthy controls. The number of circulating CD19+IgD+CD27- naive B cells was strongly associated with antibody levels ({rho}=0.761, P<0.001) and the only independent predictor for achieving antibody levels comparable to healthy controls (OR 1.07 per 10-{micro}l increase, 95%CI 1.02-1.12, P=0.009). Receiver operating characteristic analysis identified a cut-off at [≥]61 naive B cells per {micro}l to discriminate between patients with and without an optimal antibody response. Consequently, measuring naive B cells in immunocompromised hematologic patients could be useful in predicting their humoral vaccination response.

category: rheumatology


title: CD19+IgD+CD27- naive B Cells as predictors of humoral response to COVID 19 mRNA vaccination in immunocompromised patients

category: hematology


title: Estimating the effects of accelerated partner therapy (APT) on reinfection of index cases with chlamydia: a mathematical modelling study

abstract:
ObjectivesThe expected effects of accelerated partner therapy (APT) on the reinfection of treated index cases by untreated partners with Chlamydia trachomatis (chlamydia) remain unclear. We analyzed data from the LUSTRUM cluster cross-over randomised controlled trial (RCT) using a mathematical model and quantified the effects of offering APT on the probability of successful partner treatment.

MethodsWe extended a previously developed mathematical model to compute the probability of chlamydia reinfection of index cases by their untreated partners with chlamydia. We fitted the model to data from the RCT and estimated the probability of successful treatment of the partner of index cases using a Bayesian framework.

ResultsWe estimated the median probability of reinfection with chlamydia at 16.3% (50% credible interval, CrI: 12.7-20.0%) without partner treatment and 2.3% (50% CrI: 1.7-3.6%) when partner treatment is 100% successful. The observed rates of reinfection in the RCT were 6.7% (95% confidence interval, CI: 5.6-8.0%) during the control period (standard partner notification (PN)) and 4.8% (95% CI: 3.7-5.9%) during the intervention period where APT was offered in addition to standard PN. These rates correspond to a median probability of successful partner treatment of 63% (50% CrI: 47-76%) during the control period and 78% (50% CrI: 65-87%) during the intervention period.

ConclusionsOur study suggests that the observed reduction in reinfection with chlamydia when offering APT is consistent with a higher probability of successful partner treatment.

category: sexual and reproductive health


title: Functional connectome mediates the association between sleep disturbance and mental health in preadolescence

abstract:
BackgroundSleep disturbance is known to be associated with various mental disorders and typically precedes the onset of mental disorders in youth. Given the increasingly acknowledged bi-directional influence between sleep disturbance and mental disorders, we addressed the possibility of a shared neural mechanism that underlies sleep disturbance and mental disorders in preadolescents.

MethodsWe analyzed a dataset of 9350 9-10 year-old children, among whom 8845 had one-year follow-up data, from the Adolescent Brain and Cognitive Development (ABCD) Study. Linear mixed-effects models, mediation analysis, and longitudinal mediation analysis were used.

ResultsOut of 338 unique connectivities, the effect of total sleep disturbance (TSP, from Sleep Disturbance Scale) and total problems (TP, from Child Behavior Checklist) converged in the default mode network (DMN) and its anti-correlated dorsal attention network (DAN). Within- and between-network connectivities (DMN-DAN, DMN-DMN, DAN-DAN) mediated the relationship between baseline TSD and TP at one-year follow-up and the relationship between baseline TP and TSD at one-year follow-up. Moreover, the identified network connectivities (DMN-DAN, DAN-DAN) also correlated with the total cognitive composite score from the NIH toolbox.

ConclusionsThe pathway model in which sleep disturbance and mental problems affect each other through two anticorrelated brain networks (DMN and DAN) suggests a common neural mechanism between sleep disturbance and mental disorders. A less segregated DMN and DAN is also associated with negative outcomes on mental well-being, sleep disturbance, and cognition. These findings have important implications for the design of prevention and neurofeedback intervention for mental disorders and sleep problems.

HighlightsO_LIThe impact of sleep disturbance and mental disorders on functional connectivity converged in default mode and dorsal attention networks.
C_LIO_LIThe relationship between sleep disturbance and mental disorders was mediated via a shared brain network mechanism
C_LIO_LISleep disturbance and mental disorders at baseline can each predict the other one year later through the identified network connectivities
C_LIO_LIA less segregated default mode and dorsal attention networks was correlated with poorer cognitive performance.
C_LI

category: neurology


title: Genetic variants link lower segregation of brain networks to higher blood pressure and worse cognition within the general aging population

abstract: The functional architecture of the brain is composed of distinct networks, where higher system segregation, i.e. greater differentiation of such functional networks, is associated with better cognitive performance. Aging and many neurological diseases have been associated with reduced system segregation and thus cognitive impairment. The genetic basis and risk factors of system segregation are largely unknown. Here, we present the first genome-wide association study of fMRI-assessed system segregation in 16,635 UK Biobank participants, identifying nine independent genomic loci. The 66 implicated genes were significantly downregulated in brain tissue and upregulated in vascular tissue. Of major vascular risk factors (Lifes Simple 7), blood pressure showed a robust genetic correlation with system segregation. Observational and Mendelian randomization analyses confirmed a unfavourable effect of higher blood pressure on system segregation and of lower system segregation on cognition. Replication analyses in 2,414 Rotterdam Study participants supported these conclusions.


title: Heterozygous PRKN mutations are common but do not increase the risk of Parkinson's disease

abstract: PRKN mutations are the most common recessive cause of Parkinsons disease (PD) and are a promising target for gene and cell replacement therapies. Identification of biallelic PRKN patients (PRKN-PD) at the population scale, however, remains a challenge, as roughly half are copy number variants (CNVs) and many single nucleotide polymorphisms (SNPs) are of unclear significance. Additionally, the true prevalence and disease risk associated with heterozygous PRKN mutations is unclear, as a comprehensive assessment of PRKN SNPs and CNVs has not been performed at a population scale. To address these challenges, we evaluated PRKN mutations in 2 cohorts analyzed with both a genotyping array and exome or genome sequencing: the NIH PD cohort, a deeply phenotyped cohort of PD patients, and the UK Biobank, a population scale cohort with nearly half a million participants. Genotyping array identified the majority of PRKN mutations and at least 1 mutation in most biallelic PRKN mutation carriers in both cohorts. Additionally, in the NIH-PD cohort, functional assays of patient fibroblasts resolved variants of unclear significance in biallelic carriers and ruled out cryptic loss of function variants in monoallelic carriers. In the UK Biobank, we identified 2,692 PRKN CNVs from genotyping array data from nearly half a million participants (the largest collection to date). Deletions or duplications involving exons 2 accounted for roughly half of all CNVs and the vast majority (88%) involved exons 2, 3, or 4. Combining estimates from whole exome sequencing (from [~]200,000 participants) and genotyping array data, we found a pathogenic PRKN mutation in 1.8% of participants and 2 mutations in [~]1/7,800 participants. Those with 1 PRKN pathogenic variant were as likely as non-carriers to have PD (OR = 0.91, CI= 0.58 - 1.38, p-value = 0.76) or a parent with PD (OR = 1.12, CI = 0.94 - 1.31, p-value = 0.19). Together our results demonstrate that heterozygous pathogenic PRKN mutations are common in the population but do not increase the risk of PD. Additionally, they suggest a cost-effective framework to screen for biallelic PRKN patients at the population scale for targeted studies.


title: Widespread cell stress and mitochondrial dysfunction in early Alzheimers Disease

abstract: Cell stress and impaired oxidative phosphorylation are central to mechanisms of synaptic loss and neurodegeneration in the cellular pathology of Alzheimers disease (AD). We quantified the in vivo density of the endoplasmic reticulum stress marker, the sigma 1 receptor (S1R) using [11C]SA4503 PET, as well as that of mitochondrial complex I (MC1) with [18F]BCPP-EF and the pre-synaptic vesicular protein SV2A with [11C]UCB-J in 12 patients with early AD and in 16 cognitively normal controls. We integrated these molecular measures with assessments of regional brain volumes and brain perfusion (CBF) measured with MRI arterial spin labelling. 8 AD patients were followed longitudinally to estimate rates of change with disease progression over 12-18 months. The AD patients showed widespread increases in S1R ([≤] 27%) and regional decreases in MC1 ([≥] -28%), SV2A ([≥] -25%), brain volume ([≥] -23%), and CBF ([≥] -26%). [18F]BCPP-EF PET MC1 density ([≥] -12%) and brain volumes ([≥] -5%) were further reduced at follow up in brain regions consistent with the differences between AD patients and controls at baseline. Exploratory analyses showing associations of MC1, SV2A and S1R density with cognitive changes at baseline and longitudinally with AD, but not in controls, suggested a loss of metabolic functional reserve with disease. Our study thus provides novel in vivo evidence for widespread cellular stress and bioenergetic abnormalities in early AD and that they may be clinically meaningful.


title: Agent-based modeling of DFNB1A prevalence with regard to intensity of selection pressure in isolated human population: will cochlear implantation increase the cases of hereditary deafness?

abstract: It was evidenced, that the increase in the prevalence of autosomal recessive deafness 1A (DFNB1A) in populations of European descent was promoted by assortative marriages among deaf people. Assortative marriages become possible with a widespread introduction of sign language resulting in increased the genetic fitness of deaf individuals, thus relaxing selection against deafness. Currently, cochlear implantation is becoming a common method of rehabilitation for deaf patients, restoring their hearing ability and promoting the acquirement of spoken language. Whether the mass cochlear implantation could affect the spread of hereditary deafness is unknown. We have developed an agent-based computer model for analysis of the spread of DFNB1A. Using the model, we tested impact of different intensity of selection pressure on an isolated human population for 400 years. The modeling of the "purifying" selection pressure on deafness resulted in decrease of the proportion of deaf individuals and the pathogenic allele frequency. The modeling of relaxed selection resulted in increase of the proportion of deaf individuals and the decrease of the pathogenic allele frequency. The results of neutral selection pressure modeling showed no significant changes in both the proportion of deaf individuals and the pathogenic allele frequency after 400 years. Thus, initially low genetic fitness of deaf people can be significantly increased in the presence of assortative mating by deafness, resulting in a higher prevalence of DFNB1A. Contrary, frequency of pathogenic allele and the incidence of hereditary hearing loss will not increase in a population where all deaf individuals undergo cochlear implantation.

category: genetic and genomic medicine


title: Development and use analysis of 'gestioemocional.cat', a web app for promoting emotional self-care and access to professional mental health resources during the covid-19 pandemic

abstract:
BackgroundQuarantines and nationwide lockdowns dictated for containing the spread of the COVID-19 pandemic may lead to distress and increase the frequency of anxiety and depression symptoms among the general population. During the national lockdown of the first wave of the COVID-19 outbreak in Spain, we developed and launched a Web App (Gestioemocional.cat) to promote emotional self-care in the general population and facilitate contact with healthcare professionals.

MethodsGestioemocional.cat targeted all individuals aged 18 years or more and was designed by adapting the contents of a mobile App for adjuvant treatment of post-traumatic stress disorder (i.e., the PTSD Coach App) to the general population and the pandemic/lockdown scenario. We retrospectively assessed the utilization pattern of the Web App using data systematically retrieved from Google Analytics. Data were grouped into three time periods, defined using a join point analysis of COVID-19 incidence in our area: first wave, between-wave period, and second wave.

ResultsThe resulting Web App, maintains the navigation structure of the PTSD Coach App, with three main modules: tools for emotional self-care, a self-assessment test, and professional resources for on-demand contact. The self-assessment test combines the Patient Health Questionnaire-2 (PHQ-2) and the 7-item Generalized Anxiety Disorder Scale (GAD-7) and offers professional contact in the advent of a high level of depression and anxiety; contact is prioritized according to a screening questionnaire administered at the time of obtaining individual consent to be contacted. The tools for emotional self-care can be accessed either on-demand or symptom-driven. The utilization analysis showed a high number of weekly accesses during the first wave. In this period, press releases regarding critical events of the pandemic progression and government decisions on containment measures were followed by a utilization peak, irrespective of the sense (i.e., positive or negative) of the information. Positive information pieces (e.g., relaxation of containment measures due to a reduction of COVID-19 cases) resulted in a sharp increase in utilization immediately after information release, followed by a successive decline in utilization. The second wave was characterized by a lower and less responsive utilization of the Web App.

ConclusionsmHealth tools may help the general population coping with stressful conditions associated with the pandemic scenario. Future studies shall investigate the effectiveness of these tools among the general population[-]including individuals without diagnosed mental illnesses[-]and strategies to reach as many people as possible.


title: Hepatitis B and D: a forecast on actions needed to reduce incidence and achieve elimination

abstract:
BackgroundViral hepatitis negatively affects the health of millions, with the worst health outcomes associated with the hepatitis D virus (HDV). Fortunately, HDV is rare and requires prior infection with the hepatitis B virus (HBV) before it can establish infection and transmit. As such, public health officials have opted to indirectly control HDV by reducing HBV incidence, primarily through hepatitis B vaccination, which has dramatically reduced HBV incidence since its rollout in the 1980s. However, investigations into the consequences of hepatitis B vaccination on both the control and evolution of HDV remain limited.

MethodsWe developed a mathematical model of HBV and HDV transmission to investigate the effects of hepatitis B vaccination on both HBV and HDV. We calibrated our model to the HBV and HDV transmission scenarios occurring in Sub-Saharan Africa, and estimate HBV vaccination thresholds that cause HBV and HDV elimination, inhibit the spread of virulent HDV strains, and achieve the targets set by public health authorities for reducing all viral hepatitis incidence by 90%.

ResultsOur findings illustrate hepatitis B vaccination rates above 0.0096 year-1 and 0.018 year-1 will likely achieve HDV and HBV elimination, respectively. Furthermore, in the majority of transmission settings, scaling-up vaccination rates to at least 0.009 year-1 or 0.02136 year-1 will achieve the 90% reduction in hepatitis D and B, respectively, called for by health authorities.

ConclusionOur results suggest a scale-up of hepatitis B vaccination is required to achieve the targets set by public health officials for reducing all viral hepatitis by 90%. Furthermore, the scale-up required to achieve such targets would bring HBV and HDV to the brink of the vaccination threshold required for their elimination. Thus, with sufficient investments to scale up global hepatitis vaccination, prevention, testing, and treatment services, the eradication of both HBV and HDV are likely feasible endeavors, especially once the 90% reduction goal is reached.

category: health policy


title: Field performance of NowCheck Rapid antigen test for SARS-CoV-2 in Kisumu County, western Kenya

abstract:
BackgroundLow- and middle-income countries (LMICs) are increasingly adopting low-cost Coronavirus disease 2019 (COVID-19) rapid antigen tests to meet the high demand for SARS-CoV-2 testing. Whilst testing using real-time polymerase chain reaction (RT-PCR) is the current gold standard, its widespread use in LMICs is limited by high costs, turnaround times and is not readily available in most places. COVID-19 antigen tests (Ag-RDT) provide a suitable alternative due to their low cost, rapid turnaround time and easy to set up and use. This study aimed to assess the field performance of the NowCheck COVID-19 antigen kit (Ag-RDT) as a point of care test (POCT) in select healthcare facilities in western Kenya.

MethodsWe conducted a prospective multi-facility field evaluation study of the NowCheck COVID-19 rapid antigen test (Ag-RDT) compared to SARS-CoV-2 RT-PCR (RT-PCR). After obtaining informed consent, trained laboratory technicians collected two pairs of oropharyngeal and nasopharyngeal swabs, both antigen and RT-PCR testing, first for Ag-RDT and next for RT-PCR. We performed Ag-RDTs on-site and shared the results with both the study participants and their healthcare providers within 15-30 minutes. We carried out all RT-PCR tests in a central referral laboratory. The turnaround time for RT-PCR results was typically 24-48 hours. We captured the results of both methods using an electronic digital application.

FindingsBetween December 2020 and March 2021, we enrolled 997 participants who met the Kenyan Ministry of Health COVID-19 case definition. The median age of study participants was 39 years (range one to 80 years), with 54% male. Ag-RDT had a sensitivity of 84.5% (76.0-90.8) and a specificity of 94.4% (95% CI: 92.7-95.8) with an accuracy of 94.2% (92.5-95.6) when a cycle threshold value (Ct value) of [≤]35 was used. The highest sensitivity of 87.7% (77.2-94.5) was observed in samples with Ct values [≤] 30 and the highest specificity of 97.5% (96.2-98.5) at Ct value of <40.

InterpretationThe NowCheck COVID-19 Ag-RDT showed good performance in field evaluation in multiple healthcare facilities in a developing country. The sensitivity of the kit exceeded the minimum recommended cut-off of 80% as recommended by WHO1. The high specificity of this kit at 94.4% at Ct values [≤]33 and 97.5% at Ct values <40 matched that of real-time PCR, making it a good rule-out test for symptomatic patients with COVID-19-like symptoms. The faster turnaround time to results, lower cost, simple analytical steps requiring no equipment or infrastructure makes antigen testing an attractive field-screening method to meet the high demand for COVID-19 testing.

FundingAchmea Foundation, Pfizer Foundation, Dimagi and the Netherlands Ministry of Foreign Affairs supported this project. The funding sources did not have any role in study design, data collection, analysis, interpretation, summarizing the data or decision to submit the manuscript for publication.


title: Harmony COVID-19: a ready-to-use kit, low-cost detector, and smartphone app for point-of-care SARS-CoV-2 RNA detection

abstract:
RNA amplification tests allow sensitive detection of SARS-CoV-2 infection, but their complexity and cost are prohibitive for expanding COVID-19 testing. We developed "Harmony COVID-19", a point-of-care test using inexpensive consumables, ready-to-use reagents, and a simple device that processes up to 4 samples simultaneously. Our lyophilized reverse-transcription, loop-mediated isothermal amplification (RT-LAMP) can detect as little as 15 SARS-CoV-2 RNA copies per reaction, and it can report as early as 17 min for samples with high viral load (2 x 105 RNA copies per reaction). Analysis of RNA extracted from clinical nasal specimens (n = 101) showed 95% concordance with RT-PCR, including 100% specificity in specimens positive for other viruses and bacteria. Analysis of contrived samples in the nasal matrix showed detection of 92% or 100% in samples with [≥]20 or [≥]100 particles per reaction, respectively. Usability testing showed 95% accuracy by healthcare workers operating the test for the first time.

ONE SENTENCE SUMMARYHarmony COVID-19: point-of-care SARS-CoV-2 RNA detection


title: Infectious SARS-CoV-2 in Exhaled Aerosols and Efficacy of Masks During Early Mild Infection

abstract:
BackgroundSARS-CoV-2 epidemiology implicates airborne transmission; aerosol infectiousness and impacts of masks and variants on aerosol shedding are not well understood.

MethodsWe recruited COVID-19 cases to give blood, saliva, mid-turbinate and fomite (phone) swabs, and 30-minute breath samples while vocalizing into a Gesundheit-II, with and without masks at up to two visits two days apart. We quantified and sequenced viral RNA, cultured virus, and assayed sera for anti-spike and anti-receptor binding domain antibodies.

ResultsWe enrolled 49 seronegative cases (mean days post onset 3.8 {+/-}2.1), May 2020 through April 2021. We detected SARS-CoV-2 RNA in 45% of fine ([≤]5 {micro}m), 31% of coarse (>5 {micro}m) aerosols, and 65% of fomite samples overall and in all samples from four alpha-variant cases. Masks reduced viral RNA by 48% (95% confidence interval [CI], 3 to 72%) in fine and by 77% (95% CI, 51 to 89%) in coarse aerosols; cloth and surgical masks were not significantly different. The alpha variant was associated with a 43-fold (95% CI, 6.6 to 280-fold) increase in fine aerosol viral RNA, compared with earlier viruses, that remained a significant 18-fold (95% CI, 3.4 to 92-fold) increase adjusting for viral RNA in saliva, swabs, and other potential confounders. Two fine aerosol samples, collected while participants wore masks, were culture-positive.

ConclusionSARS-CoV-2 is evolving toward more efficient aerosol generation and loose-fitting masks provide significant but only modest source control. Therefore, until vaccination rates are very high, continued layered controls and tight-fitting masks and respirators will be necessary.

Key PointsO_LICases exhale infectious viral aerosols
C_LIO_LISARS-CoV-2 evolution favors more efficient aerosol generation.
C_LIO_LILoose-fitting masks moderately reduce viral RNA aerosol.
C_LIO_LIVentilation, filtration, UV air sanitation, and tight-fitting masks are needed to protect vulnerable people in public-facing jobs and indoor spaces.
C_LI


title: The role of incentives in deciding to receive the available COVID-19 vaccine

abstract:
ObjectiveTo assess the publics intention to get vaccinated immediately after COVID-19 vaccine became available, and to determine the role of incentives beyond socio-demographic, health-related and behavioral factors, in predicting this intention.

MethodsAn online survey was conducted among adults in Israel (n=461), immediately after the first COVID-19 vaccine became available (22/12/2020 to 10/1/2021). Two regressions were performed to investigate determinants of intention and sense of urgency to receive the available COVID-19 vaccine.

ResultsAlthough many adults intended to receive available COVID-19 vaccine, only 65% intended to immediately receive the vaccine; 16% preferred to wait 3 months and 18% preferred to wait a year. The sense of urgency to get vaccinated differed by age, periphery-level, perceived barriers, cues to action and availability. Monetary rewards or the "green pass" incentives didnt increase the probability of getting vaccination immediately.

ConclusionsProviding data on the role of incentives in increasing the intention to immediately receive the available COVID-19 vaccine is important for health policy makers and healthcare providers. Our findings underscore the importance of COVID-19 vaccine accessibility.

Practice ImplicationsHealth policy makers should consider allocating funds for making the vaccine accessible and encourage methods of persuasion, instead of investing funds in monetary incentives.


title: Clinical course impacts early kinetics and long-term magnitude and amplitude of SARS-CoV-2 neutralizing antibodies beyond one year after infection

abstract:
BackgroundUnderstanding the determinants of long-term immune responses to SARS-CoV-2 and the concurrent impact of vaccination and emerging variants of concern will guide optimal strategies to achieve global protection against the COVID-19 pandemic.

MethodsA prospective cohort of 332 COVID-19 patients was followed beyond one year. Plasma neutralizing activity was evaluated using HIV-based reporter pseudoviruses expressing different SARS-CoV-2 spikes and was longitudinally analyzed using mixed-effects models.

FindingsLong-term neutralizing activity was stable beyond one year after infection in mild/asymptomatic and hospitalized participants. However, longitudinal models suggest that hospitalized individuals generate both short- and long-lived memory B cells, while outpatient responses were dominated by long-lived B cells. In both groups, vaccination boosted responses to natural infection, although viral variants, mainly B.1.351, reduced the efficacy of neutralization. Importantly, despite showing higher neutralization titers, hospitalized patients showed lower cross-neutralization of B.1.351 variant compared to outpatients. Multivariate analysis identified severity of primary infection as the factor that independently determines both the magnitude and the inferior cross-neutralization activity of long-term neutralizing responses.

ConclusionsNeutralizing response induced by SARS-CoV-2 is heterogeneous in magnitude but stable beyond one year after infection. Vaccination boosts these long-lasting natural neutralizing responses, counteracting the significant resistance to neutralization of new viral variants. Severity of primary infection determines higher magnitude but poorer quality of long-term neutralizing responses.


title: Molecular and serological investigation of the 2021 COVID-19 case surge in Mongolian vaccinees

abstract: A surge in Covid-19 cases in Mongolia in March 2021 resulted in a government-mandated shutdown. This shutdown was relaxed in May 2021 as case numbers decreased and nationwide vaccination rates using Sinopharm, Covishield/AstraZeneca, Sputnik V, and Pfizer/BioNTech vaccines exceeded 50% of the population. Case rates increased again in early June 2021 in both vaccinated and non-vaccinated individuals. To determine whether the surge was due to the emergence of Delta or another variant, or vaccine failure, a rapid, opportunistic investigation was conducted that comprised virus sequence analysis of nasal swab samples from breakthrough cases and antibody assays of plasma from healthy vaccinees. More than 90% of breakthrough infections during the second case surge were due to the Alpha variant. Spike protein ELISA and SARS-CoV-2 neutralization assays data revealed large differences in plasma titers of antibodies to SARS-CoV-2, with mRNA vaccines eliciting higher titers than adenovirus-vectored or killed virus vaccines.


title: Serological detection of SARS-CoV-2 IgG using a commercially available enzyme immunoassays on dried blood spots collected from patients

abstract: Serological testing for SARS-CoV-2 antibodies provides important research and diagnostic information relating to COVID-19 immune response and surveillance. A major challenge when addressing protection post-infection or vaccination is the difficulty of specimen collection from infants and children. Dried blood spots (DBS) collected by finger prick or heel prick are a minimally invasive sample collection alternative previously used to detect antibodies to other viruses. In this study we evaluated DBS for the detection of SARS-CoV-2 antibodies on three commercially available enzyme (EIA) and chemiluminescent (CLIA) immunoassays by analysing paired DBS and serum samples collected from 54 subjects. We demonstrate that testing of DBS samples was highly sensitive and specific, and quantitative results strongly correlated with those of paired serum. These results suggest that DBS derived blood is a viable alternative to plasma or serum for use in EIAs and CLIAs, and has particular utility as a minimally invasive collection tool for COVID-19 serological testing of infants and children.


title: Serological detection of SARS-CoV-2 IgG using commercially available immunoassays on dried blood spots collected from patients


title: SARS-CoV-2 variants: levels of neutralisation required for protective immunity

abstract: A number of SARS-CoV-2 variants of concern (VOC) have been identified that partially escape serum neutralisation activity elicited by current vaccines. Recent studies have also shown that vaccines demonstrate reduced protection against symptomatic infection with SARS-CoV-2 variants. Here we integrate published data on in vitro neutralisation and clinical protection to understand and predict vaccine efficacy against existing SARS-CoV-2 variants. We find that neutralising activity against the ancestral SARS-CoV-2 is highly predictive of neutralisation of the VOC, with all vaccines showing a similar drop in neutralisation to the variants. Neutralisation levels remain strongly correlated with protection from infection with SARS-CoV-2 VOC (r=0.81, p=0.0005). We apply an existing model relating in vitro neutralisation to protection (parameterised on data from ancestral virus infection) and find this remains predictive of vaccine efficacy against VOC once drops in neutralisation to the VOC are taken into account. Modelling of predicted vaccine efficacy against variants over time suggests that protection against symptomatic infection may drop below 50% within the first year after vaccination for some current vaccines. Boosting of previously infected individuals with existing vaccines (which target ancestral virus) has been shown to significantly increase neutralising antibodies. Our modelling suggests that booster vaccination should enable high levels of immunity that prevent severe infection outcomes with the current SARS-CoV-2 VOC, at least in the medium term.


title: CARDIOVASCULAR DISEASES ASSOCIATED WITH INFLUENZA INFECTION: SYSTEMATIC REVIEW AND META-ANALYSIS

abstract:
BackgroundCardiovascular diseases represent important diagnoses that can become fatal if an early and adequate management is not carried out. Since 1930, a possible relationship between these events and influenza virus infection has been proposed.

ObjectivesTo determine the association between cardiovascular diseases and previous infection by influenza virus.

Materials and methodsWe propose to do a systematic review and meta-analysis according to PRISMA. In order to do so, we will perform an electronic search in the databases of EMBASE, PubMed, Global Index Medicus, Google Scholar and Cochrane Library. Articles will first be selected according to their respective titles and abstracts; and subsequently, the full text of each article will be evaluated. Both phases will be executed by 4 authors. The extracted data will include study details, study methodology and results. The quality of the studies will be verified using standardized tools according to the study design and we will evaluate possible biases. In addition, a meta-analysis of the association measures will be performed using Cochranes Software Review Manager 5.4.1 and we will use the GRADE tool to assess the certainty of the results obtained from the analyzed studies.

ResultsWe will publish the results of this systematic review and meta-analysis in a peer-reviewed journal.

ConclusionsThis systematic review will provide more up-to-date evidence compared to previous work on the association between laboratory-confirmed influenza and cardiovascular diseases.


title: CARDIOVASCULAR DISEASES ASSOCIATED WITH INFLUENZA INFECTION: PROTOCOL FOR A SYSTEMATIC REVIEW AND META-ANALYSIS


title: THE EFFECT OF BARICITANIB USAGE ON THE CLINICAL AND BIOCHEMICAL PROFILES OF COVID-19 PATIENTS- A RETROSPECTIVE OBSERVATIONAL STUDY

abstract:
IntroductionCoronaviruses typically cause influenza like illness which progresses to ARDS along with other systemic manifestations. India is experiencing its second wave with a huge surge in the number of cases exponentially causing huge impact on health care infrastructure and the demand supply chain. As a result several new modalities have been used, one of which is the use of remdesivir and baricitinib . Hence this study is aimed at finding out the clinical and biochemical profile of the patients who have received the combination

Materials and MethodsAll the patients who have received the combination meeting the inclusion and exclusion criteria have been included in the study. A total of 31 participants were included and their records were retrospectively analyzed.

ResultsThere was a significant reduction in the oxygen requirement, CRP and IL-6 levels with p values<0.05. However, in the non-survivors group, there was no statistically significant reduction. Serial monitoring of NLR ratio showed increase towards the fifth day, especially in the non-survivor group it was as high as 41.24. The mortality rate was found to be 10% and the cause being secondary sepsis in all of them.

ConclusionThe ACTT-2 trail has proved the efficacy of the use of the remdesivir and baricitinib combination with mortality benefit. In our study we found similar results which was well co-related with clinical and biochemical parameters like CRP and IL-6 especially in people with co-morbidites.


title: THE EFFECT OF BARICITINIB USAGE ON THE CLINICAL AND BIOCHEMICAL PROFILES OF COVID-19 PATIENTS- A RETROSPECTIVE OBSERVATIONAL STUDY


title: COVID-19 in Connecticut institutions of higher education during the 2020-2021 academic year

abstract:
BackgroundDuring the 2020-2021 academic year, many institutions of higher education reopened to residential students while pursuing strategies to mitigate the risk of SARS-CoV-2 transmission on campus. Reopening guidance emphasized PCR or antigen testing for residential students and social distancing measures to reduce the frequency of close interpersonal contact. Connecticut colleges and universities employed a variety of approaches to reopening campuses to residential students.

MethodsWe used data on testing, cases, and social contact in 18 residential college and university campuses in Connecticut to characterize institutional reopening strategies and COVID-19 outcomes. We compared institutions fall 2020 COVID-19 plans, submitted to the Connecticut Department of Public Health, and analyzed contact rates and COVID-19 outcomes throughout the academic year.

ResultsIn census block groups containing residence halls, fall student move-in resulted in a 475% (95% CI 373%-606%) increase in average contact, and spring move-in resulted in a 561% (441%-713%) increase in average contact. The relationship between test frequency and case rate per residential student was complex: institutions that tested students infrequently detected few cases but failed to blunt transmission, while institutions that tested students more frequently detected more cases and prevented further spread. In fall 2020, each additional test per student per week was associated with a reduction of 0.0014 cases per student per week (95% CI: -0.0028, -0.000012). Residential student case rates were associated with higher case rates in the town where the school was located, but it is not possible to determine whether on-campus infections were transmitted to the broader community or vice versa.

ConclusionsCampus outbreaks among residential students might be avoided or mitigated by frequent testing, social distancing, and mandatory vaccination. Vaccination rates among residential students and surrounding communities may determine the necessary scale of residential testing programs and social distancing measures during the 2021-2022 academic year.


title: Testing Denmark: A Danish nationwide surveillance study of COVID-19

abstract:
BackgroundNational data on the spread of SARS-CoV-2 infection and knowledge on associated risk factors are important for understanding the course of the pandemic. "Testing Denmark" is a national large-scale epidemiological surveillance study of SARS-CoV-2 in the Danish population.

MethodsBetween September and October 2020, approximately 1.3 million of 5.8 million Danish citizens (age > 15 years) were randomly invited to fill in an electronic questionnaire covering COVID-19 exposures and symptoms. The prevalence of SARS-CoV-2 antibodies was determined by Point-of Care rapid Test (POCT) distributed to participants home addresses.

FindingsIn total 318,552 participants (24.5% invitees) completed the questionnaire and provided the result of the POCT. Of these, 2,519 (0.79%) were seropositive (median age 55 years) and women were more often seropositive than men, interquartile range (IQR) 42-64, 40.2% males. Of participants with a prior positive Polymerase Chain Reaction (PCR) test (n=1,828), 29.1% were seropositive in the POCT. Seropositivity increased with age irrespective of sex. Elderly participants (>61 years) reported less symptoms and had less frequently been tested for SARS-CoV-2 compared to younger participants. Seropositivity was associated with physical contact with SARS-CoV-2 infected individuals (Risk ratio (RR) 7.43, 95% CI: 6.57-8.41) and in particular household members (RR 17.70, 95% CI: 15.60-20.10). Home care workers had a higher risk of seropositivity (RR 2.09 (95% CI: 1.58-2.78) as compared to office workers. Geographic population density was not associated to seropositivity. A high degree of compliance with national preventive recommendations was reported (e.g., > 80% use of face masks), but no difference was found between seropositive and seronegative participants.

InterpretationThis study provides insight into the immunity of the Danish population seven to eight months after the first COVID-19 case in Denmark. The seroprevalence was lower than expected probably due to a low sensitivity of the POCT used or due to challenges relating to the reading of test results. Occupation or exposure in local communities were major routes of infection. As elderly participants were more often seropositive despite fewer symptoms and less PCR tests performed, more emphasis should be placed on testing this age group.


title: Transmission dynamics and epidemiological characteristics of Delta variant infections in China

abstract:
BackgroundThe Delta variant of SARS-CoV-2 has become predominant globally. We evaluated the transmission dynamics and epidemiological characteristics of the Delta variant in an outbreak in southern China.

MethodsData on confirmed cases and their close contacts were retrospectively collected from the outbreak that occurred in Guangdong, China in May-June 2021. Key epidemiological parameters, temporal trend of viral loads and secondary attack rates were estimated and compared between the Delta variant and the wild-type SARS-CoV-2 virus. We also evaluated the association of vaccination with viral load and transmission.

ResultsWe identified 167 patients infected with the Delta variant in the Guangdong outbreak. The mean estimates of the latent period and the incubation period were 4.0 days and 5.8 days, respectively. A relatively higher viral load was observed in Delta cases than in wild-type infections. The secondary attack rate among close contacts of Delta cases was 1.4%, and 73.9% (95% confidence interval: 67.2%, 81.3%) of the transmissions occurred before onset. Index cases without vaccination (OR: 2.84, 95% confidence interval: 1.19, 8.45) or with one dose of vaccination (OR: 6.02, 95% confidence interval: 2.45, 18.16) were more likely to transmit infection to their contacts than those who had received 2 doses of vaccination.

DiscussionPatients infected with the Delta variant had more rapid symptom onset. The shorter and time-varying serial interval should be accounted in estimation of reproductive numbers. The higher viral load and higher risk of pre-symptomatic transmission indicated the challenges in control of infections with the Delta variant.


title: Mathematical modeling of vaccination rollout and NPIs lifting on COVID-19 transmission with VOC: a case study in Toronto, Canada

abstract:
BackgroundSince December 2020, public health agencies have implemented a variety of vaccination strategies to curb the spread of SARS-CoV-2, along with pre-existing Nonpharmaceutical Interventions (NPIs). Initial strategy focused on vaccinating the elderly to prevent hospitalizations and deaths. With vaccines becoming available to the broader population, we aimed to determine the optimal strategy to enable the safe lifting of NPIs while avoiding virus resurgence.

MethodsWe developed a compartmental deterministic SEIR model to simulate the lifting of NPIs under different vaccination rollout scenarios. Using case and vaccination data from Toronto, Canada between December 28, 2020 and May 19, 2021, we estimated transmission throughout past stages of NPI escalation/relaxation to compare the impact of lifting NPIs on different dates on cases, hospitalizations, and deaths, given varying degrees of vaccine coverages by 20-year age groups, accounting for waning immunity.

ResultsWe found that, once coverage among the elderly is high enough (80% with at least one dose), the main age groups to target are 20-39 and 40-59 years, whereby first-dose coverage of at least 70% by mid-June 2021 is needed to minimize the possibility of resurgence if NPIs are to be lifted in the summer. While a resurgence was observed for every scenario of NPI lifting, we also found that under an optimistic vaccination coverage (70% by mid-June, postponing reopening from August 2021 to September 2021can reduce case counts and severe outcomes by roughly 80% by December 31, 2021.

ConclusionsOur results suggest that focusing the vaccination strategy on the working-age population can curb the spread of SARS-CoV-2. However, even with high vaccination coverage in adults, lifting NPIs to pre-pandemic levels is not advisable since a resurgence is expected to occur, especially with earlier reopening.


title: Epidemiological Study of COVID-19 Infections: Case of Ga East Municipal Hospital Treatment Centre - Kwabenya-Ghana.

abstract:
BackgroundThe COVID-19 pandemic still poses a considerable threat to global health, resulting in an unprecedented demand for regular research to continuously identify and update its risk profiles to ensure relevant interventions.

ObjectivesThis study aimed to examine the epidemiological characteristics of the COVID-19 outbreak in Ghana and identify risk factors for severe COVID-19 disease.

MethodThis was a cross-sectional study involving the data of patients with COVID-19 clinically managed at the Ga-East Municipal Hospital, the main COVID-19 treatment centre in Ghana, from 21st March to 21st June 2020. The data were retrieved from the electronic medical records and folders of the patients. It included sociodemographic characteristics, COVID-19 disease severity, and treatment outcomes. Binomial logistic regression was used to identify risk factors of severe COVID-19 illness.

ResultAmong the 360 COVID-19 cases in this study, 55.3% were males, and 44.7% were females. Their mean age was 39.9{+/-}16.7years. Most of them were Ghanaians (92.8%) and employed (72.5%). The majority (93%) presented with mild disease, and hypertension (19.2%) was the most common comorbidity. The average length of hospital admission was 10.6{+/-}6.4day. Many of the cases recovered (98.6%), resulting in a case fatality of 1.4%. Finally, the logistic regression showed that increasing age (OR=1.12, p= 0.002) and diabetes mellitus (OR=19.85, p=0.007) are risk factors for severe COVID-19 disease.

ConclusionFindings from the study confirmed that increasing age and diabetes mellitus are risk factors for severe COVID-19 disease. Thus, Ghana could prioritise these identified populations when implementing interventions to reduce the COVID-19 disease burden.

Strength and limitations of this studyO_LIThis study is one of the few studies exploring the risk factors for severe COVID-19 disease in Ghana; thus, it presents novel context-specific findings that could inform COVID-19 case management in Ghana.
C_LIO_LIThe study was limited in drawing a causal association between the explanatory and outcome variables due to the cross-sectional design.
C_LIO_LIThe study included only one COVID-19 treatment centre. Consequently, the findings may not be generalizable to the entire COVID-19 population in Ghana, even though the included centre is the main COVID-19 treatment centre.
C_LI


title: Changing Dynamics of COVID-19 in the U.S. with the Emergence of the Delta Variant: Projections of the COVID-19 Simulator

abstract:
With the recent emergence of the B.1.617.2 (Delta) variant of SARS-CoV-2 in the U.S., many states are seeing rising cases and hospitalizations after a period of steady decline. As We used the COVID-19 Simulator, an interactive online tool that utilizes a validated mathematical model, to simulate the trajectory of COVID-19 at the state level in the U.S. COVID-19 Simulators forecasts are updated weekly and included in the Centers for Disease Control and Prevention (CDC) ensemble model. We employed our model to analyze scenarios where the Delta variant becomes dominant in every state.

The combination of high transmissibility of the Delta variant, low vaccination coverage in several regions, and more relaxed attitude towards social distancing is expected to result in as surge in COVID-19 deaths in at least 40 states. In several states - including Idaho, Maine, Montana, Nebraska, North Carolina, Oregon, Puerto Rico, Washington, and West Virginia - the projected daily deaths in 2021 could exceed the prior peak daily deaths under current social distancing behavior and vaccination rate. The number of COVID-19 deaths across the U.S. could exceed 1600 per day.

Between August 1, 2021, and December 31, 2021, there could be additional 157,000 COVID-19 deaths across the U.S. Of note, our model projected approximately 20,700 COVID-19 deaths in Texas, 16,000 in California, 12,400 in Florida, 12,000 in North Carolina, and 9,300 in Georgia during this period. In contrast, the projected number of COVID-19 deaths would remain below 200 in New Jersey, Massachusetts, Connecticut, Vermont, and Rhode Island.

We project COVID-19 deaths based on the current vaccination rates and social distancing behavior. Our hope is that the findings of this report serve a warning sign and people revert to wearing masks and maintain social distancing to reduce COVID-19 associated deaths in the U.S. Our projections are updated weekly by incorporating vaccination rates and social distancing measures in each state; the latest results can be found at the COVID-19 Simulator website.


title: The relationship between sleep disturbance and cognitive impairment in mood disorders: A systematic review

abstract:
BackgroundCognitive impairment experienced by people with bipolar disorders (BD) or major depressive disorder (MDD) is associated with impaired psychosocial function and poorer quality of life. Sleep disturbance is another core symptom of mood disorders which may be associated with, and perhaps worsen, cognitive impairments. The aim of this systematic review was to critically assess the relationship between sleep disturbance and cognitive impairment in mood disorders.

MethodsIn this systematic review, relevant studies which examined sleep disturbance and cognitive function in people with mood disorders were identified using electronic database searches of PsychINFO, MEDLINE, Embase and Web of Science.

FindingsFourteen studies were included; eight investigated people with BD, five investigated people with MDD, and one included both people with MDD and people with BD. One study was an intervention for sleep disturbance and the remaining thirteen studies used either a longitudinal or cross-sectional observational design. Ten studies reported a significant association between subjectively measured sleep disturbance and cognitive impairment in people with MDD or BD after adjusting for demographic and clinical covariates, whereas no such association was found in healthy participants. Two studies reported a significant association between objectively measured sleep abnormalities and cognitive impairment in mood disorders. One study of cognitive behavioural therapy for insomnia modified for BD (CBTI-BD) found an association between improvements in sleep and cognitive performance in BD.

InterpretationThere is preliminary evidence to suggest a significant association between sleep disturbance and cognitive impairment in mood disorders. These findings suggest that identifying and treating sleep disturbance may be important when addressing cognitive impairment in MDD and BD.

Fundingnone.


title: Pandemic excess mortality in Spain, Sweden, and Switzerland during the COVID-19 pandemic in 2020 was at its highest since 1918

abstract:
Estimating excess mortality allows quantification of overall pandemic impact. For recent decades, mortality data are easily accessible for most industrialized countries, but only a few countries have continuous data available for longer periods. Since Spain, Sweden, and Switzerland were militarily neutral and not involved in combat during both world wars, these countries have monthly all-cause mortality statistics available for over 100 years with no interruptions. We show that during the COVID-19 pandemic in 2020, Spain, Sweden and Switzerland recorded the highest aggregated monthly excess mortality (17%, 9% and 14%) since the 1918 influenza pandemic (53%, 33% and 49%), when compared to respective expected values. For Sweden and Switzerland, the highest monthly spikes in 2020 almost reached those of January 1890. These findings emphasize the historical dimensions of the ongoing pandemic and support the notion of a pandemic disaster memory gap.

One-Sentence SummaryDuring the COVID-19 pandemic in 2020, Spain, Sweden, and Switzerland recorded their highest monthly excess and all-cause mortality levels since the 1918 influenza pandemic, emphasizing the historical dimension of the ongoing pandemic.


title: A causal association between schizophrenia and bipolar disorder on rheumatoid arthritis: A two-sample Mendelian randomization study

abstract:
BackgroundSchizophrenia (SCZ) and bipolar disorder (BD) are both associated with several autoimmune disorders including rheumatoid arthritis(RA). However, a causal association of SCZ and BD on RA is controversial and elusive. In the present study, we aimed to investigate the causal association of SCZ and BD with RA by using the Mendelian randomization (MR) approach.

MethodsA two-sample MR (2SMR) study including the inverse-variance weighted(IVW), weighted median, simple mode, weighted mode and MR-Egger methods were performed. We used summary-level genome-wide association study(GWAS) data in which BD and SCZ are the exposure and RA the outcome. We used data from the Psychiatric Genomics Consortium(PGC) for BD(n= 41,917) and SCZ(n= 33,426) and RA GWAS dataset(n= 2,843) from the European ancestry for RA.

ResultsWe found 48 and 52 independent single nucleotide polymorphisms (SNPs, r2 <0.001)) that were significant for respectively BD and SCZ (p <5x10-8). Subsequently, these SNPs were utilized as instrumental variables(IVs) in 2SMR analysis to explore the causality of BD and SCZ on RA. The two out of five MR methods showed a statistically significant inverse causal association between BD and RA: weighted median method(odds ratio (OR), 0.869, [95% CI, 0.764-0.989]; P= 0.034) and inverse-variance weighted(IVW) method (OR, 0.810, [95% CI, 0.689-0.953]; P= 0.011). However, we did not find any significant association of SCZ with RA (OR, 1.008, [95% CI, 0.931-1.092]; P= 0.829, using the IVW method).

ConclusionsThese results provide support for an inverse causal association between BD and RA. Further investigation is needed to explain the underlying protective mechanisms in the development of RA.

Key messagesO_LIMendelian randomization can offer strong insight into the cause-effect relationships in rheumatology.
C_LIO_LIBipolar disorder had a protective effect on rheumatoid arthritis.
C_LIO_LIThere is no inverse causal association between schizophrenia and rheumatoid arthritis contrary to the findings from observational studies.
C_LI


title: Efficacy of SARS-CoV-2 vaccine in thoracic cancer patients: a prospective study supporting a third dose in patients with minimal serologic response after two vaccine doses

abstract:
HypothesisCoronavirus disease 2019 (COVID-19) resulted in a 30% mortality rate in thoracic cancer patients. Given that cancer patients were excluded from serum anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) vaccine registration trials, it is still unknown whether they would develop a protective anti-spike antibody response following vaccination. This prospective vaccine monitoring study primarily aimed to assess humoral responses to SARS-CoV2 vaccine in thoracic cancer patients.

MethodsSARS-CoV2-spike antibodies were measured using Abbot ARCHITECT SARS-CoV-2 IgG immunoassay, prior to first injection of BNT162b2 mRNA vaccine, as well as at Week 4, and two-to-sixteen weeks after second vaccine dose. The factors associated with antibody response were analyzed.

ResultsOverall, 306 patients, with a median age of 67.0 years (IQR=58-74), were vaccinated. Of these, 283 patients received two vaccine doses at 28-day intervals. After 4.7-month median follow-up, seven patients (2.3%) contracted proven symptomatic SARS-CoV-2 infection, with rapid favorable evolution. Of 269 serological results available beyond Day 14 post-second vaccine dose, 17 (6.3%) were still negative (<50 AU/mL) (arbitrary units/mL), while 34 (11%) were <300 AU/mL (12.5th percentile). In multivariate analysis, only age and chronic corticosteroid treatment were significantly associated with a lack of immunization. Thirty patients received a third vaccine dose, with only three patients showing persistent negative serology thereafter, whereas the others demonstrated clear seroconversion.

ConclusionSARS-CoV2 vaccines were shown to be efficient in thoracic cancer patients, most of them being immunized after two doses. A third shot given to 1% of patients with persistent low antibody titers resulted in a 88% immunization rate.

category: oncology


title: A framework for integrated clinical risk assessment using population sequencing data

abstract:
ImportanceClinical risk prediction for monogenic coding variants remains challenging even in established disease genes, as variants are often so rare that epidemiological assessment is not possible. These variants are collectively common in population cohorts -- one in six individuals carries a rare variant in nine clinically actionable genes commonly used in population health screening.

ObjectiveTo expand diagnostic risk assessment in genomic medicine by integrating monogenic, polygenic, and clinical risk factors, and to classify individuals who carry monogenic variants as having elevated risk or population-level risk.

Design, Setting, and ParticipantsParticipants aged 40-70 years were recruited from 22 UK assessment centers from 2006 to 2010. Monogenic, polygenic, and clinical risk factors are used to generate integrated predictions of risk for carriers of rare missense variants in 200,625 individuals with exome sequencing data. Relative risks and classification thresholds are validated using 92,455 participants in the Geisinger MyCode cohort recruited from 70 US sites from 2007 onward.

Conclusions and RelevanceUsing integrated risk predictions, we identify 18.22% of UK Biobank (UKB) participants carrying variants of uncertain significance are at elevated risk for breast cancer (BC), familial hypercholesterolemia (FH), and colorectal cancer (CRC), accounting for 2.56% of the UKB in total. These predictions are concordant with clinical outcomes: individuals classified as having high risk have substantially higher risk ratios (Risk Ratio=3.71 [3.53, 3.90] BC, RR=4.71 [4.50, 4.92] FH, RR=2.65 [2.15, 3.14] CRC, logrank p<10-5), findings that are validated in an independent cohort ({chi}2 p=9.9x10-4 BC,{chi} 2 p=3.72x10-16 FH). Notably, we predict that 64% of UKB patients with laboratory-classified pathogenic FH variants are not at increased risk for coronary artery disease (CAD) when considering all patient and variant characteristics, and find no significant difference in CAD outcomes between these individuals and those without a monogenic disease-associated variant (logrank p=0.68). Current clinical practice guidelines discourage the disclosure of variants of uncertain significance to patients, but integrated modeling broadens this risk analysis, and identifies over 2.5-fold additional individuals who could potentially benefit from such information. This framework improves risk assessment within two similarly ascertained biobank cohorts, which may be useful in guiding preventative care and clinical management.

Key PointsO_ST_ABSQuestionC_ST_ABSCan personalized risk assessments that consider monogenic, polygenic, and clinical characteristics improve diagnostic accuracy over traditional variant-level genetic assessments?

FindingsIn established disease genes, we predict many carriers of variants of uncertain significance have significantly elevated risk. Conversely, we identify a substantial number of patients with known pathogenic coding variants who are unlikely to develop associated disorders.

MeaningMany individuals would not learn about elevated risk for disease under current genetic diagnostic guidelines. Integrated risk assessments provide significant benefits over variant-only interpretation, and should be further evaluated for their potential to optimize clinical management, inform preventive care, and reduce potential harms.