title: Derivation and external validation of clinical prediction rules identifying children at risk of linear growth faltering (stunting) presenting for diarrheal care

abstract:
BackgroundNearly 150 million children under-5 years of age were stunted in 2020. We aimed to develop a clinical prediction rule (CPR) to identify children likely to experience additional stunting following acute diarrhea, to enable targeted approaches to prevent this irreversible outcome.

MethodologyWe used clinical and demographic data from the Global Enteric Multicenter Study (GEMS) study to build predictive models of linear growth faltering (decrease of [≥]0.5 or [≥]1.0 in height-for-age z-score [HAZ] at 60 day follow-up) in children [≤]59 months presenting with moderate-to-severe diarrhea (MSD), and community controls, in Africa and Asia. We screened variables using random forests, and assessed predictive performance with random forest regression and logistic regression using 5-fold cross-validation. We used the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study to A) re-derive, and B) externally validate our GEMS-derived CPR.

ResultsOf 7639 children in GEMS, 1744 (22.8%) experienced severe growth faltering ([≥]0.5 decrease in HAZ). In MAL-ED, we analyzed 5683 diarrhea episodes from 1322 children, of which 961(16.9%) episodes experienced severe growth faltering. Top predictors of growth faltering in GEMS were: age, HAZ at enrollment, respiratory rate, temperature, and number of people living in the household. The maximum AUC was 0.75 (95% CI: 0.75, 0.75) with 20 predictors, while 2 predictors yielded an AUC of 0.71 (95% CI: 0.71, 0.72). Results were similar in the MAL-ED re-derivation. A 2-variable CPR derived from children 0-23 months in GEMS had an AUC=0.63 (95% CI 0.62, 0.65), and AUC=0.68 (95% CI: 0.63, 0.74) when externally validated in MAL-ED.

ConclusionsOur findings indicate that use of prediction rules could help identify children at risk of poor outcomes after an episode of diarrheal illness.


title: The Adaptive Olfactory Measure of Threshold (ArOMa-T): A rapid test of olfactory function

abstract:
PurposeMany widely-used psychophysical tests of olfaction have limitations that can create barriers to adoption outside research settings. For example, tests that measure the ability to identify odors may confound sensory performance with memory recall, verbal ability, and past experience with the odor. Conversely, threshold-based tests typically avoid these issues, but are labor intensive. Additionally, many commercially available olfactory tests are slow and may require a trained administrator, making them impractical for use in a short wellness visit or other broad clinical assessment.

MethodsWe tested the performance of the Adaptive Olfactory Measure of Threshold (ArOMa-T) - a novel odor detection threshold test that employs an adaptive Bayesian algorithm paired with a disposable odor-delivery card - in a non-clinical sample of individuals (n=534) at the 2021 Twins Day Festival in Twinsburg, OH.

ResultsParticipants successfully completed the test in under 3 min with a false alarm rate of 9.6% and a test-retest reliability of 0.61. Odor detection thresholds differed by sex ([~]3.2-fold) and between the youngest and oldest age groups ([~]8.7-fold), consistent with prior work. In an exploratory analysis, we failed to observe evidence of detection threshold differences between participants who reported a history of COVID-19 and matched controls who did not. We also found evidence for broad-sense heritability of odor detection thresholds.

ConclusionTogether, these data indicate the ArOMa-T can determine odor detection thresholds. The ArOMa-T may be particularly valuable in clinical or field settings where rapid and portable assessment of olfactory function is needed.

category: otolaryngology


title: Chromosomal microarray analyses from 5,778 patients with neurodevelopmental disorders and congenital anomalies in Brazil

abstract: Chromosomal microarray analysis (CMA) has been recommended and practiced routinely since 2010 in USA and Europe as the first-tier cytogenetic test for patients with unexplained neurodevelopmental delay/intellectual disability, autism spectrum disorders, and/or multiple congenital anomalies. However, in Brazil, the use of CMA is still limited, due to its high cost and complexity of the combination of private and public health systems. Although the country has one of the world largest single payer public healthcare system, nearly all patients referred for CMA come from the private sector. This reflects on the small number of CMA studies in Brazilian cohorts. This study is by far the largest Brazilian cohort (n=5,788) studied by CMA and results from a joint collaboration formed by the University of Sao Paulo and three private genetic diagnostic centers to investigate the genetic bases of neurodevelopmental disorders and congenital abnormalities. It is common practice to investigate the inheritance of VUS; however, our results indicate an extremely low cost-benefit of this approach, and strongly suggest that in cases of limited budget, investigation of the parents of VUS carriers using CMA should not be prioritized. Another aspect discussed is the classification of variants of low penetrance, once CNV classification is mostly designed to Mendelian or highly-penetrant variants.

category: genetic and genomic medicine


title: The Construction of Multi-ethnic Polygenic Risk Score using Transfer Learning

abstract: As most existing genome-wide association studies (GWAS) were conducted in European ancestry cohorts and as the existing PRS models have limited transferability across ancestry groups, PRS research on non-European ancestry groups is negatively impacted. Here we propose a novel PRS method using transfer learning techniques. Our approach, TL-PRS, uses gradient descent to fine-tune the baseline PRS model from an ancestry group with large sample GWAS to the dataset of target ancestry. In our application of constructing PRS for the six quantitative and two dichotomous traits for 10,285 South Asian and 8,168 African ancestry individuals in UK Biobank, TL-PRS achieved up to 42% average relative improvement compared to the existing methods. Our approach increases the transferability of PRSs across ancestries and thereby helps reduce existing inequities in genetics research.


title: Risk Perceptions and Private Protective Behaviors: Evidence from COVID-19 Pandemic

abstract: We analyze data from a survey we administered during the COVID-19 pandemic to investigate the relationship between peoples subjective beliefs about risks and their private protective behaviors. On average, people substantially overestimate the absolute level of risk associated with economic activity, but have correct signals about their relative risk. Subjective risk beliefs are predictive of changes in economic activities independently of government policies. Government mandates restricting economic behavior, in turn, attenuate the relationship between subjective risk beliefs and protective behaviors.

category: health policy


title: Pharmaceutical Payments to Japanese Board-certified Infectious Disease Specialists: A Four-year Retrospective Analysis of Payments from 92 Pharmaceutical Companies between 2016 and 2019

abstract:
ObjectiveConflict of interest with pharmaceutical companies is one of the most contentious issues in infectious diseases. However, there is a lack of whole picture of detailed payments in Japan.

Study Design and SettingThis retrospective study assessed financial relationships between pharmaceutical companies and all infectious disease specialists board-certified by the Japanese Association for Infectious Disease, using publicly disclosed payment data from 92 pharmaceutical companies. Descriptive analyses were conducted for the payments. Payment trends were examined by the generalized estimating equations.

ResultsOf 1614 board-certified infection disease specialists, 1,055 (65.4%) received a total of $17,784,070 payments, corresponding to 21,680 cases between 2016 and 2019. The mean{+/-}SD and median (interquartile range: IQR) were $16,857{+/-}$45,010 and $3,183 ($938{square}$11,250) in payments. All board executive members of Japanese Association of Infectious Disease received higher payments averaging $163,792. There were no significant changes in payments per specialist (annual change rate: -1.4% [95% CI: -4.7{square}2.3%], p=0.48) and prevalence of specialists with payments (annual change rate: -1.4% [95% CI: -3.1%{square}0.2%], p=0.093) over the four years.

ConclusionThere were substantial financial relationships between pharmaceutical companies and board-certified infectious disease specialists in Japan. Such personal payments must be restricted to a certain level to avoid potential conflict of interest.


title: Impact of Epstein-Barr virus co-infection on natural acquired Plasmodium vivax antibody response

abstract:
BackgroundThe simultaneous infection of Plasmodium falciparum and Epstein-Barr virus (EBV) could promote the development of the aggressive endemic Burkitts Lymphoma (eBL) in children living in P. falciparum holoendemic areas. While it is well-established that eBL is not related to other human malaria parasites, the impact of EBV infection on the generation of human malaria immunity remains largely unexplored. Considering that this highly prevalent herpesvirus establishes a lifelong persistent infection on B-cells with possible influence on malaria immunity, we hypothesized that EBV co-infection could have impact on the naturally acquired antibody responses to P. vivax, the most widespread human malaria parasite.

Methodology/Principal FindingsThe study design involved three cross-sectional surveys at six-month intervals (baseline, 6 and 12 months) among long-term P. vivax exposed adults living in the Amazon rainforest. The approach focused on a group of malaria-exposed individuals whose EBV-DNA (amplification of balf-5 gene) was persistently detected in the peripheral blood (PersVDNA, n=27), and an age-matched malaria-exposed group whose EBV-DNA could never be detected during the follow-up (NegVDNA, n=29). During the follow-up period, the serological detection of EBV antibodies to lytic/ latent viral antigens showed that IgG antibodies to viral capsid antigen (VCA-p18) were significantly different between groups (PersVDNA > NegVDNA). A panel of blood-stage P. vivax antigens covering a wide range of immunogenicity confirmed that in general PersVDNA group showed low levels of antibodies as compared with NegVDNA. Interestingly, more significant differences were observed to a novel DBPII immunogen, named DEKnull-2, which has been associated with long-term neutralizing antibody response. Differences between groups were less pronounced with blood-stage antigens (such as MSP1-19) whose levels can fluctuate according to malaria transmission.

Conclusions/SignificanceIn a proof-of-concept study we provide evidence that a persistent detection of EBV DNA in peripheral blood of adults in a P. vivax semi-immune population may impact the long-term immune response to major malaria vaccine candidates.

Author SummaryIn the Amazon rain forest, both Plasmodium vivax and Epstein-Barr virus (EBV) infections are common, yet the Burkitts lymphoma (BL) is rare, despite an association between endemic BL with chronic P. falciparum exposure. Nevertheless, the influence of EBV infection on malaria immunity remains undetermined. Here, we investigated for the first time whether continuous detection of EBV DNA in the peripheral blood of adults exposed to P. vivax could impact the antibody response to blood-stage malaria vaccine candidates. The methodological approach involved 12-month follow-up among P. vivax-exposed Amazonian classified as persistent EBV-DNA carriers (PersVDNA) and an age-matched group with no viral DNA detection (NegVDNA); groups were further differentiated based on profile of viral antibodies (mainly IgG VCA-p18). Collectively, our findings demonstrated that antibody levels against P. vivax antigens were in general lower in the PersVDNA group as compared with NegVDNA. More significant differences were observed to a novel vaccine candidate (DEKnull-2) whose antibody response were previously associated with broadly neutralizing P. vivax antibodies. Differences between groups were less pronounced with P. vivax antigens associated with seasonal changes in the antibody responses. In this conceptual study, we provide evidence that long-term detection of EBV in peripheral blood may impact immune response to major malaria vaccine candidates.

category: infectious diseases


title: Performance evaluation of a non-invasive one-step multiplex RT-qPCR assay for detection of SARS-CoV-2 direct from human saliva

abstract: Polymerase chain reaction (PCR) has proven to be the gold-standard for SARS-CoV-2 detection in clinical settings. The most common approaches rely on nasopharyngeal specimens obtained from swabs, followed by RNA extraction, reverse transcription and quantitative PCR. Although swab-based PCR is sensitive, swabbing is invasive and unpleasant to administer, reducing patient compliance for regular testing and resulting in an increased risk of improper sample collection. To overcome these obstacles, we developed a non-invasive one-step RT-qPCR assay performed directly on saliva specimens. The University of Nottingham Asymptomatic Testing Service (UoNATS) protocol simplifies sample collection and bypasses the need for RNA extraction, additives, or extraneous processing steps, thus helping to encourage more regular testing and reducing processing time and costs. We have evaluated the assay against the performance criteria specified by the UK regulatory bodies and attained accreditation (BS EN ISO/IEC 17025:2017) for SARS-CoV-2 diagnostic testing by the United Kingdom Accreditation Service (UKAS). We observed a sensitivity of 1 viral copy per microlitre of saliva and demonstrated a concordance of >99.4% between our results and those of other accredited testing facilities. We concluded that saliva is a stable medium with surprising longevity, and allows for a highly precise, repeatable, and robust testing method.


title: Comparison of influenza and COVID-19-associated hospitalizations among children < 18 years old in the United States - FluSurv-NET (October-April 2017-2021) and COVID-NET (October 2020-September 2021)

abstract:
BackgroundInfluenza virus and SARS-CoV-2 are significant causes of respiratory illness in children.

MethodsInfluenza and COVID-19-associated hospitalizations among children <18 years old were analyzed from FluSurv-NET and COVID-NET, two population-based surveillance systems with similar catchment areas and methodology. The annual COVID-19-associated hospitalization rate per 100 000 during the ongoing COVID-19 pandemic (October 1, 2020-September 30, 2021) was compared to influenza-associated hospitalization rates during the 2017-18 through 2019-20 influenza seasons. In-hospital outcomes, including intensive care unit (ICU) admission and death, were compared.

ResultsAmong children <18 years old, the COVID-19-associated hospitalization rate (48.2) was higher than influenza-associated hospitalization rates: 2017-18 (33.5), 2018-19 (33.8), and 2019-20 (41.7). The COVID-19-associated hospitalization rate was higher among adolescents 12-17 years old (COVID-19: 59.9; influenza range: 12.2-14.1), but similar or lower among children 5-11 (COVID-19: 25.0; influenza range: 24.3-31.7) and 0-4 (COVID-19: 66.8; influenza range: 70.9-91.5) years old. Among children <18 years old, a higher proportion with COVID-19 required ICU admission compared with influenza (26.4% vs 21.6%; p<0.01). Pediatric deaths were uncommon during both COVID-19- and influenza-associated hospitalizations (0.7% vs 0.5%; p=0.28).

ConclusionsIn the setting of extensive mitigation measures during the COVID-19 pandemic, the annual COVID-19-associated hospitalization rate during 2020-2021 was higher among adolescents and similar or lower among children <12 years old compared with influenza during the three seasons before the COVID-19 pandemic. COVID-19 adds substantially to the existing burden of pediatric hospitalizations and severe outcomes caused by influenza and other respiratory viruses.

SummaryAnnual hospitalization rates and proportions of hospitalized children experiencing severe outcomes were as high or higher for COVID-19 during October 2020-September 2021 compared with influenza during the three seasons before the COVID-19 pandemic, based on U.S. population-based surveillance data.


title: Not all mosquitoes are created equal: incriminating mosquitoes as vectors of arboviruses

abstract:
The globalization of mosquito-borne arboviral diseases has placed more than half of the human population at risk. Understanding arbovirus ecology, including the role individual mosquito species play in virus transmission cycles, is critical for limiting disease. Canonical virus-vector groupings, such as Aedes- or Culex-associated flaviviruses, have historically been defined using phylogenetic associations, virus isolation in the field, and mosquito feeding patterns. These associations less frequently rely on vector competence, which quantifies the intrinsic ability of a mosquito to become infected with and transmit a virus during a subsequent blood feed. Herein, we quantitatively synthesize data from 80 laboratory vector competence studies of 115 mosquito-virus pairings of Australian mosquito species and viruses of public health concern to further substantiate existing canonical vector-virus groupings, uncover new associations, and quantify variation within these groupings. Our synthesis reinforces current canonical vector-virus groupings but reveals substantial variation within them. While Aedes species were generally the most competent vectors of canonical "Aedes-associated flaviviruses" (such as dengue, Zika, and yellow fever viruses), there are some notable exceptions; for example, Aedes notoscriptus is an incompetent vector of dengue viruses. Culex spp. were the most competent vectors of many traditionally Culex-associated flaviviruses including West Nile, Japanese encephalitis and Murray Valley encephalitis viruses, although some Aedes spp. are also moderately competent vectors of these viruses. Conversely, many mosquito genera were associated with the transmission of the arthritogenic alphaviruses, Ross River, Barmah Forest, and chikungunya viruses. We also confirm that vector competence is impacted by multiple barriers to infection and transmission within the mesenteron and salivary glands of the mosquito. Although these barriers represent important bottlenecks, species that were susceptible to infection with a virus were often likely to transmit it. Importantly, this synthesis provides essential information on what species need to be targeted in mosquito control programs.

Author summaryThere are over 3,500 species of mosquitoes in the world, but only a small proportion are considered important vectors of arboviruses. Vector competence, the physiological ability of a mosquito to become infected with and transmit arboviruses, is used in combination with virus detection in field populations and analysis of vertebrate host feeding patterns to incriminate mosquito species in virus transmission cycles. Here, we quantified the vector competence of Australian mosquitoes for endemic and exotic viruses of public health concern by analyzing 80 laboratory studies of 115 mosquito-virus pairings. We found that Australia has species that could serve as efficient vectors for each virus tested and it is these species that should be targeted in control programs. We also corroborate previously identified virus-mosquito associations at the mosquito genus level but show that there is considerable variation in vector competence between species within a genus. We also confirmed that vector competence is influenced by infection barriers within the mosquito and the experimental protocols employed. The framework we developed could be used to synthesize vector competence experiments in other regions or expanded to a world-wide overview.


title: Risks for death after admission to pedaitric intensive care (PICU) - a comparison with the general population

abstract:
Objective/AimThe aim of the study was to investigate the mortality rate in children after admission to a Pediatric Intensive Care Unit (PICU), compared to the matched general Swedish population.

DesignSingle-center, retrospective cohort study.

SettingRegistry study of hospital registers, a national population register and Statistics Sweden.

PatientsChildren admitted to a tertiary PICU in Sweden in 2008-2016.

InterventionsNone

Main ResultsIn total, 6,487 admissions (4,682 patients) were included in the study. During the study period 444 patients died. Median follow-up time for the entire PICU cohort was 7.2 years (IQR 5.0-9.9 years). Patients were divided into four different age groups (0-28 d, > 28 d -1 yr, > 1-4 yr, and > 4 yr) and four different risk stratification groups [Predicted Death Rate (PDR) intervals: 0-10%, > 10-25%, > 25-50%, and > 50%] at admission. Readmission was seen in 929 (19.8%) patients. The Standardized Mortality Ratios (SMRs) were calculated using the matched Swedish population as a reference group. The SMR for the entire study group was 49.8 (95% CI: 44.8-55.4). For patients with repeated PICU admissions SMR was 108.0 (95% CI: 91.9-126.9), and after four years 33.9 (95% CI: 23.9-48.0). Patients with a single admission had a SMR of 35.2 (95% CI: 30.5-40.6), and after four years 11.0 (95% CI: 7.0-17.6). The highest SMRs were seen in readmitted children with oncology/hematology (SMR=358) and neurologic (SMR=192) diagnosis. Children aged >1-4 years showed the highest SMR (325). In PDR group 0-10% children with repeated PICU admissions (n=798), had a SMR of 100.

ConclusionSMRs were greatly elevated up to four years after PICU admission, declining from over 100 to 33 for patients with repeated PICU admissions, and from 35 to 11 for patients with a single PICU admission, compared to the matched Swedish population.

category: intensive care and critical care medicine


title: Genetic overlap between mood instability and alcohol-related phenotypes suggests shared biological underpinnings

abstract: Alcohol use disorder (AUD) is a pervasive and devastating mental illness with high comorbidity rates with other mental disorders. We aimed to characterize the shared vs. unique polygenicity of AUD, alcohol consumption (AC) and mood instability (MOOD), a relevant transdiagnostic factor, using large genome-wide association studies (GWASs) data. We hypothesize that cross-analyzing these phenotypes would shed light on their unique and shared polygenicity, increase our knowledge regarding the genetic basis of the comorbidity between AUD and mood disorders, and boost discovery for jointly-associated loci. Summary statistics for MOOD, AC and AUD GWASs (Ns =363,705; 200,680 and 200,004; respectively) were analysed to characterize the cross-phenotype associations between MOOD and AC, MOOD and AUD and AC and AUD, respectively. To do so, we used a newly-established pipeline that combines (i) the bivariate causal mixture model (MiXeR) to quantify the cross-phenotype polygenic overlap and (ii) the conjunctional false discovery rate (conjFDR) to discover specific jointly-associated genomic loci. These loci were functionally characterized and mapped to genes and biological functions. We also performed validation in independent samples and phenotypic analyses. MOOD was highly polygenic (10,400 single nucleotide polymorphisms, SNPs) compared to AC and AUD (4,900 SNPs, SD =600 and 4,300 SNPs, SD =2,000; respectively). The polygenic overlap of MOOD and AC was much larger than that of MOOD and AUD (98% vs. 49%) and genetic correlation was opposite (-0.2 vs. 0.23), which was confirmed in independent samples. MOOD&AUD causal SNPs were significantly enriched for brain genes, conversely to MOOD&AC. Among 38 loci identified in the joint analysis, sixteen were novel for MOOD, AC and AUD. Similarly distinct patterns were evidenced for SNP localization, function and previous GWAS associations outside of the phenotypes that were currently studied. MOOD, AC and AUD were also strongly associated at the phenotypic level. Overall, using multilevel polygenic quantification, joint loci discovery and functional annotation methods, we evidenced that the polygenic overlap between MOOD and AC/AUD implicated shared biological underpinnings but clearly distinct functional patterns between MOOD&AC and MOOD&AUD. Using the MOOD endophenotype, the current study suggests new mechanisms for the comorbidity of AUD with mood disorders.

category: addiction medicine


title: Impacts of COVID-19 on glycemia and risk of diabetic ketoacidosis

abstract:
BackgroundReports indicate that COVID-19 may impact pancreatic function and increase type 2 diabetes (T2D) risk, although real-world COVID-19 impacts on HbA1c and T2D are unknown. We tested whether COVID-19 increased HbA1c, risk of T2D, or diabetic ketoacidosis (DKA).

MethodsWe compared pre- and post-COVID-19 HbA1c, and risk of developing T2D in a large real-world clinical cohort of 8,755 COVID-19(+) patients and a matched control cohort of 11,998 COVID-19(-) patients. We investigated if DKA risk was modified in COVID-19(+) patients with type 1 diabetes (T1D) (N=704) or T2D (N=22,904), or by race and sex.

FindingsWe observed a statistically significant, albeit clinically insignificant, HbA1c increase post-COVID-19 (all patients {Delta}HbA1c=0.06%, P<.001; with T2D {Delta}HbA1c=0.1%; P<.001), and no increase among COVID-19(-) patients (P>.05). COVID-19(+) patients were 40% more likely to be diagnosed with T2D compared to COVID-19(-) patients (P<.001) and 28% more likely to be diagnosed with T2D for the same HbA1c change as COVID-19(-) patients (P<.001). COVID-19(+) patients with T2D on insulin were 34% more likely to develop DKA compared to COVID-19(-) patients on insulin (P<.05), and COVID-19(+) Black patients with T2D displayed disproportionately increased DKA risk (HR:1.63, P=.007). There was no significant difference in DKA risk between COVID-19(+) and COVID-19(-) patients with T1D.

InterpretationDKA risk is increased in T2D patients on insulin and in Black patients with T2D after COVID-19 infection.T2D risk is greater in COVID-19(+) patients for the same HbA1c increase in COVID-19(-) patients, indicating that T2D risk attributed to COVID-19 may be due to increased recognition during COVID-19 management.

FundingNo funding to report.

category: endocrinology


title: Epidemiology and genomic analysis of Klebsiella oxytoca from a single hospital network in Australia

abstract: Infections caused by Klebsiella oxytoca are the second most common cause of Klebsiella infections in humans. Most studies to date have focused on K. oxytoca outbreaks and few have examined the broader clinical context of K. oxytoca. Here, we collected all clinical isolates identified as K. oxytoca in a hospital microbiological diagnostic lab across a 15-month period (n=239). The majority of isolates were sensitive to antimicrobials, however 22 isolates were resistant to third-generation cephalosporins (3GCR), of which five were also carbapenem resistant. Whole genome sequencing of a subset of 92 isolates (all invasive, 3GCR and non-urinary isolates collected >48h after admission) showed those identified as K. oxytoca by the clinical laboratory actually encompassed four distinct species (K. oxytoca, Klebsiella michiganensis, Klebsiella grimontii and Klebsiella pasteurii), referred to as the K. oxytoca species complex (KoSC). There was significant diversity within the population, with only 10/67 multi-locus sequence types (STs) represented by more than one isolate. Strain transmission was rare, with only a single likely event identified. Six isolates had either extended spectrum beta-lactamase (blaSHV-12 and/or blaCTX-M-9) or carbapenemase (blaIMP-4) genes. One pair of K. michiganensis and K. pasteurii genomes carried an identical blaIMP-4 IncL/M plasmid, indicative of plasmid transmission. Whilst antimicrobial resistance was rare, the resistance plasmids were similar to those found in other Enterobacterales, demonstrating that KoSC has access to the same plasmid reservoir and thus there is potential for multi-drug resistance. Further genomic studies are required to improve our understanding of the KoSC population and facilitate investigation into the attributes of successful nosocomial isolates.

category: epidemiology


title: Symptoms of depression and anxiety among Vietnamese immigrants in Japan during the COVID-19 pandemic

abstract:
ObjectiveWe aimed to examine the mental health status and related factors among Vietnamese immigrants in Japan during the coronavirus disease 2019 (COVID-19) pandemic.

DesignOnline cross-sectional survey administered from September 21 to October 21, 2021

SettingOnline survey of Vietnamese immigrants in Japan

ParticipantsThe inclusion criteria for participation were 1) Vietnamese citizenship or Japanese citizenship in those of Vietnamese descent, current residence in Japan, and 2) age [≥]18 years.

Main OutcomesPatient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder 7-item (GAD-7) scores were considered the main outcome measures. Multivariable logistic regression was used to identify factors related to symptoms of depression and anxiety, and the chosen variables were entered simultaneously in the survey.

ResultsAmong 621 participants (age: 26.0{+/-}4.8 years; male: 347 [55.9%]) who completed the questionnaire, 73.7% reported a decrease in income when compared with the period before the COVID-19 pandemic, and 60.4% reported being recently affected by poor socioeconomic status. Moderate-to-severe symptoms of depression (PHQ-9 score [≥]10 points) and mild-to-severe symptoms of anxiety (GAD-7 [≥]5 points) were observed in 203 (32.7%) and 285 (45.9%) individuals, respectively. Factors related to depressive symptoms were age (odds ratio [OR]=0.94, p=0.043), medical or psychiatric co-morbidity (OR=2.46, p<0.001), and low socioeconomic status (OR=2.47, p<0.001). Factors related to anxiety symptoms were being single (OR=1.72, p=0.044), medical or psychiatric co-morbidity (OR=2.52, p<0.001), low socioeconomic status (OR=2.72, p<0.001), and absence of a partner with whom to discuss ones health (OR=1.66, p=0.013).

ConclusionsThe current findings demonstrate that, when compared with Japanese citizens, Vietnamese immigrants experienced a decrease in income, worsening working conditions, and poor mental health status during the COVID-19 pandemic. These findings highlight the potential contribution of low socioeconomic status and social isolation to poor mental health status.

Strengths and limitations of this studyO_LIVietnamese immigrants, who are the second largest immigrant group in Japan, were studied. No previous assessment of their mental health during the COVID-19 pandemic has been carried out.
C_LIO_LIThis study provided a non-contact approach to prevent infection using online surveys. Therefore, we received a wide range of responses from areas with low COVID-19 infection rate area to high COVID-19 infection rate area in Japan.
C_LIO_LIThe survey may not be a complete representation of all Vietnamese immigrants living in Japan, as some elderly Vietnamese immigrants may not have been able to participate due to the online format.
C_LI

category: psychiatry and clinical psychology


title: Symptoms of depression and anxiety among Vietnamese immigrants in Japan during the COVID-19 pandemic: a cross-sectional web-based study


title: Protocol for a multi-site case control study evaluating child and adolescent mental health service transformation in England using the i-THRIVE model

abstract: The National i-THRIVE Programme seeks to evaluate the impact of the NHS England-funded whole system transformation on child and adolescent mental health services (CAMHS). This article reports on the design for a model of implementation that has been applied in CAMHS across over 70 areas in England using the  THRIVE needs-based principles of care. The implementation protocol in which this model,  i-THRIVE (implementing-THRIVE), will be used to evaluate the effectiveness of the THRIVE intervention is reported, together with the evaluation protocol for the process of implementation. To evaluate the effectiveness of i-THRIVE to improve care for children and young peoples mental health, a case-control design will be conducted. N = 10 CAMHS sites that adopt the i-THRIVE model from the start of the NHS England-funded CAMHS transformation will be compared to N = 10  comparator sites that choose to use different transformation approaches within the same timeframe. Sites will be matched on population size, urbanicity, funding, level of deprivation and expected prevalence of mental health care needs. To evaluate the process of implementation, a mixed-methods approach will be conducted to explore the moderating effects of context, fidelity, dose, pathway structure and reach on clinical and service level outcomes. This study addresses a unique opportunity to inform the ongoing national transformation of CAMHS with evidence about a popular new model for delivering children and young peoples mental health care, as well as a new implementation approach to support whole system transformation. If the outcomes reflect benefit from i-THRIVE, this study has the potential to guide significant improvements in CAMHS by providing a more integrated, needs-led service model that increases access and involvement of patients with services and in the care they receive.


title: Cultural adaptation of the person-centered maternity care scale at governmental health facilities in Cambodia

abstract:
BackgroundIn Cambodia, the importance of valuing womens childbirth experiences in improving quality of care has been understudied. This is largely because of absence of reliable Khmer tools for measuring womens intrapartum care experiences. Generally, cross-cultural development of those tools often involves translation from a source language into a target language. Yet, few earlier studies considered Cambodian cultural context. Thus, we developed the Cambodian version of the Person-Centered Maternity Care (PCMC) scale, by culturally adapting its original to Cambodian context for ensuring cultural equivalence and content validity.

MethodsThree rounds of cognitive interviewing with 20 early postpartum women were conducted at two governmental health facilities in Cambodia. Cognitive interviewing was composed of structured questionnaire pretesting and qualitative probing. The issues identified in the process of transcribing and translating audio-recorded cognitive interviews were iteratively discussed among study team members, and further analyzed.

ResultsA total of 14 issues related to cultural adaptations were identified in the 31 translated questions for the Cambodian version of the PCMC scale. Our study identified three key findings: (i) discrepancies between the WHO recommendations on intrapartum care and Cambodian field realities; (ii) discrepancies in recognition on PCMC between national experts and local women; and (iii) challenges in correctly collecting and interpreting less-educated womens views on intrapartum care.

ConclusionNot only womens verbal data but also their non-verbal data and cultural contexts should be comprehensively counted, when reflecting Cambodian womens intrapartum practice realities in the translated version. This is the first study that attempted to develop the tool for measuring Cambodian womens experiences during childbirth, by addressing cross-cultural issues.

category: sexual and reproductive health


title: Blood transcriptomic biomarkers of alcohol consumption and cardiovascular disease risk factors: the Framingham Heart Study

abstract:
BackgroundThe relations of alcohol consumption and gene expression remain to be elucidated in large study samples.

ObjectivesTo study the relationship between alcohol consumption, gene expression, and cardiovascular disease (CVD) risk factors.

MethodsWe performed cross-sectional association analysis of whole blood derived gene expression levels with alcohol consumption in 5,531 Framingham Heart Study (FHS) participants (mean age 55 years; 54% women) by splitting the sample into a discovery sample and a replication sample (2:1 ratio) using independent pedigrees. We also examined the cross-sectional association of alcohol-associated genes with three CVD risk factors: obesity, hypertension, and diabetes. Linear mixed models or generalized estimation equations were used to quantify associations accounting for familial relationship and multiple covariates.

ResultsWe identified 25 alcohol-associated genes (false discovery rate < 0.05 in the discovery sample and Bonferroni corrected P < 0.05 in the replication sample). We further showed cross-sectional associations of 16 alcohol-associated genes with obesity, nine genes with hypertension, and eight genes with diabetes (all P < 0.002). For example, we observed decrease in expression of PROK2 ({beta} = -0.0018; 95%CI: -0.0021, -0.0007; P = 6.5e-5) and PAX5 ({beta} = -0.0014; 95%CI: -0.0021, -0.0007; P = 6.5e-5) per 1 g/day increase in alcohol consumption. Consistent with our previous observation on the inverse association of alcohol consumption with obesity and positive association of alcohol consumption with hypertension, we found that PROK2 was positively associated with obesity (OR = 1.42; 95%CI: 1.17, 1.72; P = 4.5e-4) and PAX5 was negatively associated with hypertension (OR = 0.73; 95%CI: 0.59, 0.89; P = 1.6e-3). We also observed that alcohol consumption was positively associated with expression of ABCA13 ({beta} = 0.0012; 95%CI: 0.0007, 0.0017; P = 1.3e-6) and ABCA13 was positively associated with diabetes (OR = 2.57; 95%CI: 1.73, 3.84; P = 3.5e-06); this finding, however, was inconsistent with our observation on the inverse association between alcohol consumption and diabetes.

ConclusionsWe observed that alcohol consumption was associated with whole blood expression levels of 25 genes in middle aged to older adults in the FHS. In addition, complex relationships may exist between alcohol-associated genes and CVD risk factors.

category: nutrition


title: Evaluation of systemic immune response in patients with inflammatory complications of large joint replacements

abstract: We studied the features of systemic immunity in patients with inflammatory complications of their knee replacements and used the factor analysis to find immune characteristics associated with the progress of the pathological condition. The components indicative of changes related to the development of cell and humoral immune response in patients were isolated. Our findings present prospects for the development of new diagnostic techniques ensuring higher precision in searching for adequate surgical methods.

category: orthopedics


title: Multiple Sclerosis: Exploring the Limits of Genetic and Environmental Susceptibility

abstract:
OBJECTIVETo explore the nature of genetic and environmental susceptibility to multiple sclerosis (MS) and to define the limits of this nature based on the statistical uncertainties regarding the various epidemiological observations that have been made.

BACKGROUNDCertain parameters of MS-epidemiology can be directly observed (e.g., the risk of MS-recurrence in siblings and twins of an MS proband, the proportion of women among MS patients, the population-prevalence of MS, and the time-dependent changes in the sex-ratio). By contrast, other parameters can only be inferred from the observable parameters (e.g., the proportion of the population that is genetically susceptible, the proportion of women among susceptible individuals, the probability that a susceptible individual will experience an environment sufficient to cause MS given their genotype, and if they do, the probability that they will ultimately develop the disease).

DESIGN/METHODSThe "genetically-susceptible" subset (G) of the population (Z) is defined to include everyone with any non-zero life-time chance of developing MS. For the observed parameters, plausible ranges are assigned values such that they include either the 95% confidence intervals or the estimated parameter-ranges for each observation. By contrast, for the non-observed parameters, the ranges are assigned such that they cover any plausible value for each parameter. Using both a Cross-sectional Model and a Longitudinal Model, together with established parameter relationships, we explore iteratively trillions of potential parameter combinations and determine those combinations (solutions) that are constrained by the observed parameter ranges.

RESULTSUsing both Models, under all circumstances, genetic-susceptibitly is limited to to less than 52% of the population. If solutions are excluded, in which susceptible women either comprise less than 18% of susceptible individuals or have a penetrance more than 20 times that in susceptible men, then both Models agree that genetic-susceptibility is limited to less than 12% of the population. Consequently, a large number (and likely the large majority) of individuals have no chance whatsoever of developing MS, regardless of their environmental exposure. Also, although the penetrance of MS in susceptible women is greater than it is in men and, for most solutions, susceptible men outnumber susceptible women. As expected, the probability that susceptible individuals will develop MS increases with an increased likelihood of individuals experiencing a sufficient environmental exposure. Nevertheless, as this probability approaches 1, these response-curves plateau at <64% for women and at <23% for men. Finally, under current environmental conditions are such that more than 68% of susceptible individuals are experiencing an environment sufficient to cause MS given their particular genotype.

CONCLUSIONSThe development of clinical MS (in an individual) requires both that they have the appropriate genotype (which is quite rare in the population) and that they have an environmental exposure sufficient to cause MS given their particular genotype (which is currently quite common among susceptible individuals). Nevertheless, even when the necessary genetic and environmental factors, required for MS pathogenesis, co-occur for an individual, this is still insufficient for that person to develop MS. Rather, disease pathogenesis, even in this circumstance, involves an important element of chance.

Author SummaryCertain parameters of MS-epidemiology can be directly observed. These parameters include the risk of MS recurrence in siblings and twins of an MS proband, the proportion of women among MS patients, the population-prevalence of MS, and the time-dependent changes in the sex-ratio. By contrast, there are other parameters of MS-epidemiology, which cant be observed, but which must be inferred based on the values of the observable parameters. These parameters include the proportion of the general population (Z) that is genetically susceptible to MS, the proportion of women among susceptible individuals, the probability that a susceptible individual will experience an environment sufficient to cause MS, and if they do, the likelihood that they will actually develop the MS. We define the subset (G) - i.e., the genetically-susceptible subset - to include everyone in (Z) who has any non-zero chance of developing MS over their life-time. For the observed parameters, plausible ranges are assigned values such that they include either the 95% confidence intervals or the estimated parameter-ranges for each observation. By contrast, for the non-observed parameters, the ranges are assigned such that they cover any plausible value for each parameter. Then, using both a Cross-sectional Model and a Longitudinal Model, together with established parameter relationships, we explore iteratively trillions of potential parameter combinations and determine those combinations (solutions) that are constrained by the observed parameter values. The Cross-sectional Model requires two assumptions, commonly made in studies of monozygotic twins, to establish certain relationships between the observed and non-observed parameters. By contrast, the Longitudinal Model makes neither of these assumptions but, rather, this Model utilizes the observed changes in the female-to-male (F:M) sex-ratio, which have taken place over the past 4-5 decades, to determine the response curves for susceptible individuals, relating their probability of developing MS to their probability of experiencing an environment sufficient to cause MS. Using both of these analytic Models, under all circumstances, genetic-susceptibitly is limited to to less than 52% of the population. If solutions are excluded, in which susceptible women either comprise less than 18% of susceptible individuals or have a penetrance greater than 20 times that in susceptible men, then both Models agree that genetic-susceptibility is limited to less than 12% of the population. Consequently, a large number (and likely the large majority) of individuals have no chance whatsoever of developing MS, regardless of their environmental experiences. Also, the penetrance of MS in susceptible women is considerably greater than it is in men although, for most solutions, susceptible men outnumber susceptible women. As expected, MS-probability increases with an greater likelihood of a sufficient environmental exposure although these response-curves plateau at <64% for women and at <27% for men. Finally, the current environmental conditions are such that more than 68% of susceptible individuals, at present, are experiencing an environment sufficient to cause MS given their particular genotype. Consequently, the development of clinical MS (in an individual) requires both that they have the appropriate genotype (which is quite rare in the population) and that they have an environmental exposure sufficient to cause MS given their individual genotype (which is currently quite common among susceptible individuals). Nevertheless, even when the necessary genetic and environmental factors, required for MS pathogenesis, co-occur for an individual, this is still insufficient for that person to develop MS. Rather, disease pathogenesis, even in this circumstance, involves an important element of chance.


title: Longitudinal associations between perceived stress and anhedonia during psychotherapy

abstract:
BackgroundChronic stress alters reward sensitivity and contributes to the emergence of anhedonia. In clinical samples, the perception of stress is a strong predictor of anhedonia. While there is substantial evidence demonstrating psychotherapy reduces perceived stress, little is known regarding the effects of treatment-related decreases in perceived stress on anhedonia.

MethodsThe current study investigated reciprocal relations between perceived stress and anhedonia using a cross-lagged panel model approach in a 15-week clinical trial examining the effects of Behavioral Activation Treatment for Anhedonia (BATA), a novel psychotherapy to treat anhedonia, compared to a Mindfulness-Based Cognitive Therapy (MBCT) comparison intervention (ClinicalTrials.gov Identifiers NCT02874534 and NCT04036136).

ResultsTreatment completers (n=72) experienced significant reductions in anhedonia (M=-8.94, SD=5.66) on the Snaith-Hamilton Pleasure Scale (t(71)=13.39, p<.0001), and significant reductions in perceived stress (M=-3.71, SD=3.88) on the Perceived Stress Scale (t(71)=8.11, p<.0001) following treatment. Across all treatment-seeking participants (n=87), a longitudinal autoregressive cross-lagged model revealed significant paths showing that higher levels of perceived stress at treatment Week 1 predicted reductions in anhedonia at treatment Week 4.

ConclusionsLongitudinal models illustrated that individuals with relatively high perceived stress at the start of treatment were likely to report relatively lower anhedonia a few weeks into treatment. At mid-treatment, individuals with low perceived stress were more likely to report lower anhedonia towards the end of treatment. Early treatment components are thought to reduce perceived stress, allowing for mid-to-late treatment components to exert their direct effects on anhedonia. The findings presented here demonstrate the importance of including stress-reducing components in cognitive-behavioral-based anhedonia treatments.


title: Polygenic risk vectors (PRV) improve genetic risk stratification for cardio-metabolic diseases

abstract: 1.Accurate disease risk stratification can lead to more precise and personalized prevention and treatment of diseases. As an important component to disease risk, genetic risk factors can be utilized as an early and stable predictor for disease onset. Recently, the polygenic risk score (PRS) method has combined the effects from hundreds to millions of single nucleotide polymorphisms (SNPs) into a score that can be used for genetic risk stratification. However, current PRS approaches only utilize the additive associations between SNPs and disease risk in a one-dimensional score. Here, we show that leveraging multiple types of genetic effects in multi-dimensional risk vectors, or a polygenic risk vector (PRV), can improve the stratification of cardio-metabolic diseases risks. Using data from UK Biobank (UKBB) and Electronic Medical Records and Genomics (eMERGE) Network biobank linked electronic health records (EHR) as development and evaluation data, we found that the combined effects between the additive PRS and the dominant PRS outperformed either one in terms of disease risk stratification, especially for the individuals in the high-risk group. Our results demonstrate that disease risks are likely to be influenced by multiple types of genetic effects, and PRV could utilize these effects for better risk stratification while retaining the simplicity of the PRS method.


title: Avey: An Accurate AI Algorithm for Self-Diagnosis

abstract:
ObjectivesTo present our AI-based symptom checker, rigorously measure its accuracy, and compare it against existing popular symptom checkers and seasoned primary care physicians.

DesignVignettes study.

Setting400 gold-standard primary care vignettes.

Intervention/ComparatorWe utilized 7 standard accuracy metrics for evaluating the performance of 6 symptom checkers. To this end, we developed and peer-reviewed 400 vignettes, each approved by at least 5 out of 7 independent and experienced general practitioners. To the best of our knowledge, this yielded the largest benchmark vignette suite in the field thus far. To establish a frame of reference and interpret the results of symptom checkers accordingly, we further directly compared the best-performing symptom checker against 3 primary care physicians with an average experience of 16.6 years.

Primary Outcome MeasuresWe thoroughly studied the diagnostic accuracies of symptom checkers and physicians from 7 standard angles, including: (a) M1, M3, and M5 as measures of a symptom checkers or a physicians ability to return a vignettes main diagnosis at the top, among the first 3 diseases, or among the first 5 diseases of their differential diagnosis, respectively (b) recall as a measure of the percentage of relevant diseases that are returned in a symptom checkers or a physicians differential diagnosis, (c) precision as a measure of the percentage of diseases in a symptom checkers or a physicians differential diagnosis that are relevant, (d) F1-measure as a trade-off measure between recall and precision, and (e) Normalized Discounted Cumulative Gain or NDCG as a measure of ranking quality of a symptom checkers or a physicians differential diagnosis.

ResultsOur AI-based symptom checker, namely, Avey significantly outperformed 5 popular symptom checkers, namely, Ada, WebMD, K Health, Buoy, and Babylon by averages of 24.5%, 175.5%, 142.8%, 159.6%, 2968.1% using M1; 22.4%, 114.5%, 123.8%, 118.2%, 3392% using M3; 18.1%, 79.2%, 116.8%, 125%, 3114.2% using M5; 25.2%, 65.6%, 109.4%, 154%, 3545% using recall; 8.7%, 88.9%, 66.4%, 88.9%, 2084% using F1-measure; and 21.2%, 93.4%, 113.3%, 136.4%, 3091.6% using NDCG, respectively. Under precision, Ada outperformed Avey by an average of 0.9%, while Avey surpassed WebMD, K Health, Buoy, and Babylon by averages of 103.2%, 40.9%, 49.6%, and 1148.5%, respectively. To the contrary of symptom checkers, physicians outperformed Avey by averages of 37.1% and 1.2% using precision and F1-measure, while Avey exceeded them by averages of 10.2%, 20.4%, 23.4%, 56.4%, and 25.1% using M1, M3, M5, recall, and NDCG, respectively. To facilitate the reproducibility of our study and support future related studies, we made all our gold-standard vignettes publicly and freely available. Moreover, we posted online all the results of the symptoms checkers and physicians (i.e., 45 sets of experiments) to establish a standard of full transparency and enable verifying and cross validating our results.

ConclusionsAvey tremendously outperformed the considered symptom checkers. In addition, it compared favourably to physicians, whereby it underperformed them under some accuracy metrics (e.g., precision and F1-measure), but outperformed them under some others (e.g., M1, M3, M5, recall, and NDCG). We will continue evolving Aveys AI model. Furthermore, we will study its usability with real patients, examine how they respond to its suggestions, and measure its impact on their subsequent choices for care, among others.

category: health informatics


title: Immunogenicity and safety of a recombinant adenovirus type-5 COVID 19 vaccine in adults: data from a randomised, double-blind, placebo-controlled, single-dose, phase 3 trial in Russia

abstract:
BackgroundTo determine the immunogenicity, efficacy, reactogenicity, and safety of a single dose of recombinant adenovirus type-5 vectored COVID-19 vaccine (Ad5-nCoV, 5 x 1010 viral particles per 0.5 mL dose), we conducted a single-dose, randomised, double-blind, placebo-controlled, parallel group (3:1 Ad5-nCoV:placebo), phase 3 trial (Prometheus).

MethodsFrom 11-September-2020 to 05-May-2021, across six sites in the Russian Federation, 496 participants were injected with either placebo or Ad5-nCoV expressing the full-length spike (S) protein from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

ResultsSeroconversion (the primary endpoint) rates of 78.5% (95% CI: 73.9; 82.6) against receptor binding domain (RBD), 90.6% (95% CI: 87.2; 93.4) against S protein and 59% (95% CI: 53.3; 64.6) against neutralising SARS-CoV2 antibodies 28 days post-vaccination. Geometric mean titres (GMTs) were also elevated for antibodies against the RBD (405.32 [95% CI: 361.58; 454.46]) and S protein (678.86 [95% CI: 607.44; 754.40]) compared to the GMT of neutralising antibodies against SARS-CoV-2 (16.73 [95% CI: 15.36; 18.22]). Using an IFN-{gamma} ELISpot assay after stimulating the cells with full-length S protein we showed that the Ad5-nCoV vaccine induced the most robust cellular immune response on Days 14 and 28. Up to Day 28, the primary and all secondary endpoints of the Ad5-nCoV vaccine were statistically superior to the placebo ([p] <0.001). Systemic reactions were reported in 113 of 496 (22.8%) participants (Ad5-nCoV, 26.9%; Placebo, 10.5%), and local reactions were reported in 108 (21.8%) participants (Ad5-nCoV, 28.5%; Placebo, 1.6%). These were generally mild and resolved within 7 days after vaccination. Of the six serious adverse events reported, none of the events were vaccine related. There were no deaths or premature withdrawals.

ConclusionA single-dose of Ad5-nCoV vaccine induced a marked specific humoral and cellular immune response with a favourable safety profile.

Trial RegistrationClinicalTrials.gov: NCT04540419


title: Trajectories of gene expression, seasonal influenza, and within-host seasonal immunity: transfer value to covid-19

abstract:
As a novel approach we will combine trajectories or longitudinal studies of gene expression with information on annual influenza epidemics. Seasonality of gene expression in immune cells from blood could be a consequence of within-host seasonal immunity interacting with the seasonal pandemics of influenza (flu) in temperate regions and, thus, with potential valuable analogy transfer to the proposed seasonal development of covid-19.

Here we operationalized within-host immunity as genes with both a significant seasonal term and a significant flu term in the sine-cosine model. Information on gene expression was based on microarray using RNase buffered blood samples collected randomly from a population-based cohort of Norwegian middle-aged women in 2003-2006, The Norwegian Women and Cancer (NOWAC) study. The unique discovery (N=425) and replication (N=432) design were based on identical sampling and preprocessing. Data on proportion of sick leaves due to flu, and the flu intensities per week was obtained from the National Institute of Public Health, giving a semi-ecological analysis.

The discovery analysis found 2942 (48.1%) significant genes in a generalized seasonal model over four years. For 1051 within-host genes both the seasonal and the flu term were significant. These genes followed closely the flu intensities. The trajectories showed slightly more genes with a maximum in early winter than in late summer. Moving the flu intensity forward in time indicated a better fit 3-4 weeks before the observed influenza. In the replication analyses, 369 genes (35.1% of 1051) were significant. Exclusion of genes with unknown functions and with more than a season in difference reduced the number of genes in the discovery dataset to 305, illustrating the variability in the measurements and the problem in assessing weak biological relationships. Thus, we found for the first time a clear seasonality in gene expression with marked responses to the annual seasonal influenza in a unique discovery - replication design. Hypothetically, this could support the within-host seasonal immunity concept.


title: Temporal trends, socio-economic inequalities in obesity and responses by federal government, Nepal: a systematic review of observational studies, policies, strategies and plans, 2005-2019

abstract:
BackgroundObesity has risen to epidemic proportions in low-income countries such as Nepal whose achievements in reducing maternal and child-undernourishment is well known. However, scientific evidence concerning recent transition towards obesity and corresponding responses by the state remains scanty. This review purported to assess the trends and disparities in obesity prevalence among women and children, and to analyse the governmental policies and programmes.

MethodsWe searched PubMed and Google Scholar for articles published between January 1, 2005 and April 10, 2019, and websites of Demographic and Health Survey, Non-Communicable Diseases Risk Factor Survey, and Micronutrient Status Survey. We extracted data on the prevalence of obesity and overweight from the selected studies and synthesised narratively. Overweight and obesity prevalence data from the latest available nationwide surveys were disaggregated by gender, geographical location and household wealth quintile. We retrieved the federal governmental policies, strategies and plans from the websites of Ministry of Health and Population and the National Nutrition and Food Security Secretariat, National Planning Commission.

ResultsTwenty studies that reported prevalence of overweight and/or obesity, with data from 79,082 men and women aged 15 years or more and 11,866 children under five years, were included. Obesity or overweight among men and women increased from 20.0% in 2004 to 36.1% in 2016 while obesity alone rose from 5.3% to 7.5%. Prevalence of childhood obesity or overweight remained very low, although doubled between 2006 and 2016, from 0.6% to 1.2%. Prevalences of overweight and obesity were much higher among women, inhabitants of urban areas and central provinces, and the affluent. Governmental policies, strategies and plans on nutrition were primarily designed to control undernutrition, with some direct and indirect implications for preventing obesity.

ConclusionsPrevalence of overweight and obesity increased substantially between 2005 and 2019, disproportionately affecting socio-economic and geographical groups in Nepal. Governmental efforts to contain the obesity epidemic should be reinforced by actions that are more specifically targeted to addressing obesogenic environments.

Systematic review registrationPROSPERO CRD42019132332

category: public and global health


title: High-throughput discovery of SLC6A1 variants affecting GABA transport in neurological disorders

abstract: SLC6A1 encodes the neuronal GABA transporter GAT-1. Pathogenic variants in SLC6A1 lead to haploinsufficiency and are associated with epilepsy, autism and schizophrenia. Most variants observed in patients are rare missense mutations whose functional impact and pathogenicity remain unknown. We quantified GABA uptake of 182 SLC6A1 variants using plasmid expression constructs in SLC6A1-deficient HEK293T cells. Cells were incubated with deuterated GABA, then analyzed by mass spectrometry to assess transporter activity. Of the 102 variants with partial or complete loss of transporter function compared to wildtype, only 24 (23.5%) had previously been classified as Pathogenic or Likely pathogenic in the ClinVar database. This suggests an increase in the number of SLC6A1 variants that are likely pathogenic, implying a 40% increased diagnostic yield for SLC6A1 haploinsufficiency. SLC6A1 variants associated with Schizophrenia did not lead to complete loss of function, suggesting either an association between hypomorphic variants and Schizophrenia or an alternative mechanism of pathogenesis.

category: neurology


title: Assessment of Androgen Receptor splice variant-7 as a biomarker of clinical response in castration-sensitive prostate cancer

abstract:
BackgroundTherapies targeting the androgen receptor (AR) have improved the outcome for patients with castration-sensitive prostate cancer (CSPC). Expression of the constitutively active AR splice variant-7 (AR-V7) has shown clinical utility as a predictive biomarker of AR-targeted therapy resistance in castration-resistant prostate cancer (CRPC), but its importance as predictive biomarker in CSPC remains understudied.

MethodsWe explored multiple approaches to quantify AR-V7 mRNA and protein in prostate cancer cell lines and patient-derived xenograft (PDX) models, in both publicly available and independent institutional clinical cohorts, to identify reliable approaches for detecting AR-V7 mRNA and protein, and its association with clinical outcome.

ResultsIn publicly available benign prostate, CSPC and CRPC cohorts, AR-V7 mRNA was much less abundant when detected using reads across splice boundaries than when considering isoform-specific exonic reads. The RM7 AR-V7 antibody had increased sensitivity and specificity for AR-V7 protein detection by immunohistochemistry (IHC) in CRPC cohorts and identified AR-V7 protein reactivity very rarely in CSPC cohorts, when compared to the EPR15656 AR-V7 antibody. Using multiple CRPC PDX models, we demonstrated that AR-V7 expression was exquisitely sensitive to hormonal manipulation. In CSPC cohorts, AR-V7 protein quantification by either assay did not associate with time to development of castration-resistance or overall survival, and intense neoadjuvant androgen-deprivation therapy did not lead to significant detectable AR-V7 mRNA or staining following treatment, and neither pre- nor post-treatment AR-V7 levels associated with the volume of residual disease after therapy.

ConclusionThis study demonstrates that further analytical validation and clinical qualification is required before AR-V7 can be considered for clinical use in CSPC as a predictive biomarker.

category: oncology


title: Unified classification and risk-stratification in Acute Myeloid Leukemia

abstract: Clinical recommendations for AML classification and risk-stratification remain heavily reliant on cytogenetic findings at diagnosis, which are present in <50% of patients. Using comprehensive molecular profiling data from 3,653 patients we characterize and validate 16 molecular classes describing 100% of AML patients. Each class represents diverse biological AML subgroups, and is associated with distinct clinical presentation, likelihood of response to induction chemotherapy, risk of relapse and death over time. Secondary AML-2, emerges as the second largest class (24%), associates with high-risk disease, poor prognosis irrespective of flow MRD negativity, and derives significant benefit from transplantation. Guided by class membership we derive a 3-tier risk-stratification score that re-stratifies 26% of patients as compared to standard of care. This results in a unified framework for disease classification and risk-stratification in AML that relies on information from cytogenetics and 32 genes. Last, we develop an open-access patient-tailored clinical decision support tool.

category: hematology


title: Seroneutralization of Omicron BA.1 and BA.2 in patients receiving anti-SARS-CoV-2 monoclonal antibodies.

abstract: The SARS-CoV-2 Omicron BA.1 variant has been supplanted in many countries by the BA.2 sub-lineage. BA.2 differs from BA.1 by about 21 mutations in its spike. Human anti-spike monoclonal antibodies (mAbs) are used for prevention or treatment of COVID-19. However, the capacity of therapeutic mAbs to neutralize BA.1 and BA.2 remains poorly characterized. Here, we first compared the sensitivity of BA.1 and BA.2 to neutralization by 9 therapeutic mAbs. In contrast to BA.1, BA.2 was sensitive to Cilgavimab, partly inhibited by Imdevimab and resistant to Adintrevimab and Sotrovimab. Two combinations of mAbs, Ronapreve (Casirivimab + Imdevimab) and Evusheld (Cilgavimab + Tixagevimab), are indicated as a pre-exposure prophylaxis in immunocompromised persons at risk of severe disease. We analyzed sera from 29 such individuals, up to one month after administration of Ronapreve and/or Evusheld. After treatment, all individuals displayed elevated antibody levels in their sera and neutralized Delta with high titers. Ronapreve recipients did not neutralize BA.1 and weakly impaired BA.2. With Evusheld, neutralization of BA.1 and BA.2 was detected in 19 and 29 out of 29 patients, respectively. As compared to Delta, titers were more severely decreased against BA.1 (344-fold) than BA.2 (9-fold). We further report 4 breakthrough Omicron infections among the 29 participants. Therefore, BA.1 and BA.2 exhibit noticeable differences in their sensitivity to therapeutic mAbs. Anti-Omicron activity of Ronapreve, and to a lesser extent that of Evusheld, is reduced in patients sera, a phenomenon associated with decreased clinical efficacy.


title: SHERLOCK4HAT: a CRISPR-based tool kit for diagnosis of Human African Trypanosomiasis

abstract: Elimination of Human African Trypanosomiasis (HAT) requires highly specific and sensitive tools for both diagnostic at point of care and epidemiological surveys. We have adapted SHERLOCK (Specific High-sensitivity Enzymatic Reporter unLOCKing) for the detection of trypanosome nucleic acids. Our SHERLOCK4HAT diagnostic tool kit, using 7SLRNA, TgSGP and SRA targets, distinguishes between Trypanosoma brucei (T. b.) brucei, T. b. gambiense (g) and T. b. rhodesiense (r) without cross-reactivity and with sensitivity between 0.01 and 0.1 parasite/{micro}L. SHERLOCK4HAT can accurately detect a trypanosome infection in cryo-banked patient buffy coats, with 85.1% sensitivity and 98.4% specificity for gHAT, and 100% sensitivity and 94.1% specificity for rHAT. Our SHERLOCK4HAT diagnostic showed 85.6% correlation with a reference standard qPCR in gHAT patients, 96.2% correlation in rHAT patients, discriminates between r/gHAT with 100% accuracy and is compatible with lateral flow assay readout for use at the point of care.


title: Plasma metabolites associated with cognitive function across race/ethnicities affirming the importance of healthy nutrition

abstract:
INTRODUCTIONWe studied the replication and generalization of previously identified metabolites potentially associated with global cognitive function in multiple race/ethnicities and assessed the contribution of diet to these associations.

METHODSWe tested metabolite-cognitive function associations in U.S.A. Hispanic/Latino adults (n= 2,222) from the Community Health Study/ Study of Latinos (HCHS/SOL) and in European (n=1,365) and African (n=478) Americans from the Atherosclerosis Risk In Communities (ARIC) Study. We applied Mendelian Randomization (MR) analyses to assess causal associations between the metabolites and cognitive function and between Mediterranean diet and cognitive function.

RESULTSSix metabolites were consistently associated with lower global cognitive function across all studies. Of these, four were sugar related (e.g., ribitol). MR analyses provided weak evidence for a potential causal effect of ribitol on cognitive function and bi-directional effects of cognitive performance on diet.

DISCUSSIONSeveral diet-related metabolites were associated with global cognitive function across studies with different race/ethnicities.


title: SARS-CoV-2 seroconversion in response to infection and vaccination: A time series local study in Brazil

abstract: The investigation of antibodies raised against different SARS-CoV-2 antigens can help to determine the extent of previous SARS-CoV-2 infections in the population and track the humoral response to vaccination. Therefore, serological surveys can provide key information to better manage the pandemic and/or to implement the most effective vaccination program. Here we describe a time series anti-Nucleocapsid, anti-Spike IgG serological survey analysis in the city of Matinhos, PR, Brazil during the year of 2021. Seroconversion rates to the Nucleocapsid antigen was not influenced by gender or age. Comparison of the serological data with official COVID-19 cases in the city suggest that case sub notification is higher than 47%. Furthermore, by applying serological data, the corrected infection fatality rate was estimated to be lower than 2.4 % in contrast with the official estimative of 3.6 %. The rates of IgG reactive to Spike antigen resembled the curve of the fraction the population that had taken the second vaccine dose. Up to 82% of Spike seroconversion was detected in the end of 2021 confirming the effective of the COVID-19 vaccination program in the city. This SARS-CoV-2 serological study unraveled the SARS-CoV-2 infection rates and the response to vaccination in the city of Matinhos. It is likely that the numbers reported here may be similar in other cities in Brazil.


title: Pharmacokinetics of favipiravir in adults with mild COVID-19 in Thailand

abstract: We assessed the pharmacokinetics of favipiravir (FPV) in adults with symptomatic SARS-CoV-2 infection without pneumonia in Thailand. FPV dosing was 1800 mg twice-daily on day 1, then 800 mg twice-daily for 14 days. Eight subjects (7 female), median (range) age 39 (19-53) years and BMI 27.9 (18.0-33.6) were included. Inter-subject variability was high but all achieved minimum plasma concentrations (Cmin) above EC50 (9.7 mg/L). FPV was well tolerated; 1 subject stopped prematurely due to rash.

category: pharmacology and therapeutics


title: Development of medical device software for the screening and assessment of depression severity using data collected from a wristband-type wearable device: SWIFT study protocol

abstract:
IntroductionFew biomarkers can be clinically used to diagnose and assess the severity of depression. However, a decrease in activity and sleep efficiency can be observed in depressed patients, and recent technological developments have made it possible to measure these changes. In addition, physiological changes, such as heart rate variability, can be used to distinguish depressed patients from normal persons; these parameters can be used to improve diagnostic accuracy. The proposed research will explore and construct machine learning models capable of detecting depressive episodes and assessing their severity using data collected from wristband-type wearable devices.

MethodsPatients with depressive symptoms and healthy subjects will wear a wristband-type wearable device for 7 days; data on triaxial acceleration, pulse rate, skin temperature, and ultraviolet light will be collected. On the seventh day of wearing, the severity of depressive episodes will be assessed using SCID-5, HAMD, and other scales. Data for up to five 7-day periods of device wearing will be collected from each subject. Using wearable device data associated with clinical symptoms as supervisory data, we will explore and build a machine learning model capable of identifying the presence or absence of depressive episodes and predicting the HAMD scores for an unknown data set.

DiscussionOur machine learning model could improve the clinical diagnosis and management of depression through the use of a wearable medical device.

Trial RegistrationjRCT1031210478, Japan Registry of Clinical Trials (jRCT)


title: Using remotely delivered Spring Forest Qigong to reduce neuropathic pain in adults with spinal cord injury: Protocol of a quasi-experimental clinical trial

abstract:
BackgroundAbout 50% of Americans living with spinal cord injury (SCI) suffer from long-term debilitating neuropathic pain, interfering with quality of daily life. Neuropathic pain is refractory to many available treatments -some carrying a risk for opioid addiction- highlighting an urgent need for new treatments. In this study, we will test our hypothesis that Spring Forest Qigong will reduce SCI-related neuropathic pain by improving body awareness. We will determine whether remotely delivered Qigong is feasible and whether it reduces neuropathic pain (primary outcome). We will also determine whether it reduces spasms frequency and/or severity, improves functional performance, mood, or body awareness (secondary outcomes).

MethodsIn this quasi-experimental study, adults with SCI will practice Qigong at home with a 45min video, at least 3x/week for 12 weeks. The Qigong practice includes movements with guided breathing and is individualized based on functional abilities, i.e., the participants will do kinesthetic imagery of Qigong movements with guided breathing, for movements that they are unable to perform actively. The primary clinical outcome [boxh]the highest, average, and lowest neuropathic pain ratings perceived in the prior week[boxh] will be recorded weekly throughout the study period. The secondary outcomes will be collected at 4 time points: at baseline, midway during the Qigong intervention (6 weeks), after the Qigong intervention (12 weeks), and after the 6-week follow-up. The data will be analyzed with a repeated measure ANOVA and with Tukey post-hoc tests.

DiscussionSuccessful outcomes will provide promising evidence for remotely delivered Qigong for neuropathic pain and spasm reduction in individuals living with SCI.

Clinical Trial registration number: ClinicalTrials.gov: NCT04917107

HIGHLIGHTSO_LISpinal cord injury-related neuropathic pain is notoriously difficult to treat.
C_LIO_LIQigong is a mind and body approach, accessible for adults with spinal cord injury.
C_LIO_LIWe will investigate the feasibility of a remotely delivered Qigong intervention.
C_LI

category: rehabilitation medicine and physical therapy


title: Different Covid-19 Outcomes Among Systemic Rheumatic Diseases: A Nation-wide Cohort Study

abstract:
BackgroundNationwide data at a country level on Covid-19 in unvaccinated patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are scarce.

MethodsBy interlinking data from national electronic registries, covering nearly 99% of the Greek population (approximately 11,000,000), between March 2020 and February 2021, when vaccination became available, we recorded confirmed infections and Covid-19-associated hospitalizations and deaths in essentially all adult patients with RA, AS, PsA, SLE, and SSc under treatment (n=74,970, median age of 67.5, 51.2, 58.1, 56.2, 62.2 years, respectively) and in individually matched (1:5) on age, sex, and region of domicile random comparators from the general population.

ResultsBinary logistic regression analysis after adjusting for age, sex and biologic agents, revealed that RA, PsA, SLE and SSc, but not AS patients, had significantly higher risk of infection (by 43%, 25%, 20% and 49%, respectively), and hospitalization for Covid-19 (by 81%, 56%, 94%, and 111%, respectively), possibly due, at least in part, to increased testing and lower threshold for admission. Patients with RA and SSc had indeed higher Covid-19 associated mortality rates [OR:1.86 (95% CI 1.37 to 2.52) and OR:2.90 (95% CI 0.97 to 8.67), respectively] compared to the general population. Each additional year of age increased the risk of hospitalization for Covid-19 by 3% (OR 1.030, 95% CI: 1.028 to 1.034) and the risk of Covid-19 related death by 8% (OR 1.08, 95% CI: 1.07 to 1.09), independently of gender, systemic rheumatic disease, and biologic agents. A further analysis using AS patients as the reference category, adjusting again for age, sex and use of biologic agents showed that patients with SSc had increased mortality (OR: 6.90, 95% CI: 1.41 to 33.72), followed by SLE (OR: 4.05 95% CI: 0.96 to 17.12) and RA patients (OR: 3.65, 95% CI: 1.06 to 12.54), whereas PsA patients had comparable mortality risk with AS patients.

ConclusionComparing to the general population, Covid-19 may have a more severe impact in real-world patients with systemic rheumatic disease. Covid-19 related mortality is increased in subgroups of patients with specific rheumatic diseases, especially in older ones, underscoring the need for priority vaccination policies and access to targeted treatments.

category: rheumatology


title: Prevention of SARS-CoV-2 airborne transmission in a workplace based on CO2 sensor network

abstract:
We measured the compartmental air change per hour (ACH) using a CO2 sensor network in an office space where a cluster of COVID-19 infections attributed to aerosol transmission occurred. Generalized linear mixed models and dynamic time warping were used for a time series data analysis, and the results indicated that the ventilation conditions were poor at the time of the cluster outbreak, and that the low ACH in the room likely contributed to the outbreak. In addition, the adverse effects of inappropriate partitions and the effectiveness of ventilation improvements were investigated in detail. ACH of less than 2 /h was considered a main contributor for the formation of the COVID-19 cluster in the studied facility.

Practical ImplicationsA systematic method for measuring and evaluating indoor ventilation to prevent the spread of infectious diseases caused by aerosols is presented. Ventilation bias caused by ventilation pathways and inappropriate use of plastic sheeting can be detected by a CO2 sensor network and time series data analysis. Estimated ventilation rate will be a good index to suppress the formation of the COVID-19 cluster.

category: occupational and environmental health


title: Evidence for SARS-CoV-2 Delta and Omicron co-infections and recombination

abstract: Between November 2021 and February 2022, SARS-CoV-2 Delta and Omicron variants co-circulated in the United States, allowing for co-infections and possible recombination events. We sequenced 29,719 positive samples during this period and analyzed the presence and fraction of reads supporting mutations specific to either the Delta or Omicron variant. We identified 18 co-infections, one of which displayed evidence of a low Delta-Omicron recombinant viral population. We also identified two independent cases of infection by a Delta-Omicron recombinant virus, where 100% of the viral RNA came from one clonal recombinant. In the three cases, the 5-end of the viral genome was from the Delta genome, and the 3-end from Omicron including the majority of the spike protein gene, though the breakpoints were different. Delta-Omicron recombinant viruses were rare, and there is currently no evidence that Delta-Omicron recombinant viruses are more transmissible between hosts compared to the circulating Omicron lineages.

category: infectious diseases


title: Blood group O and post-COVID-19 syndrome

abstract:
ObjectiveThe ABO blood group system modulates the inflammatory response and has been involved in COVID-19. O-group protects against SARS-CoV-2 infection, but there are no data regarding post-COVID-19 syndrome (PCS). Our aim was to assess this possible association.

Subjects and methodsCase-control study in a community setting, with subjects who had experienced mild COVID-19. Cases were PCS+, controls were PCS-, and the exposure variable, O-group. Epidemiological data (age, sex, BMI, smoking, comorbidities), laboratory parameters (inflammatory markers, IgG antibodies, blood type) and clinical data were collected. Composite inflammatory indices were developed. Multivariate analyses were performed.

ResultsWe analyzed 121 subjects (56.2% women), mean age 45.7 {+/-} 16 years. Blood group frequencies were 43.3%, 7.7%, 5.7%, and 43.3% for A, B, AB and O, respectively. Thirty-six patients were PCS+. There were no significant differences between cases and controls. Compared to non-O, a higher prevalence of PCS (p=0.036), number of symptoms (p=0.017) and myalgia (p=0.030) were noted in O-group. Concerning inflammatory markers, PCS+ and PCS-showed no differences in A, B, and AB groups. In contrast, O-group PCS+ patients had significantly higher lymphocyte count, higher levels of fibrinogen and CRP, and higher percentages of 3 composite indices, than PCS-subjects. The O-group showed a 4-fold increased risk of PCS compared to non-O (adjusted OR=4.20 [95%CI, 1.2-14]; p=0.023).

ConclusionAn increased risk of PCS has shown to be associated with O-group, after controlling for confounders. In O-group subjects with PCS, slightly albeit significant, raised levels of fibrinogen, CRP, and lymphocyte count, have been demonstrated.


title: Current epidemiological situation of COVID-19 in the Republic of Belarus: characteristics of the epidemic process, sanitary and anti-epidemic measures

abstract:
This is an analysis of the features of the COVID-19 pandemic the population of the Republic of Belarus from February 2020 to January 2022, the characteristics of sanitary and anti-epidemic measures carried out in the country, assessment of study the safety (tolerance) of the vaccines used the epidemiological efficacy of the vaccination.

A retrospective analysis of COVID-19 cases in the Republic of Belarus from the beginning of registration (February 28, 2020) to January, 3, 2022 was performed. Vaccine safety (tolerance) and efficacy were assessed in an observational study. Safety (tolerance) was assessed by presence/absence of adverse reactions: general (fever, malaise, headache, muscle pain, runny nose, nausea, vomiting, sore throat, etc) and local ones (redness, swelling, soreness at the injection place).

The COVID-19 pandemic in the Republic of Belarus is characterized by successive development stages: from no cases in early 2020 to detected cases where most individuals had no history of contact with COVID-19 patients; periods of rising and falling incidence

Vaccines against COVID-19 (Gam-COVID-Vac (Russia), inactivated vaccine against SARS-CoV-2 (Vero Cell) Sinopharm / BIBP (China) demonstrated a high safety profile in mass vaccination of the population of the Republic of Belarus.


title: FHIR Profiliferation: A Data Science Approach

abstract: Profiling is a mechanism for shaping Fast Healthcare Interoperability Resources (FHIR) for particular use cases. "Profiliferation" (profile + proliferation) is a coinage referring to the explosive growth in the number of FHIR profiles over the past few years. By reviewing a broad sample of almost 3000 FHIR profiles from 125 implementation guides, it was determined that just two items, Observation and Extension, accounted for half the profiles. FHIRs 80/20 rule was determined to be closer to 65/35, revealing that FHIR is more dependent on profiling than initially intended. Use of the Observation resource was inconsistent, hinting that the resource is either poorly designed, or that users lack proper guidance. Better management of reusable items and certain changes in FHIR and profiling practices could improve the consistency of FHIR artifacts and reduce unnecessary and potentially incompatible profiles.


title: Comparing People-Like-Me and linear mixed model predictions of functional recovery following knee arthroplasty

abstract:
ObjectivePrediction models can be useful tools for monitoring patient status and personalizing treatment in health care. The goal of this study was to compare the relative strengths and weaknesses of two different approaches for predicting functional recovery after knee arthroplasty: a neighbors-based "people-like-me" (PLM) approach and a linear mixed model (LMM) approach.

Materials and MethodsWe used two distinct datasets to train and then test PLM and LMM prediction approaches for functional recovery following knee arthroplasty. We used Timed Up and Go (TUG)--a commonly used test of mobility--to operationalize physical function. Both approaches used patient characteristics and baseline postoperative TUG values to predict TUG recovery from days 1-425 following surgery. We compared the accuracy and precision of PLM and LMM predictions in the testing dataset.

ResultsA total of 317 patient records with 1379 TUG observations were used to train PLM and LMM approaches, and 456 patient records with 1244 TUG observations were used to test the predictions. The approaches performed similarly in terms of mean squared error and bias, but the PLM approach provided more accurate and precise estimates of prediction uncertainty.

Discussion and ConclusionOverall, the PLM approach more accurately and precisely predicted TUG recovery following knee arthroplasty. These results suggest PLM predictions may be more clinically useful for monitoring recovery and personalizing care following knee arthroplasty. However, clinicians and organizations seeking to use predictions in practice should consider additional factors (e.g., resource requirements) when selecting a prediction approach.


title: Possible Role of P-selectin Adhesion in Long-COVID: A Comparative Analysis of a Long-COVID Case Versus an Asymptomatic Post-COVID Case

abstract:
BackgroundLong-term outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are now recognized as an emerging public health challenge - a condition termed Long-COVID. The pathophysiology of Long-COVID remains to be established. Functional P-selectin activity, implicated in COVID-19 sequalae, was measured between two convalescent COVID-19 subjects, one with (Long-COVID subject) and another without Long-COVID symptoms.

MethodsFlow adhesion of whole blood or isolated white blood cells to P-selectin (FA-WB-Psel and FA-WBC-Psel) was measured using a standardized microfluidics clinical assay; impedance aggregometry with a collagen agonist was measured using model 590 Chrono-Log impedance aggregometer; standard laboratory assays were performed to evaluate changes in blood chemistries.

ResultsFor both subjects, hemoglobin, WBC, platelet counts, electrolytes and ferritin were within normal reference ranges, with FA-WB-Psel significantly elevated compared to healthy controls (p< 0.01). In vitro treatment of whole blood samples with crizanlizumab (anti-p-selectin monoclonal antibody) within the clinical dose range (10 g/ml) mL) inhibited FA-WB-Psel only in samples from asymptomatic post-COVID subject, with the Long-COVID subject sample requiring close to 5-fold elevated dose to achieve a response. Pronounced inhibition of P-selectin adhesion of isolated leukocytes was observed for both subjects in autologous platelet-poor plasma and buffer. Impedance aggregometry showed greater baseline platelet aggregation to collagen in the Long-COVID sample, although both samples responded similarly to aspirin-induced platelet inhibition.

ConclusionsPresented results suggest that elevated platelet activation in Long-COVID subject may be associated with increased P-Selectin activity. The results are discussed in terms of possible use on P-selectin inhibition therapies in treating Long-COVID.


title: Bebtelovimab, alone or together with bamlanivimab and etesevimab, as a broadly neutralizing monoclonal antibody treatment for mild to moderate, ambulatory COVID-19

abstract:
BACKGROUNDBebtelovimab is a potent, fully human IgG1 monoclonal antibody (mAb) targeting the S-protein of SARS-CoV-2, with broad neutralizing activity to all currently known SARS-CoV-2 variants of concern, including omicron variant lineages. Specialized developmental approaches accelerated the initiation of a clinical trial designed to evaluate the efficacy and safety of bebtelovimab alone (BEB) or together with bamlanivimab (BAM) and etesevimab (ETE) delivered via slow intravenous push for the treatment of mild-to-moderate COVID-19.

METHODSThis portion of the phase 2, BLAZE-4 trial (J2X-MC-PYAH; NCT04634409) enrolled 714 patients (between May and July 2021) with mild-to-moderate COVID-19 within 3 days ([≤]3 days) of laboratory diagnosis of SARS-CoV-2 infection. Patients at low risk for severe COVID-19 were randomized 1:1:1 (double-blinded) to placebo, BEB 175 mg, or BEB 175 mg+BAM 700 mg+ETE 1400 mg (BEB+BAM+ETE). Patients at high risk for progression to severe COVID-19 were randomized 2:1 (open-label) to BEB or BEB+BAM+ETE, and a subsequent treatment arm enrolled patients to BEB+BAM+ETE using Centers for Disease Control and Prevention (CDC) updated criteria for High-risk. All treatments were administered intravenously over [≥]30 seconds (open-label BEB) or [≥]6.5 minutes (all other treatment arms). For the placebo-controlled patients (termed Low-risk), the primary endpoint was the proportion of patients with persistently high viral load (PHVL) (log viral load >5.27) on Day 7. For the open-label patients (termed High-risk), the primary endpoint was safety. In nonclinical studies, SARS-CoV-2 isolates were tested using an endpoint neutralization assay to measure BEBs inhibitory concentration greater than 99% (IC99).

RESULTSBaseline viral sequencing data were available from 611 patients; 90.2% (n=551) aligned with a variant of interest or concern (WHO designation), with the majority infected with delta (49.8%) or alpha (28.6%) variants. Among the Low-risk patients, PHVL occurred in 19.8% of patients treated with placebo, as compared to 12.7% (p=0.132) of patients treated with BEB+BAM+ETE and 12.0% (p=0.097) of patients treated with BEB, a 36% and 40% relative risk reduction, respectively. Viral load-area under the curve analysis from baseline to Day 11 showed statistically signficant reductions for patients treated with BEB (p=0.006) and BEB+BAM+ETE (p=0.043) compared to patients who received placebo. Time to sustained symptom resolution was reduced by a median of 2 days for patients treated with BEB (6 days; p=0.003) and 1 day for patients treated with BEB+BAM+ETE (7 days; p=0.289) compared to placebo (8 days). The incidence of COVID-19-related hospitalization or all-cause deaths by day 29 were similar across treatment arms, as expected given the patients risk status (the Low risk cohorts had a Low risk of hospitalization, and High risk cohorts received only active therapy without placebo). Overall, safety results were consistent with previous studies investigating mAbs targeting SARS-CoV-2. The proportion of patients with treatment emergent adverse events (AEs) were 9.7% in Low-risk (n=37/380) and 14.7% in High-risk (n=48/326) patients treated with BEB or BEB+BAM+ETE; majority of AEs were considered mild or moderate in severity. Serious AEs were reported in 2.1% of High-risk patients (n=7/326), including one death (a cerebrovascular accident); 1 serious AE was reported among Low-risk patients. In an in vitro neutralization assay, BEB neutralized the omicron isolate (BA.1) with <2.44ng/ml estimated IC99.

CONCLUSIONSIn patients with mild-to-moderate COVID-19, treatment with BEB or BEB+BAM+ETE was associated with greater viral clearance, a reduction in time to sustained symptom resolution, and safety results consistent with mAbs that target SARS-CoV-2. Integration of clinical findings with in vitro neutralization of emerging viral variants offered a pragmatic framework for investigating the efficacy of a new antiviral mAb agent, as demonstrated by bebtelovimab.


title: Rare Variants in Inborn Errors of Immunity Genes Associated with Covid-19 Severity

abstract: Covid-19 is a contagious disease caused by SARS-CoV-2, a novel severe acute respiratory syndrome coronavirus. Common variants and networks underlying host genetic mechanisms have been extensively studied to identify disease-associated genetic factors. However, there are few studies about the rare variants, typically inborn errors of immunity, in understanding the host genetics behind Covid-19 infection, especially in the Chinese population. To fill this gap, we investigate likely-deleterious missense and high-confidence predicted loss-of-function variants by (a) performing gene- and pathway-level association analyses, (b) examining known genes involved in type I interferon signaling and others previously reported in Covid-19 disease, and (c) identifying candidate genes with accumulating mutations and their potential protein-protein interactions with known genes. Based on our analyses, several putative genes and pathways are uncovered and worth further investigation, for example, genes IL12RB1, TBK1, and TLR3, and pathways Tuberculosis (hsa:05152), Primary Immunodeficiency (hsa:05340), and Influenza A (hsa:05164). These regions generally play an essential role in regulating antiviral innate immunity responses to foreign pathogens and in responding to many inflammatory diseases. We believe that to some extent, as an acute inflammatory disease, Covid-19 is also affected by these inborn errors of immunity. We hope that the identification of these rare genetic factors will provide new insights into the genetic architecture of Covid-19.


title: Novel Application of a Multistate Model to Evaluate the Opioid Use Disorder Care Cascade: A Retrospective Cohort Study

abstract:
BackgroundEvaluating the opioid use disorder (OUD) care cascade can improve OUD treatment retention and care.

ObjectivesTo identify risk and protective factors for retention among patients in OUD treatment.

MethodsWe conducted a retrospective cohort study among patients diagnosed with OUD using data from the Rhode Island (RI) All-Payer Claims Database from 2011 to 2019. Patients who initiated treatment (Stage 2) were classified into sub-stages of retention (Stage 3) corresponding to multistate modeling states capturing early retention (sub-stage 1), short and long-term retention (sub-stage 2), and short and long-term disengagement (sub-stage 3). The association of baseline characteristics with state transitions were evaluated.

ResultsA cohort of 6,939 RI residents diagnosed with OUD included 41% aged 40 to 60 years, 57.6% male, and 70.8% Medicaid beneficiaries. In sub-stage 1, cannabis (Relative risk ratios (RRR) = 1.16; 95% confidence interval (CI) = 1.04,1.29) and cocaine use disorders (RRR=1.15; 95% CI=1.05,1.25) increased early disengagement risk after engagement. Medicaid beneficiaries were less likely to experience early disengagement (RRR=0.81; 95% CI =0.76,0.87). In sub-stage 2, alcohol (RRR=1.29; 95% CI=1.13,1.47) or cocaine use disorders (RRR=1.18; 95% CI=1.01,1.40) increased risk of disengagement among patients in the retention states. In sub-stage 3, tobacco (RRR=1.10; 95% CI=1.01,1.21) and alcohol (RRR=1.14; 95% CI=1.03,1.27) use disorders were associated with re-engagement from disengaged states.

ConclusionThe multistate model applied to a cohort of patients initiating medication for OUD led to the identification of factors associated with treatment engagement and retention. These results may guide strategies to sustain treatment among OUD patients.

category: addiction medicine


title: Prevalence and Predictors of Depression, Anxiety and Stress among Elderly in the aftermath of COVID-19: A Quantitative Study from Central India

abstract:
BackgroundElderly persons have been more prone to depression, anxiety and stress during COVID-19 pandemic. They need more care and support towards mental health during these difficult times.

MethodologyThis was a cross-sectional and quantitative study conducted in the state of Madhya Pradesh, during the month of March 2021 to August 2021. Participants were recruited from a population aged more than 60 years, those who were able to read and write Hindi/English or having at least one family member; reporting to a tertiary care teaching hospital during the second wave of COVID-19 in India. Those who were confirmed COVID-19 cases & undergoing treatment, with diagnosed mental health disorders and who didnt give consent were excluded. A semi-structured questionnaire along with DASS-21 scale was completed by participants online.

ResultsOut of 690 subjects, 7.25% had mild and moderate depression, 0.58% had severe and extremely severe depression. Mild and moderate anxiety symptoms were reported by 9.56%, 2.46% reported severe and extremely severe anxiety. Mild and moderate stress was reported by 4.78%, while 0.42% were severely and extremely stressed. A positive statistical association was found between alcohol addiction and depression (p=0.028). The elderly subjects had a nap the day time were significantly less depressed during COVID-19 pandemic (p=0.033). It was found that older the subjects, more were they anxious during the pandemic (p=0.042). An association was found between alcohol addiction and stress (p=0.043).

ConclusionsDepressive symptoms in participants were positively correlated with alcohol addiction. Females reported higher level of stress. There is a felt need to formulate psychological interventions for elderly to improve their mental health and psychological resilience. We need to tackle and fight the stigma, fear and anxiety related to the COVID-19, which is greater than disease itself.

Key messageO_ST_ABSWhat is already knownC_ST_ABSPsychological problems like anxiety, depressive symptoms, fearfulness, a state of uncertainty and stress are common in all age groups; furthermore older adults are more prone to develop mental health issues in wake of stressful situations.

What this study adds toAbout one fourth of elderly developed anxiety, depression and stress during the COVID-19 pandemic.

Effect on practice and policyThere is a need for proactive identification through screening of elderly for mental health issues following unprecedented stress like COVID-19 pandemic.