title: Effectiveness of COVID-19 vaccines against Omicron and Delta hospitalisation: test negative case-control study

abstract:
BackgroundThe omicron (B.1.1.529) variant has been associated with reduced vaccine effectiveness (VE) against infection and mild disease with rapid waning, even after a third dose, nevertheless omicron has also been associated with milder disease than previous variants. With previous variants protection against severe disease has been substantially higher than protection against infection.

MethodsWe used a test-negative case-control design to estimate VE against hospitalisation with the omicron and delta variants using community and in hospital testing linked to hospital records. As a milder disease, there may be an increasing proportion of hospitalised individuals with Omicron as an incidental finding. We therefore investigated the impact of using more specific and more severe hospitalisation indicators on VE.

ResultsAmong 18-64 year olds using all Covid-19 cases admitted via emergency care VE after a booster peaked at 82.4% and dropped to 53.6% by 15+ weeks after the booster; using all admissions for >= 2 days stay with a respiratory code in the primary diagnostic field VE ranged from 90.9% down to 67.4%; further restricting to those on oxygen/ventilated/on intensive care VE ranged from 97.1% down to 75.9%. Among 65+ year olds the equivalent VE estimates were 92.4% down to 76.9%; 91.3% down to 85.3% and 95.8% down to 86.8%.

ConclusionsWith generally milder disease seen with Omicron, in particular in younger adults, contamination of hospitalisations with incidental cases is likely to reduce VE estimates against hospitalisation. VE estimates improve and waning and waning is more limited when definitions of hospitalisation that are more specific to severe respiratory disease are used.


title: Consistent Pattern of Epidemic Slowing Across Many Geographies Led to Longer, Flatter Initial Waves of the COVID-19 Pandemic

abstract:
To define appropriate planning scenarios for future pandemics of respiratory pathogens, it is important to understand the initial transmission dynamics of COVID-19 during 2020. Here, we fit an age-stratified compartmental model with a flexible underlying transmission term to daily COVID-19 death data from states in the contiguous U.S. and to national and sub-national data from around the world. The daily death data of the first months of the COVID-19 pandemic was categorized into one of four main types: "spring single-peak profile", "summer single-peak profile", "spring/summer two-peak profile" and "broad with shoulder profile". We estimated a reproduction number R as a function of calendar time tc and as a function of time since the first death reported in that population (local pandemic time, tp). Contrary to the multiple categories and range of magnitudes in death incidence profiles, the R(tp) profiles were much more homogeneous. We find that in both the contiguous U.S. and globally, the initial value of both R(tc) and R(tp) was substantial: at or above two. However, during the early months, pandemic time R(tp) decreased exponentially to a value that hovered around one. This decrease was accompanied by a reduction in the variance of R(tp). For calendar time R(tc), the decrease in magnitude was slower and non-exponential, with a smaller reduction in variance. Intriguingly, similar trends of exponential decrease and reduced variance were not observed in raw death data. Our findings suggest that the combination of specific government responses and spontaneous changes in behaviour ensured that transmissibility dropped, rather than remaining constant, during the initial phases of a pandemic. Future pandemic planning scenarios should be based on models that assume similar decreases in transmissibility, which lead to longer epidemics with lower peaks when compared with models based on constant transmissibility.

Author summaryIn planning for a future novel respiratory pandemic, or the next variant of SARS-Cov-2, it is important to characterize and understand the observed epidemic patterns during the first months of the COVID-19 outbreak. Here, we describe COVID-19 epidemic patterns observed in the U.S. and globally in terms of patterns of the basic reproduction number, R(t), using an age-stratified compartmental model. We find that daily death data of the first months of the COVID-19 pandemic can be classified into one of four types: "spring single-peak profile", "summer single-peak profile", "spring/summer two-peak profile" and "broad with shoulder profile". Using the concept of local pandemic time, tp, we show a consistent pattern on four continents of an initial large magnitude and variance in reproductive number R(tp) that decreases monotonically and hovers around one for many days, regardless of specific intervention measures imposed by local authorities and without an accompanying decrease in daily death prevalence. We attribute this to significant behavior changes in populations in response to the perceived risk of COVID-19.

category: epidemiology


title: Latent Factors of Language Disturbance and Relationships to Quantitative Speech Features

abstract:
Background and HypothesisQuantitative acoustic and textual measures derived from speech ("speech features") may provide valuable biomarkers for psychiatric disorders, particularly schizophrenia spectrum disorders (SSD). We sought to identify cross-diagnostic latent factors for speech disturbance with relevance for SSD and computational modeling.

Study DesignClinical ratings for speech disturbance were generated across 14 items for a cross-diagnostic sample (N=343), including SSD (n=97). Speech features were quantified using an automated pipeline for brief recorded samples of free-speech. Factor models for the clinical ratings were generated using exploratory factor analysis, then tested with confirmatory factor analysis in the cross-diagnostic and SSD groups. Relationships among factor scores, speech features and other clinical characteristics were examined using network analysis.

Study ResultsWe found a 3-factor model with good fit in the cross-diagnostic group and acceptable fit for the SSD subsample. The model identifies an impaired expressivity factor and two interrelated disorganized factors for inefficient and incoherent speech. Incoherent speech was specific to psychosis groups, while inefficient speech and impaired expressivity showed intermediate effects in people with nonpsychotic disorders. Network analysis showed that the factors had distinct relationships with speech features, and that the patterns were different in the cross-diagnostic versus SSD groups.

ConclusionsWe report a cross-diagnostic 3-factor model for speech disturbance which is supported by good statistical measures, intuitive, applicable to SSD, and relatable to linguistic theories. It provides a valuable framework for understanding speech disturbance and appropriate targets for modeling with quantitative speech features.

category: psychiatry and clinical psychology


title: An investigation of age-related neuropathophysiology in autism spectrum disorder using fixel-based analysis of corpus callosum white matter micro- and macrostructure

abstract:
BackgroundCorpus callosum anomalies are commonly noted in autism spectrum disorder (ASD). Given the complexity of its microstructural architecture, with crossing fibers projecting throughout, we applied fixel-based analysis to probe white matter micro- and macrostructure within this region. As ASD is a neurodevelopmental condition with noted abnormalities in brain growth, age was also investigated.

MethodsData for participants with (N=54) and without (N=50) ASD, aged 5-34 years, were obtained from the Autism Brain Imaging Data Exchange-II (ABIDE-II). Within each site, indices of fiber density (FD), fiber cross-section (FC), and combined fiber density and cross-section (FDC) were compared between those groups.

ResultsYoung adolescents with ASD (age = 11.19 {+/-} 7.54) showed reduced macroscopic FC and FDC compared to age-matched neurotypical controls (age = 10.04 {+/-} 4.40). Reduced FD and FDC was noted in a marginally older ASD (age 13.87 {+/-} 3.15) cohort compared to matched controls (age = 13.85 {+/-} 2.90). Among the oldest cohorts, a non-significant trend indicated reduced FD in older adolescents/young adults with ASD (age = 17.07 {+/-} 3.56) compared to controls (age = 16.55 {+/-} 2.95). There was a positive correlation between age and callosal mean FC and FDC in the youngest cohort. When stratified by diagnosis, this finding remained only for the ASD sample.

ConclusionWhite matter aberration appears greatest among younger ASD cohorts. In older adolescents and young adults, less of the corpus callosum seems affected. This supports the suggestion that some early neuropathophysiological indicators in ASD may dissipate with age.


title: Decontamination of Geobacillus Stearothermophilus Using the Arca Aerosolized Hydrogen Peroxide Decontamination System

abstract:
IntroductionIn response to the limited supply of personal protective equipment during the pandemic caused by SARS-CoV-2, recent studies demonstrate that gaseous H2O2 is an effective decontaminant of N95 filtering facepiece respirators to enable reuse of these items in a clinical setting. This paper evaluates the efficacy of the Arca Aerosolized Hydrogen Peroxide Decontamination System (Arca), a novel aerosolized H2O2 decontamination system, using biologic indicator testing.

Materials and MethodsThe Arca produces and circulates H2O2 aerosol inside of a sealed stainless steel chamber. The Arcas decontamination efficacy was evaluated in 8 decontamination trials with 2 H2O2 concentrations (3% and 12%) and 4 decontamination cycle durations (45, 60, 90, and 120 minutes). Efficacy was evaluated by testing: 1) the concentration in parts per million (ppm) of H2O2 produced inside the chamber and the concentration in ppm of H2O2 vented from the chamber, and 2) the decontamination of Mesa Biologic Indicator filter strips (BI) inoculated with Geobacillus Stearothermophilus. Control tests were conducted by submerging BI strips in 3mL of 3% and 12% H2O2 for 120 minutes (negative controls) and by not exposing one BI strip to H2O2 (positive control).

ResultsGreater than 5000 ppm of H2O2 was detected on the concentration strips inside the chamber for each of the eight decontamination trials. No vented H2O2 was detected on the external concentration strips after any decontamination trial. No growth was observed for any of the negative controls after seven days. The positive control was positive for growth.

ConclusionThe Arca Aerosolized Hydrogen Peroxide Decontamination System is effective at decontaminating bacterial G. Stearothermophilus at a cycle time of 45 minutes utilizing 6mL of 3% H2O2 solution.

category: public and global health


title: Internet and mental health during the COVID-19 pandemic: Evidence from the UK

abstract: With the COVID-19 pandemic, the Internet has become a key player in the daily lives of most people. We investigate the relationship between mental health and internet use frequency and purpose six months after the first lockdown in the UK, September 2020. Using data from the UK Household Longitudinal Study on the 12-item General Health Questionnaire and the Internet use module, and controlling for sociodemographic characteristics and personality traits, we find that older individuals (aged 59 or above) have a lower internet use frequency (twice a day or less). Younger women use the Internet for social purposes more than men do, while younger men use the Internet for leisure-and-learning purposes more than women and older men do. Both high frequency internet use and use for social purposes appear to be a protective factor for social dysfunction. Interestingly, high internet use is a protective factor for social dysfunction among younger women, but a risk factor for psychological distress among younger men. Finally, while leisure-and-learning purpose is a protective factor for social dysfunction among younger women, it is a risk factor for social dysfunction among younger men.


title: What factors converged to create a COVID-19 hot-spot? Lessons from the South Asian community in Ontario.

abstract:
BackgroundSouth Asians represent the largest non-white ethnic group in Canada. The Greater Toronto Area (GTA), home to a high proportion of South Asians, emerged as a COVID-19 hot spot. Early in the pandemic, the South Asian community was identified as having risk factors for exposure and specific barriers to accessing testing and reliable health information, rendering them uniquely vulnerable to SARS-CoV-2 infection.

ObjectivesTo investigate the burden of SARS-CoV-2 infection among South Asians in the GTA, and to determine which demographic characteristics were most closely aligned with seropositivity, in this cross-sectional analysis of a prospective cohort study.

MethodsParticipants from the GTA were enrolled between April and July 2021. Seropositivity for anti-spike and anti-nucleocapsid antibodies was determined from dried blood spots, and age and sex standardized to the Ontario South Asian population. Demographics, risk perceptions, and sources of COVID-19 information were collected via questionnaire in a subset.

ResultsAmong the 916 South Asians enrolled, mean age 41 years, the age and sex standardized seropositivity was 23.6% (95% CI: 20.8%-26.4%). Approximately one-third identified as essential workers, and 19% reported living in a multi-generational household. Over half perceived high COVID-19 risk due to their geographic location, and 36% due to their type of employment. The top three most trusted sources of COVID-related information included healthcare providers/public health, traditional media sources, and social media.

ConclusionBy the third wave of the COVID-19 pandemic, approximately one-quarter of a sample of South Asians in Ontario had serologic evidence of prior SARS-CoV-2 infection. Insight into factors that render certain populations at risk can help future pandemic planning and disease control efforts.


title: Using genetic information to define idiopathic pulmonary fibrosis in UK Biobank

abstract:
IntroductionIdiopathic pulmonary fibrosis (IPF) is a rare lung disease characterised by progressive scarring in the alveoli. IPF can be defined in population studies using electronic healthcare records (EHR) but recent genetic studies of IPF using EHR have shown an attenuation of effect size for known genetic risk factors when compared to clinically-derived datasets, suggesting misclassification of cases.

MethodsWe used EHR (ICD-10, Read (2 & 3)) and questionnaire data to define IPF cases in UK Biobank, and evaluated these definitions using association results for the largest genetic risk variant for IPF (rs35705950-T, MUC5B). We further evaluated the impact of exclusions based on co-occurring codes for non-IPF pulmonary fibrosis and restricting codes according to changes in diagnostic practice.

ResultsOdds ratio (OR) estimates for rs35705950-T associations with IPF defined using EHR and questionnaire data in UK Biobank were significant and ranged from 2.06 to 3.09 which was lower than those reported using clinically-derived IPF datasets (95% confidence intervals: 3.74, 6.66). Code-based exclusions of cases gave slightly closer effect estimates to those previously reported, but sample sizes were substantially reduced.

DiscussionWe show that none of the UK Biobank IPF codes replicate the effect size for the association of rs35705950-T on IPF risk when using clinically-derived IPF datasets. Further code-based exclusions also did not lead to effect estimates closer to those expected. Whilst the apparent increased sample sizes available for IPF from general population cohorts may be of benefit, future studies should take these limitations of the case definition into account.

Key MessagesO_ST_ABSWhat is already known on this topicC_ST_ABSUK Biobank is a very large prospective cohort that can be utilised to increase sample sizes for studies of rare diseases such as idiopathic pulmonary fibrosis (IPF). However, effect size estimates for genetic risk factors for IPF in UK Biobank and other general population cohorts, when defining cases using electronic healthcare records (EHR), are smaller than those estimated from clinically-derived IPF datasets.

What this study addsUsing Hospital Episode Statistics (HES) data, primary care data, death registry data and self-report data in UK Biobank, we used the association rs35705950-T, the largest genetic risk factor for IPF, to evaluate code-based definitions of IPF. We show that none of the available IPF coding replicates the effect size for rs35705950-T on IPF risk that is observed in clinically-derived IPF datasets.

How this study might affect research, practice or policyResearch using large general population cohorts and datasets for observational studies of IPF should take these limitations of EHR definitions of IPF into consideration.

category: respiratory medicine


title: The HIV and STI syndemic following mass scale-up of combination HIV interventions in Uganda: a population-based cross-sectional study

abstract:
BackgroundCombination HIV interventions (CHIs) have led to significant declines in HIV incidence in sub-Saharan Africa; however, population-level data on non-HIV sexually transmitted infection (STI) burden in the context of CHIs are rare. We aimed to assess STI burden in Uganda following mass scale-up of CHIs, including universal HIV treatment.

MethodsThe Sexually Transmitted Infection Prevalence Study (STIPS) was a cross-sectional study nested within the Rakai Community Cohort Study (RCCS), a population-based cohort among inland agrarian and Lake Victoria fishing populations in southern Uganda. STIPS enrolled consenting participants, 18-49 years, between May and October 2019 and measured prevalence of Chlamydia trachomatis (chlamydia), Neisseria gonorrhoeae (gonorrhea), Trichomonas vaginalis (trichomonas), syphilis, and herpes simplex virus type 2 (HSV-2).

FindingsSTIPS enrolled 1,825 participants, including 965 women (53%), of whom 9% (n=107) were pregnant. Overall, there was 9.8% prevalence of chlamydia (95%CI:8.5-11%), 6.7% gonorrhea (95%CI:5.7-8.0%), and 11% trichomonas (95%CI:9.5-12%). In the fishing population, syphilis reactivity was 24% (95%CI:22-27%), with 9.4% (95%CI:7.7-11%) having high titer (RPR [≥] 1:8) infection, including 17% (95%CI:12-24%) of HIV-positive men. Prevalence of [≥] 1 curable STI (chlamydia, gonorrhea, trichomonas, or high titer syphilis) was 44% higher among HIV-positive persons (adjusted prevalence risk ratio [adjPRR]=1.44,95%CI:1.22-1.71), with no differences by HIV treatment status. HIV-positive pregnant women were more likely than HIV-negative pregnant women to have a curable STI (adjPRR=1.87, 95%CI: 1.08-3.23).

InterpretationSTI burden remains extremely high in Uganda, particularly among HIV-positive persons. There is an urgent need to integrate STI diagnostic testing and treatment with HIV services in African settings.

FundingNational Institutes of Health

category: sexual and reproductive health


title: Cervicovaginal immune mediators increase when young women begin to have sexual intercourse: a prospective study and meta-analysis

abstract:
BackgroundAdolescent girls and young women (AGYW) are at high risk of sexually transmitted infections (STIs). It is unknown whether beginning to have sexual intercourse causes changes to immune mediators in the cervicovaginal tract that contribute to this risk.

MethodsWe collected cervicovaginal lavages from Kenyan AGYW in the months before and after first penile-vaginal sexual intercourse and measured the concentrations of 20 immune mediators. We compared concentrations pre- and post-first sex using mixed effects models. Secondary analyses included adjustment for possible confounding factors. We additionally performed a systematic review to identify similar studies and combined them with our results by meta-analysis of individual participant data.

ResultsWe included 180 samples from 95 AGYW, with 44% providing only pre-first sex samples, 35% matched pre and post, and 21% only post. We consistently detected 19/20 immune mediators, all of which increased post-first sex (median increase 54%; p<0.05 for 13/19; Holm-Bonferroni-adjusted p<0.05 for IL-1{beta}, IL-2 and CXCL8). Effects remained similar after adjusting for confounding factors including STIs and Nugent score.

Our systematic review identified two eligible studies, one of 93 Belgian participants and the other of 18 American participants. Nine immune mediators were measured in at least 2/3 studies. Meta-analysis confirmed higher levels post-first sex for 8/9 immune mediators (median increase 47%; p<0.05 for six mediators, most prominently IL-1, IL-1{beta} and CXCL8).

ConclusionsCervicovaginal immune mediator concentrations increased after the beginning of sexual activity independently of confounding factors including STIs. Results were consistent across three studies conducted on three different continents.


title: Determinants of mobility decline in nephrology-referred patients with CKD: a longitudinal cohort study

abstract:
Background and ObjectiveChronic kidney disease (CKD) is associated with loss of muscle quality leading to mobility limitation and decreased independence. Identifying predictors of gait speed decline may help target rehabilitative therapies to those at highest risk of mobility impairment.

Design, setting and participants, and measurementsThe current prospective cohort study recruited ambulatory patients with stage 1-4 CKD (eGFR 15-89 ml/min/1.73m2) from nephrology clinics. Predictors included demographic and clinical variables including GFR estimated using serum cystatin C. Outcomes were average change in gait speed (m/s) per year and inclusion in the top tertile of gait speed decline over 3 years. Linear mixed models and relative risk regression were used to estimate associations with annual gait speed changes and fastest tertile of decline.

ResultsAmong 213 participants, 81% were male, 22% were black and 43% had diabetes. Mean age was 57{+/-}13 years, median follow-up 3.15 years, mean baseline eGFRcysc 47.9{+/-}21ml/min/1.73 m2, and median baseline gait speed 0.95m/s [IQR 0.81, 1.10]. Lower baseline eGFRcysc was associated with more rapid loss of gait speed (-0.029 m/s/year [95% CI -0.042, -0.015] per 30 ml/min/1.73 m2 lower eGFR; p<0.001). Diabetes was associated with -0.024m/s/year faster change (95% CI -0.042, -0.007; p=.007). Lower eGFRcysc was associated with a 49% greater risk of rapid gait speed decline (IRR 1.49; 95% CI 1.11, 2.00, p=.008) after adjustment.

Prevalent cardiovascular disease and African American race were associated with a 45% greater (IRR 1.45; 95% CI 1.04, 2.01, p=.03) and 58% greater rate of rapid gait speed decline (IRR 1.58; 95% CI 1.09, 2.29, p=.02), respectively.

ConclusionsAmong ambulatory, disability-free patients with CKD, lower eGFRcysc and diabetes status were associated with faster gait speed decline. Lower eGFRcysc, cardiovascular disease, and African American race were associated with rapid gait speed decline.

category: nephrology


title: Quickest Way to Less Headache Days: an operational research model and its implementation for Chronic Migraine

abstract:
Structured AbstractO_ST_ABSBackgroundC_ST_ABSChoosing migraine prevention medications often involves trial and error. Operations research methodologies, however, allow us to derive a mathematically optimum way to conduct such trial and error processes.

ObjectiveGiven probability of success (defined as 50% reduction in headache days) and adverse events as a function of time, we seek to develop and solve an operations research model, applicable to any arbitrary patient, minimizing time until discovery of an effective migraine prevention medication. We then seek to apply our model to real life data for chronic migraine prevention.

MethodsWe develop a model as follows: Given a set of D many preventive medications, for drug i in D, we describe the likelihood of reaching 50% headache day reduction over the course of time, (ti,1 [≤] ti,2 [≤] ...) by probability (pi,1 [≤] pi,2 [≤] ...). We additionally assume a probability of adverse event(qi,1 [≤] qi,2 [≤] ...). We then solve for a sequence of prescription trials that minimizes the expected time until an effective drug is identified.

Once we identify the optimal sequence for our model, we estimate p, t and q for topiramate and OnabotulinumtoxinA based on the FORWARD study by Rothrock et al as well as erenumab data published by Barbanti et al. at IHC 2019.

ResultsThe solution for our model is to order the drugs by probability of efficacy per unit time. When the efficacy of each drug i is known only for one period ti and there are no adverse effects, then the optimum sequence is to administer drug i for ti periods in decreasing order pi/ti. In general, the optimum sequence is to administer drug i for ti,k* periods in decreasing order of the Gittins index{sigma} i,k*

Based on the above data, the optimum sequence of chronic migraine prevention medication is a trial of erenumab for 12 weeks, followed by a trial of OnabotulinumtoxinA for 32 weeks, followed by a trial of topiramate for 32 weeks.

ConclusionWe propose an optimal sequence for preventive medication trial for patients with chronic migraine. Since our model makes limited assumptions on the characteristics of disease, it can be readily applied also to episodic migraine, given the appropriate data as input.

Indeed, our model can be applied to other scenarios so long as probability of success/adverse event as a function of time can be estimated. As such, we believe our model may have implications beyond our sub-specialty.

Trial RegistrationNot applicable.

category: pain medicine


title: Effect of vaccination rates on the prevalence and mortality of COVID-19

abstract: By looking at trends in global epidemic data, we evaluate the effectiveness of vaccines on the incidence and mortality from the delta variant of COVID-19. By comparing countries of varying vaccination levels, we find that more vaccinated countries have lower deaths while not having lower cases. This cannot be explained by testing rates or restrictions, but can be partly explained by the most susceptible countries also being the highest vaccinated countries. We also find that during the period when many countries have high vaccination rates, cases and deaths are both increasing in time. This seems to be caused by the waning of the protection vaccines grant against infection.

category: health informatics


title: COVID-19 in people with neurofibromatosis 1, neurofibromatosis 2, or schwannomatosis

abstract:
PurposePeople with pre-existing conditions may be more susceptible to severe Coronavirus disease 2019 (COVID-19) when infected by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The relative risk and severity of SARS-CoV-2 infection in people with rare diseases like neurofibromatosis (NF) type 1 (NF1), neurofibromatosis type 2 (NF2), or schwannomatosis (SWN) is unknown.

MethodsWe investigated the proportions of SARS-CoV-2 positive or COVID-19 patients in people with NF1, NF2, or SWN in the National COVID Collaborative Cohort (N3C) electronic health record dataset.

ResultsThe cohort sizes in N3C were 2,501 (NF1), 665 (NF2), and 762 (SWN). We compared these to N3C cohorts of other rare disease patients (98 - 9844 individuals) and the general non-NF population of 5.6 million. The site- and age-adjusted proportion of people with NF1, NF2, or SWN who tested positive for SARS-CoV-2 or were COVID-19 patients (collectively termed positive cases) was not significantly higher than in individuals without NF or other selected rare diseases. There were no severe outcomes reported in the NF2 or SWN cohorts. The proportion of patients experiencing severe outcomes was no greater for people with NF1 than in cohorts with other rare diseases or the general population.

ConclusionHaving NF1, NF2, or SWN does not appear to increase the risk of being SARS-CoV-2 positive or of being a COVID-19 patient, or of developing severe complications from SARS-CoV-2.


title: Emulation of epidemics via Bluetooth-based virtual safe virus spread: experimental setup, software, and data

abstract:
We describe an experimental setup and a currently running experiment for evaluating how physical interactions over time and between individuals affect the spread of epidemics. Our experiment involves the voluntary use of the Safe Blues Android app by participants at The University of Auckland (UoA) City Campus in New Zealand. The app spreads multiple virtual safe virus strands via Bluetooth depending on the social and physical proximity of the subjects. The evolution of the virtual epidemics is recorded as they spread through the population. The data is presented as a real-time (and historical) dashboard. A simulation model is applied to calibrate strand parameters. Participants locations are not recorded, but participants are rewarded based on the duration of participation within a geofenced area, and aggregate participation numbers serve as part of the data. Once the experiment is complete, the data will be made available as an open-source anonymized dataset.

This paper outlines the experimental setup, software, subject-recruitment practices, ethical considerations, and dataset description. The paper also highlights current experimental results in view of the lockdown that started in New Zealand at 23:59 on August 17, 2021. The experiment was initially planned in the New Zealand environment, expected to be free of COVID and lockdowns after 2020. However, a COVID Delta strain lockdown shuffled the cards and the experiment is currently extended into 2022.

Author summaryIn this paper, we describe the Safe Blues Android app experimental setup and a currently running experiment at the University of Auckland City Campus. This experiment is designed to evaluate how physical interactions over time and between individuals affect the spread of epidemics.

The Safe Blues app spreads multiple virtual safe virus strands via Bluetooth based on the subjects unobserved social and physical proximity. The app does not record the participants locations, but participants are rewarded based on the duration of participation within a geofenced area, and aggregate participation numbers serve as part of the data. When the experiment is finished, the data will be released as an open-source anonymized dataset.

The experimental setup, software, subject recruitment practices, ethical considerations, and dataset description are all described in this paper. In addition, we present our current experimental results in view of the lockdown that started in New Zealand at 23:59 on August 17, 2021. The information we provide here may be useful to other teams planning similar experiments in the future.


title: Metabolic alkalosis and mortality in COVID-19

abstract:
BackgroundAs a new infectious disease affecting the world, COVID-19 has caused a huge impact on countries around the world. At present, its specific pathophysiological mechanism has not been fully clarified. We found in the analysis of the arterial blood gas data of critically ill patients that the incidence of metabolic alkalosis in such patients is high.

MethodWe retrospectively analyzed the arterial blood gas analysis results of a total of 16 critically ill patients in the intensive ICU area of Xiaogan Central Hospital and 42 severe patients in the intensive isolation ward, and analyzed metabolic acidosis and respiratory acidosis. Metabolic alkalosis and respiratory alkalosis, and the relationship between metabolic alkalosis and death.

ResultAmong the 16 critically ill patients, the incidence of metabolic alkalosis was 100%, while the incidence of metabolic alkalosis in severe patients was 50%; the mortality rate in critically ill patients was 81.3%, and 21.4% in severe patients; The mortality of all patients with metabolic alkalosis is 95.5%,and 4.5% in without metabolic alkalosis.

ConclusionThe incidence of metabolic alkalosis in critically ill COVID-19 patients is high, and it is associated with high mortality.

category: infectious diseases


title: If you build it, will they use it? Use of a Digital Assistant for Self-Reporting of COVID-19 Rapid Antigen Test Results during Large Nationwide Community Testing Initiative

abstract:
ImportanceWide-spread distribution of rapid-antigen tests is integral to the United States strategy to address COVID-19; however, it is estimated that few rapid-antigen test results are reported to local departments of health.

ObjectiveTo characterize how often individuals in six communities throughout the United States used a digital assistant to log rapid-antigen test results and report them to their local Department of Health.

DesignThis prospective cohort study is based on anonymously collected data from the beneficiaries of The Say Yes! Covid Test program, which distributed 3,000,000 rapid antigen tests at no cost to residents of six communities between April and October 2021. We provide a descriptive evaluation of beneficiaries use of digital assistant for logging and reporting their rapid antigen test results.

Main Outcome and MeasuresNumber and proportion of tests logged and reported to the Department of Health through the digital assistant

ResultsA total of 178,785 test kits were ordered by the digital assistant, and 14,398 households used the digital assistant to log 41,465 test results. Overall, a small proportion of beneficiaries used the digital assistant (8%), but over 75% of those who used it reported their rapid antigen test results to their state public health department. The reporting behavior varied between communities and was significantly different for communities that were incentivized for reporting test results (p < 0.001). In all communities, positive tests were less reported than negative tests (60.4% vs 75.5%; p<0.001).

Conclusions and RelevanceThese results indicate that app-based reporting with incentives may be an effective way to increase reporting of rapid tests for COVID-19; however, increasing the adoption of the digital assistant is a critical first step.


title: Effects of Intravenous and Inhaled Anesthetics on the Postoperative Complications for the patients undergoing One Lung Ventilation

abstract:
IntroductionWith the widely used technique of One Lung Ventilation (OLV) in patients throughout thoracic surgery, its unclear whether inhaled or intravenous anesthetics were associated with postoperative complications. The purpose of the current study is to compare the effects of intravenous and inhaled anesthetics on the postoperative complications within the patients suffering OLV.

MethodsWe searched the related randomized controlled trials in PubMed\EMBASE\Medline and the Cochrane library up to 09\2021.Inclusive criteria were as follows: We included all the randomized controlled trials which compared the effects of intravenous and inhaled anesthetics on the postoperative complications[listed as: (a) major complications; (b)postoperative pulmonary complications (PPCs); (c) postoperative cognitive function (MMSE score); (d) length of hospital stay; (e) 30-days mortality] for the patients undergoing one lung ventilation.

ResultsThirteen randomized controlled trials with 2522 patients were included for analysis. Overall, there were no significant differences in the postoperative major complications between inhaled and intravenous anesthetics groups (OR 0.78, 95%CI 0.54 to 1.13, p=0.19; I2=0%). However, more PPCs were detected in intravenous groups when compared to inhaled groups (OR 0.62, 95%CI 0.44 to 0.87, p=0.005; I2=37%). Both the postoperative MMSE scores (SMD -1.94, 95%CI -4.87 to 0.99, p=0.19; I2=100%) and the length of hospital stay (SMD 0.05, 95%CI -0.29 to 0.39, p=0.76; I2=73%) were comparable between two groups. Besides, the 30-day mortality didnt differ significantly across groups either (OR 0.79, 95%CI 0.03 to 18, p=0.88; I2=63%).

ConclusionsIn patients undergoing OLV, generous anesthesia with inhaled anesthetics could reduce PPCs compared with intravenous anesthetics, but no evident advantages were provided over other major complications, cognitive function, hospital stay or mortality.

category: anesthesia


title: Use of glycolysis enhancing drugs has less risk of Parkinson's disease than 5α-reductase inhibitors

abstract:
BackgroundTerazosin and closely related 1-adrenergic receptor antagonists (doxazosin and alfuzosin; TZ/DZ/AZ) enhance glycolysis and reduce neurodeneration in animal models. Observational evidence in humans from several databases support this finding; however, a recent study has suggested that tamsulosin, the comparator medication, increases risk of Parkinsons disease. We consider a different comparison group of men taking 5-reductase inhibitors as a new, independent comparison allowing us to both obtain new estimates of the association between TZ/DZ/AZ and Parkinsons disease outcomes and validate tamsulosin as an active comparator.

MethodsUsing the Truven Health Analytics Marketscan database, we identified men without Parkinsons disease, newly started on TZ/DZ/AZ, tamsulosin, or 5-reductase inhibitors. We followed these matched cohorts to compare the hazard of developing Parkinsons disease.

ResultsWe found that men taking TZ/DZ/AZ had a lower hazard of Parkinsons disease than men taking tamsulosin (HR=0.72, 95% CI: 0.66-0.78, n=239,946) and lower than men taking a 5-reductase inhibitors (HR=0.81, 95% CI: 0.72-0.92, n=129,320). The hazard for men taking tamsulosin was not statistically significantly different than for men taking 5-reductase inhibitors (HR=1.10, 95% CI: 1.00-1.22, n=157,490).

ConclusionsThese data suggest that men using TZ/DZ/AZ have a lower risk of developing Parkinsons disease than those using tamsulosin or 5-reductase inhibitors while users of tamsulosin and 5-reductase inhibitors have relatively similar survival functions.


title: Effectiveness of an Inactivated Covid-19 Vaccine with Homologous and Heterologous Boosters against the Omicron (B.1.1.529) Variant

abstract:
BackgroundLarge outbreaks of the SARS-CoV-2 Omicron (B.1.1.529) variant have occurred in countries with high coverage of inactivated Covid-19 vaccines, raising urgent questions about effectiveness of these vaccines against disease and hospitalization with Omicron.

MethodsWe conducted a nationwide, test-negative, case-control study of adults who were tested for SARS-CoV-2 infection. We evaluated vaccine effectiveness against symptomatic Covid-19 and severe Covid-19 (hospital admission or deaths) for the primary series of CoronaVac and homologous and heterologous (BNT162b2) booster doses.

FindingsBetween September 6, 2021, and March 10, 2022, a total of 1,339,986 cases were matched to 1,339,986 test-negative controls. In the period of Omicron predominance, vaccine effectiveness [≥]180 days after the second CoronaVac dose was 8{middle dot}1% (95% CI, 7{middle dot}0 to 9{middle dot}1) and 57{middle dot}0% (95% CI, 53{middle dot}5 to 60{middle dot}2) against symptomatic and severe Covid-19, respectively. Vaccine effectiveness against symptomatic disease was 15{middle dot}0% (95% CI, 12{middle dot}0 to 18{middle dot}0) and 56{middle dot}8% (95% CI, 56{middle dot}3 to 57{middle dot}4) in the period 8-59 days after receiving a homologous and heterologous booster, respectively. During the same interval, vaccine effectiveness against severe Covid-19 was 71{middle dot}3% (95% CI, 60{middle dot}3 to 79{middle dot}2) and 85{middle dot}5% (95% CI, 83{middle dot}3 to 87{middle dot}0) after receiving a homologous and heterologous booster, respectively. Whereas waning of vaccine effectiveness against symptomatic Covid-19 was observed [≥]90 days after a homologous and heterologous booster, waning against severe Covid-19 was only observed after a homologous booster.

InterpretationA homologous CoronaVac booster dose provided limited additional protection, while a BNT162b2 booster dose afforded sustained protection against severe disease for at least three months.


title: Protocol for the British Paediatric Surveillance Study of Neonatal Stroke in the United Kingdom and the Republic of Ireland in babies in the first 90 days of life

abstract:
BackgroundNeonatal stroke is a devastating condition that causes brain injury in babies and often leads to lifelong neurological impairment. Recent, prospective whole population studies of neonatal stroke are lacking. Neonatal strokes are different from those seen in older children and adults. A better understanding of the aetiology, current management and outcomes of neonatal stroke could reduce the burden of this rare condition. Most healthcare professionals see only a few cases of neonatal stroke in their careers, so population-based prospective studies are needed.

ObjectivesTo explore the incidence and two-year outcomes of neonatal stroke across an entire population in the UK and the Republic of Ireland.

PopulationAny infant presenting with neonatal stroke in the first 90 days of life.

DesignActive national surveillance study using a purpose-built integrated case notification-data collection online platform.

MethodsOver a 13-month period, British and Irish clinicians will notify any cases of neonatal stroke electronically via the online platform monthly. Clinicians will complete a primary questionnaire via the platform detailing clinical information, demographic details and investigations, including neuroimaging for detailed analysis and classification. An outcome questionnaire will be sent at two years of age via the platform. Appropriate ethical and regulatory approvals have been received from England, Wales, Scotland, Northern Ireland and the Republic of Ireland.

ConclusionThe neonatal stroke study represents the first multinational population surveillance study delivered via a purpose-built integrated case notification-data collection online platform and data safe haven, overcoming the challenges of setting up the study.

SynopsisO_ST_ABSStudy questionC_ST_ABSThe neonatal stroke active surveillance study aims to explore the incidence and two-year outcome of neonatal stroke in the UK and Ireland.

What is already known?Neonatal stroke is a rare but often devastating condition with lifelong consequences including cerebral palsy, epilepsy and cognitive delay. There are no contemporary, prospective multinational population studies on the presentation and outcomes of neonatal stroke. Whilst often the aetiology is multifactorial further information on underlying aetiology may help to identify potential future preventative treatments leading to improved outcomes.

What does this study add?International collaboration is required to understand the epidemiology, management and outcomes of rare diseases or conditions. This is the first multinational surveillance study delivered via a purpose-built integrated case notification-data collection online platform and data safe haven, presenting practical and ethical challenges. The study will describe the burden of neonatal stroke while providing parents/carers and healthcare professionals with up-to-date information about the condition including the two-year outcomes.

category: pediatrics


title: Long-term psychological consequences of long Covid: a propensity score matching analysis comparing trajectories of depression and anxiety symptoms before and after contracting long Covid vs short Covid

abstract:
BackgroundThere is a growing global awareness of the psychological consequences of long Covid, supported by emerging empirical evidence. However, the mergence and long-term trajectories of psychological symptoms following the infection are still unclear.

AimsTo examine when psychological symptoms first emerge following the infection with SARS-CoV-2, and the long-term trajectories of psychological symptoms comparing long and short Covid groups.

MethodsWe analysed longitudinal data from the UCL Covid-19 Social Study (March 2020-November 2021). We included data from adults living in England who reported contracting SARS-CoV-2 by November 2021 (N=3,115). Of these, 15.9% reported having had long Covid (N=495). They were matched to participants who had short Covid using propensity score matching on a variety of demographic, socioeconomic and health covariates (N=962, n=13,325) and data were further analysed using growth curve modelling.

ResultsDepressive and anxiety symptoms increased immediately following the onset of infection in both long and short Covid groups. But the long Covid group had substantially greater initial increases in depressive symptoms and heightened levels over 22 months follow-up. Initial increases in anxiety were not significantly different between groups, but only the short Covid group experienced an improvement in anxiety over follow-up, leading to widening differences between groups.

ConclusionsThe findings shed light on the psychobiological pathways involved in the development of psychological symptoms relating to long Covid. The results highlight the need for monitoring of mental health and provision of adequate support to be interwoven with diagnosis and treatment of the physical consequences of long Covid.


title: Metabolic Disturbances, Hemoglobin A1c, and Social Cognition Impairment in Schizophrenia Spectrum Disorders

abstract: Social cognitive impairments are core features of schizophrenia spectrum disorders (SSD) and are associated with greater functional impairment and decreased quality of life. Metabolic disturbances have been related to greater impairment in general neurocognition, but their relationship to social cognition has not been previously reported. In this study, metabolic measures and social cognition were assessed in 245 participants with SSD and 165 healthy comparison subjects (HC), excluding those with hemoglobin A1c (HA1c)>6.5%. Tasks assessed emotion processing, theory of mind, and social perception. Functional connectivity within and between social cognitive networks was measured during a naturalistic social task. Among SSD, a significant inverse relationship was found between social cognition and cumulative metabolic burden ({beta}=-0.38, p<0.001) and HA1c ({beta}=-0.37, p<0.001). The relationship between social cognition and HA1c was robust across domains and measures of social cognition and after accounting for age, sex, race, non-social neurocognition, hospitalization, and treatment with different antipsychotic medications. Negative connectivity between affect sharing and motor resonance networks was a partial mediator of this relationship across SSD and HC groups ({beta}=-0.05, p=0.008). There was a group x HA1c effect indicating that SSD participants were more adversely affected by increasing HA1c. Thus, we provide the first report of a robust relationship in SSD between social cognition and abnormal glucose metabolism. If replicated and found to be causal, insulin sensitivity and blood glucose may present as promising targets for improving social cognition, functional outcomes, and quality of life in SSD.


title: Uptake of COVID-19 vaccines among pregnant women: a systematic review and meta-analysis

abstract:
BackgroundMass vaccination against the COVID-19 is essential to control the pandemic. COVID-19 vaccines are recommended now during pregnancy to prevent adverse outcomes.

ObjectiveTo evaluate the evidence from the literature regarding the uptake of COVID-19 vaccination among pregnant women.

MethodsWe conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. We searched PubMed, Medline, Scopus, ProQuest, Web of Science, CINAHL, and a pre-print service (medRxiv) from inception to March 23, 2022. We included quantitative studies reporting COVID-19 vaccination uptake among pregnant women, studies that examine predictors of COVID-19 vaccination uptake and studies that examine reasons for decline of vaccination. We performed meta-analysis to estimate the overall proportion of vaccinated pregnant women against the COVID-19.

ResultsWe found 11 studies including 703,004 pregnant women. The overall proportion of vaccinated pregnant women against the COVID-19 was 27.5% (95% CI: 18.8-37.0%). The pooled proportion for studies that were conducted in Israel was higher than the proportion for studies that were conducted in USA and other countries. Predictors of COVID-19 vaccination uptake were older age, ethnicity, race, trust in COVID-19 vaccines, and fear of COVID-19 during pregnancy. On the other hand, mistrust in the government, diagnosis with COVID-19 during pregnancy, and worry about the safety and the side effects of the COVID-19 vaccines were reasons for decline of vaccination.

ConclusionsThe global COVID-19 vaccination prevalence in pregnant women is low. There is a large gap in the literature on the factors influencing the decision of pregnant women to be vaccinated against the COVID-19. Targeted information campaigns are essential to improve trust and build vaccine literacy among pregnant women. Given the ongoing high case rates and the known increased risks of COVID-19 in pregnant women, our findings could help policy makers to improve the acceptance rate of COVID-19 vaccines in pregnant women especially in vulnerable subgroups.


title: A Randomized, Double-Blinded, Placebo-Controlled, Phase 2 Study of Safety, Tolerability and Efficacy of Pirfenidone in Patients with Rheumatoid Arthritis Interstitial Lung Disease

abstract:
BackgroundInterstitial lung disease (ILD) is a known complication of rheumatoid arthritis (RA) with a lifetime risk in any individual of 7.7%. The TRAIL1 trial was a randomized, double-blinded, placebo-controlled, phase 2 study of safety, tolerability, and efficacy of pirfenidone for the treatment of patients with RA-ILD.

MethodsThe TRAIL1 was a phase 2 trial intended to enroll 270 adult patients (18 to 85 years) with established RA-ILD at 33 sites in 4 countries. Patients were randomly assigned (1:1) to 2,403 mg oral pirfenidone or placebo daily. The primary endpoint was the incidence of the composite endpoint of decline from baseline in percent predicted forced vital capacity (FVC%) of 10% or greater or death during the 52-week treatment period. Key secondary endpoints included change in absolute and FVC% over 52 weeks.

FindingsThe trial was stopped early due to slow recruitment and soon after the shutdown of clinical trials as a consequence of the coronavirus disease 2019 (COVID-19) pandemic. Data from 123 patients enrolled were analyzed. The primary endpoint was met by 11.1% on pirfenidone vs. 15% on placebo [OR=0.67 (0.22, 2.03), p=0.48]. Subjects receiving pirfenidone had a slower rate of decline in lung function as measured by estimated annual change in FVC(ml) (-66 vs. -146, p=0.0082) and FVC(%) (-1.02 vs. -3.21, p=0.0028). This effect on decline was also seen when analyzed within participants with baseline usual interstitial pneumonia (UIP) pattern on HRCT (FVC(ml) (-43 vs. -169, p=0.0014) and FVC% (-0.2 vs. -3.81, p=0.0002)). There was no significant difference in the rate of treatment-emergent serious adverse events.

InterpretationDue to early termination of the study, results should be interpreted with caution. Despite being underpowered to evaluate the primary endpoint, pirfenidone slowed the rate of decline of FVC over time in subjects with RA-ILD. Safety in patients with RA-ILD was similar to that seen in other pirfenidone trials.

FundingFunding for this investigator initiated trial was provided by Genentech, Inc. to Ivan O. Rosas, MD, on behalf of the TRAIL1 Investigators.


title: Long-term performance assessment of fully automatic biomedical glottis segmentation at the point of care

abstract: Deep Learning has a large impact on medical image analysis and lately has been adopted for clinical use at the point of care. However, there is only a small number of reports of long-term studies that show the performance of deep neural networks (DNNs) in such a clinical environment. In this study, we measured the long-term performance of a clinically optimized DNN for laryngeal glottis segmentation. We have collected the video footage for two years from an AI-powered laryngeal high-speed videoendoscopy imaging system and found that the footage image quality is stable across time. Next, we determined the DNN segmentation performance on lossy and lossless compressed data revealing that only 9% of recordings contain segmentation artefacts. We found that lossy and lossless compression are on par for glottis segmentation, however, lossless compression provides significantly superior image quality. Lastly, we employed continual learning strategies to continuously incorporate new data to the DNN to remove aforementioned segmentation artefacts. With modest manual intervention, we were able to largely alleviate these segmentation artefacts by up to 81%. We believe that our suggested deep learning-enhanced laryngeal imaging platform consistently provides clinically sound results, and together with our proposed continual learning scheme will have a long-lasting impact in the future of laryngeal imaging.

category: otolaryngology


title: Automated development of clinical prediction models enables real-time risk stratification with exemplar application to hypoxic-ischaemic encephalopathy

abstract: Real-time updated risk prediction of disease outcomes could lead to improvements in patient care and better resource management. Established monitoring during pregnancy at antenatal and intrapartum periods could be particularly amenable to benefits of this approach. This proof-of-concept study compared automated and manual prediction modelling approaches using data from the Collaborative Perinatal Project with exemplar application to hypoxic-ischaemic encephalopathy (HIE). Using manually selected predictors identified from previously published studies we obtained high HIE discrimination with logistic regression applied to antenatal only (0.71 AUC [95% CI 0.64-0.77]), antenatal and intrapartum (0.70 AUC [95% CI 0.64-0.77]), and antenatal, intrapartum and birthweight (0.73 AUC [95% CI 0.67-0.79]) data. In parallel, we applied a range of automated modelling methods and found penalised logistic regression had best discrimination and was equivalent to the manual approach but required little human input giving 0.75 AUC for antenatal only (95% CI 0.69, 0.81), 0.70 AUC for antenatal and intrapartum (95% CI 0.63, 0.78), and 0.74 AUC using antenatal, intrapartum, and infant birthweight (95% CI 0.65, 0.81). These results demonstrate the feasibility of developing automated prediction models which could be applied to produce disease risk estimates in real-time. This approach may be especially useful in pregnancy care but could be applied to any disease.


title: Spatial-temporal and phylogenetic analyses of epidemiologic data to help understand the modes of transmission of endemic typhoid fever in Samoa

abstract:
Salmonella enterica serovar Typhi (S. Typhi) is either widely distributed or proximally transmitted via fecally-contaminated food or water to cause typhoid fever. In Samoa, where endemic typhoid fever has persisted over decades despite water quality and sanitation improvements, the local patterns of S. Typhi circulation remain undistinguished. From April 2018-June 2020, epidemiologic data and GPS coordinates were collected during household investigations of 260 acute cases of typhoid fever, and 27 asymptomatic shedders of S. Typhi were detected among household contacts. Spatial and temporal distributions of cases were examined using Average Nearest Neighbor and space-time hotspot analyses. In rural regions, infections occurred in sporadic, focal clusters contrasting with persistent, less clustered cases in the Apia Urban Area. Restrictions to population movement during nationwide lockdowns in 2019-2020 were associated with marked reductions of cases. Phylogenetic analyses of isolates with whole genome sequences (n=186) revealed one dominant genotype 3.5.4 (n=181/186) that contains three Samoa-exclusive sub-lineages: 3.5.4.1, 3.5.4.2, and 3.5.4.3. Variables of patient sex, age, and geographic region were examined by phylogenetic groupings, and significant differences (p<0.05) associated genetically-similar isolates in urban areas with working ages (20-49 year olds), and in rural areas with age groups typically at home (<5, 50+). Isolates from asymptomatic shedders were among all three sub-lineages. Whole genome sequencing also corroborated bacterial genetic similarity in 10/12 putative epidemiologic linkages among cases and asymptomatic shedders as well as 3/3 repeat positives (presumed relapses), with a median of one single nucleotide polymorphism difference. These findings highlight various patterns of typhoid transmission in Samoa that differ between urban and rural regions as well as genomic subtypes. Asymptomatic shedders, detectable only through household investigations, are likely an important reservoir and mobile agent of infection. This study advances a "Samoan S. Typhi framework" that supports current and future typhoid surveillance and control efforts in Samoa.

AUTHOR SUMMARYMany typhoid endemic countries have evident transmission contributions from widely distributed contaminated water supplies and/or asymptomatic S. Typhi carriers who intermittently cause sporadic outbreaks. However, these patterns have not yet been examined in the island nation of Samoa, where typhoid has remained endemic for decades. In this study, we incorporated the discerning powers of spatial-temporal cluster analyses as well as phylogenetics of whole genome sequences (WGS) of S. Typhi isolates to examine detailed epidemiologic data collected through household investigations of culture-confirmed cases of typhoid fever occurring in Samoa from April 2018 through June 2020. We detected patterns consistent with both modes of transmission, varying between urban and rural regions, and we provided evidence of intra-household transmission of genetically similar isolates, thereby supporting a majority of putative epidemiologic linkages made during household investigations, and identifying important roles for asymptomatic shedders of S. Typhi. These findings advance our understanding of persistently endemic typhoid fever in Samoa and directly support the efforts of the Samoa Typhoid Fever Control Program of the Ministry of Health of Samoa.

category: genetic and genomic medicine


title: Characteristics of Kenyan Women Enrolled in a Trial on Doxycycline Post-exposure Prophylaxis for Sexually Transmitted Infection Prevention

abstract:
IntroductionThe global incidence of sexually transmitted infections (STIs) has been rapidly increasing over the past decade, with more than one million curable STIs being acquired daily. Young women in sub-Saharan Africa have a high prevalence and incidence of both curable STIs and HIV. The use of doxycycline as a prophylaxis to prevent STI infections is promising; however, clinical trials, to date, have only been conducted among men who have sex with men (MSM) in high-income settings. We describe the characteristics of participants enrolled in the first trial to determine the efficacy of doxycycline post-exposure prophylaxis (PEP) to reduce STI incidence among women.

MethodsThis is an open-label 1:1 randomized clinical trial of doxycycline PEP efficacy to reduce incident bacterial STIs - Neisseria gonorrhoeae, Chlamydia trachomatis, and Treponema pallidum - among Kenyan women aged [≥]18 and [≤]30 years. All were also taking HIV pre-exposure prophylaxis (PrEP). We describe the baseline characteristics of participants.

ResultsBetween February 2020 and November 2021, 449 women were enrolled. The median age was 24 years (IQR 21-27), the majority were never married (66.1%), 370 women (82.4%) reported having a primary sex partner, and 33% had sex with new partners in the 3 months prior to enrolment. Two-thirds (67.5%, 268 women) did not use condoms, 36.7% reported transactional sex, and 43.2% suspected their male partners of having sex with other women. Slightly less than half (45.9%, 206 women) were recently concerned about being exposed to an STI. The prevalence of STIs was 17.9%, with C. trachomatis accounting for the majority of infections.

ConclusionYoung cisgender women using HIV PrEP in Kenya and enrolled in a trial of doxycycline postexposure prophylaxis had a high prevalence of curable STIs and represent a target population for an STI prevention intervention.


title: A comparative analysis of depression between pregnant and non-pregnant adolescents in a southwestern town in Nigeria

abstract:
BackgroundAdolescence constitutes a risk factor for mental health problems, and this may be further complicated by pregnancy. The rate of adolescent pregnancy is still extremely high in the sub-Saharan Africa including Nigeria. Pregnancy and mental health problems during adolescence constitute double vulnerability for negative outcomes for the adolescents and their offspring.

MethodologyThe study was cross-sectional in design and it compared prevalence of depression and associated factors among pregnant and non-pregnant adolescents. It was conducted in Osogbo metropolis, Osun State, Southwest, Nigeria. The study population comprised pregnant adolescents (aged 15-19 years) attending antenatal care (ANC) in selected formal and informal health facilities. Non-pregnant adolescents who were equally attending services at the facilities were recruited as the control group. Information was obtained from the adolescents with the use of a structured questionnaire and data was analysed with IBM-SPSS version 21 software.

ResultsThree hundred and thirty-four respondents (167 per group) were involved in the study; the pregnant adolescents had a mean age ({+/-}SD) of 17.92 ({+/-}1.13) years while the non-pregnant adolescents had a mean age of 17.70 ({+/-}1.23) years. The prevalence of depression among the pregnant adolescents was 8.4% while that of the non-pregnant adolescents was 3.0%. The result showed a statistically significant association between pregnancy status and depression among the adolescents (p= 0.033). Living arrangement was the only socio-demographic variable that had significant relationship with depression among the pregnant adolescents while living arrangement and employment status had significant relationships with depression among the non-pregnant adolescents. History of mental illness, childhood sexual abuse and anxiety symptoms showed significant relationship with depression among pregnant adolescents, however, only anxiety symptoms showed significant relationship with depression among non-pregnant adolescents.

ConclusionThe study concluded that the prevalence of depression is significantly higher among pregnant adolescents with similarities and differences in the factors associated with depression in the two groups.


title: VentRa. Validation study of the ventricle feature estimation and classification tool to differentiate behavioral variant frontotemporal dementia from psychiatric disorders and other degenerative diseases

abstract:
IntroductionLateral ventricles are reliable and sensitive indicators of brain atrophy and disease progression in behavioral variant frontotemporal dementia (bvFTD). Here we validate our previously developed automated tool using ventricular features (known as VentRa) for the classification of bvFTD vs a mixed cohort of neurodegenerative, vascular, and psychiatric disorders from a clinically representative independent dataset.

MethodsLateral ventricles were segmented for 1110 subjects - 14 bvFTD, 30 other Frontotemporal Dementia (FTD), 70 Lewy Body Disease (LBD), 898 Alzheimer Disease (AD), 62 Vascular Brain Injury (VBI) and 36 Primary Psychiatric Disorder (PPD) from the publicly accessible National Alzheimers Coordinating Center dataset to assess the performance of VentRa.

ResultsUsing ventricular features to discriminate bvFTD subjects from PPD, VentRa achieved an accuracy of 84%, 71% sensitivity and 89% specificity. VentRa was able to identify bvFTD from a mixed age-matched cohort (i.e., Other FTD, LBD, AD, VBI and PPD) and to correctly classify other disorders as  not compatible with bvFTD with a specificity of 83%. The specificity against each of the other individual cohorts were 80% for other FTD, 83% for LBD, 83% for AD and 84% for VBI.

DiscussionVentRa is a robust and generalizable tool with potential usefulness for improving the diagnostic certainty of bvFTD, particularly for the differential diagnosis with PPD.

category: neurology


title: Delineating the heterogeneity of preimplantation development via unsupervised clustering of embryo candidates for transfer using automated, accurate and standardized morphokinetic annotation

abstract: The majority of human embryos, whether naturally or in vitro fertilized (IVF), do not poses the capacity to implant within the uterus and reach live birth. Hence, selecting the embryos with the highest developmental potential to implant is imperative for improving pregnancy rates without prolonging time to pregnancy. The developmental potential of embryos can be assessed based on temporal profiling of the discrete morphokinetic events of preimplantation development. However, manual morphokinetic annotation introduces intra- and inter-observer variation and is time-consuming. Using a large clinically-labeled multicenter dataset of video recordings of preimplantation embryo development by time-lapse incubators, we trained a convolutional neural network and developed a classifier that performs fully automated, robust, and standardized annotation of the morphokinetic events with R-square 0.994 accuracy. To delineate the morphokinetic heterogeneity of preimplantation development, we performed unsupervised clustering of high-quality embryo candidates for transfer, which was independent of maternal age and blastulation rate. Retrospective comparative analysis of transfer versus implantation rates reveals differences between embryo clusters that are distinctively marked by poor synchronization of the third meiotic cell-cleavage cycle. We expect this work to advance the integration of morphokinetic-based decision support tools in IVF treatments and deepen our understanding of preimplantation heterogeneity.

category: obstetrics and gynecology


title: Prediction models with survival data: a comparison between machine learning and the Cox proportional hazards model

abstract: Recent years have seen increased interest in using machine learning (ML) methods for survival prediction, chiefly using big datasets with mixed datatypes and/or many predictors Model comparisons have frequently been limited to performance measure evaluation, with the chosen measure often suboptimal for assessing survival predictive performance. We investigated ML model performance in an application to osteosarcoma data from the EURAMOS-1 clinical trial (NCT00134030). We compared the performance of survival neural networks (SNN), random survival forests (RSF) and the Cox proportional hazards model. Three performance measures suitable for assessing survival model predictive performance were considered: the C-index, and the time-dependent Brier and Kullback-Leibler scores. Comparisons were also made on predictor importance and patient-specific survival predictions. Additionally, the effect of ML model hyper-parameters on performance was investigated. All three models had comparable performance as assessed by the C-index and Brier and Kullback-Leibler scores, with the Cox model and SNN also comparable in terms of relative predictor importance and patient-specific survival predictions. RSFs showed a tendency for according less importance to predictors with uneven class distributions and predicting clustered survival curves, the latter a result of tuning hyperparameters that influence forest shape through restrictions on terminal node size and tree depth. SNNs were comparatively more sensitive to hyperparameter misspecification, with decreased regularization resulting in inconsistent predicted survival probabilities. We caution against using RSF for predicting patient-specific survival, as standard model tuning practices may result in aggregated predictions, which is not reflected in performance measure values, and recommend performing multiple reruns of SNNs to verify prediction consistency.

category: oncology


title: Psychosocial and psychological Interventions effectiveness among Nurses in Intensive Care Units caring for pediatric patients: A Systematic Review and Meta-Analysis

abstract:
PurposeThis review aimed to evaluate the effectiveness of psychosocial and psychological interventions in nurses among intensive care units caring for pediatric patients.

MethodsThis study was applied to the Participants, Intervention, Comparisons, Outcomes, Timing of Outcome Measurement, Settings, Study Design and PubMed, EMBASE, CINAHL databases were searched. To estimate the effect size, a meta-analysis of the studies was performed using the RevMan 5.3 program. The effect size used was the standardized mean difference.

ResultsOf 1,630 studies identified, 4 met the inclusion criteria, and 3 studies were used to estimate the effect size of psychosocial and psychological interventions. The primary outcome variable of these studies was stress. The effect of the intervention program on stress was also found to have no effect in individual studies, and the overall effect size was not statistically significant (SMD = -0.06; 95% CI: -0.33, 0.20; Z = 0.48, p = 0.630). However, according to the individual literature included in this study, after the stress management program was applied as a group, a significant stress reduction was shown in the experimental group (p = 0.021).

ConclusionsThese results show that psychosocial and psychological interventions were effective in stress management by a group approach. Therefore, it is necessary to develop psychosocial support interventions for stress management of nurses among intensive care units caring for pediatric patients more diversely.

category: health systems and quality improvement


title: Safety and immunogenicity of a SARS-CoV-2 recombinant protein nanoparticle vaccine (GBP510) adjuvanted with AS03: a phase 1/2, randomized, placebo-controlled, observer-blinded trial

abstract:
BackgroundVaccination has helped to mitigate the COVID-19 pandemic. Ten traditional and novel vaccines have been listed by the World Health Organization for emergency use. Additional alternative approaches may better address ongoing vaccination globally, where there remains an inequity in vaccine distribution. GBP510 is a recombinant protein vaccine, which consists of self-assembling, two-component nanoparticles displaying the receptor-binding domain (RBD) in a highly immunogenic array.

MethodsWe conducted a randomized, placebo-controlled, observer-blinded, phase 1/2 trial to evaluate the safety and immunogenicity of GBP510 (2-doses at a 28-day interval) adjuvanted with or without AS03 in adults aged 19-85 years. The main outcomes included solicited and unsolicited adverse events; anti-SARS-CoV-2 RBD IgG antibody and neutralizing antibody responses; T-cell immune responses.

FindingsOf 328 participants who underwent randomization, 327 participants received at least 1 dose of vaccine. Each received either 10 g GBP510 adjuvanted with AS03 (n = 101), 10 g unadjuvanted GBP510 (n = 10), 25 g GBP510 adjuvanted with AS03 (n = 104), 25 g unadjuvanted GBP510 (n = 51), or placebo (n = 61). Most solicited adverse events were mild-to-moderate in severity and transient. Higher reactogenicity was observed in the GBP510 adjuvanted with AS03 groups compared to the non-adjuvanted and placebo groups. Reactogenicity was higher post-dose 2 compared to post-dose 1, particularly for systemic adverse events. The geometric mean concentrations of anti-SARS-CoV-2-RBD IgG antibody reached 2163.6/2599.2 BAU/mL in GBP510 adjuvanted with AS03 recipients (10 g/25 g) by 14 days after the second dose. Two-dose vaccination with 10 g or 25 g GBP510 adjuvanted with AS03 induced high titers of neutralizing antibody via pseudovirus (1369.0/1431.5 IU/mL) and wild-type virus (949.8/861.0 IU/mL) assays.

InterpretationGBP510 adjuvanted with AS03 was well tolerated and highly immunogenic. These results support further development of the vaccine candidate, which is currently being evaluated in Phase 3.

FundingCoalition for Epidemic Preparedness Innovations

RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed for research articles published by December 31, 2021, using the terms "COVID-19" or "SARS-CoV-2," "vaccine," and "clinical trial." In previously reported randomized clinical trials, we found that mRNA vaccines were more immunogenic than adenovirus-vectored vaccines. Solicited adverse events were more frequent and more severe in intensity after the first dose compared to the second dose for adenovirus-vectored vaccines, whereas they increased after the second dose of mRNA or recombinant spike-protein nanoparticle vaccines.

Added value of this studyThis is the first human study evaluating the immunogenicity and safety of recombinant SARS-CoV-2 protein nanoparticle with and without adjuvant AS03, designed to elicit functional cross-protective responses via receptor-binding domain (RBD). Both 10 and 25 g of GBP510 with AS03 formulations were well tolerated with an acceptable safety profile. Potent humoral immune responses against the SARS-CoV-2 RBD were induced and peaked by day 42 (14 days after the second dose). In addition, GBP510 adjuvanted with AS03 elicited a noticeable Th1 response, with production of IFN-{gamma}, TNF-, and IL-2. IL-4 was inconsistent and IL-5 nearly inexistent response across all groups.

Implications of the available evidenceThe results from this phase 1/2 trial indicate that GBP510 adjuvanted with AS03 has an acceptable safety profile with no vaccine-related serious adverse events. Two-dose immunization with GBP510 adjuvanted with AS03 induced potent humoral and cellular immune responses against SARS-CoV-2.


title: Immunogenicity of Pfizer-BioNTech COVID-19 mRNA Primary Vaccination Series in Recovered Individuals Depends on Symptoms at Initial Infection.

abstract:
ImportancePublic health vaccination recommendations for COVID-19 primary series and boosters in previously infected individuals differ worldwide. As infection with SARS-CoV-2 is often asymptomatic, it remains to be determined if vaccine immunogenicity is comparable in all previously infected subjects. We present detailed immunological evidence to clarify the requirements for one-or two-dose primary vaccination series for naturally primed individuals.

ObjectiveEvaluate the immune response to COVID-19 mRNA vaccines in healthcare workers (HCWs) who recovered from a SARS-CoV-2 infection.

DesignMulticentric observational prospective cohort study of HCWs with a PCR-confirmed SARS-CoV-2 infection designed to evaluate the dynamics of T and B cells immune responses to primary infection and COVID-19 mRNA vaccination over 12 months.

ParticipantsUnvaccinated HCWs with PCR-confirmed SARS-CoV-2 infection were selected based on the presence or absence of symptoms at infection and serostatus at enrollment. Age- and sex-matched adults not infected with SARS-CoV-2 prior to vaccination were included as naive controls.

ExposureVaccination with Pfizer BioNTech BNT162b2 mRNA vaccine.

Main Outcome(s) and Measure(s)Immunity score (zero to three), before and after vaccination, based on anti-RBD IgG ratio, serum capacity to neutralize live virus and IFN-{gamma} secretion capacity in response to SARS-CoV-2 peptide pools above the positivity threshold for each of the three assays. We compared the immunity score between groups based on subjects symptoms at diagnosis and/or serostatus prior to vaccination.

ResultsNone of the naive participants (n=14) showed a maximal immunity score of three following one dose of vaccine compared to 84% of the previously infected participants (n=55). All recovered individuals who did not have an immunity score of three were seronegative prior to vaccination, and 67% had not reported symptoms resulting from their initial infection. Following one dose of vaccine, their immune responses were comparable to naive individuals, with significantly weaker responses than those who were symptomatic during infection.

Conclusions and RelevanceIndividuals who did not develop symptoms during their initial SARS-CoV-2 infection and were seronegative prior to vaccination present immune responses comparable to that of naive individuals. These findings highlight the importance of administering the complete two-dose primary regimen and following boosters of mRNA vaccines to individuals who experienced asymptomatic SARS-CoV-2 infection.

KEY POINTS

QuestionIs a single dose of COVID-19 mRNA vaccine sufficient to induce robust immune responses in individuals with prior SARS-CoV-2 infection?

FindingsIn this cohort of 55 health care workers previously infected with SARS-CoV-2, we show that the absence of symptoms during initial infection and negative serostatus prior to vaccination predict the strength of immune responses to COVID-19 mRNA vaccine. Lack of symptoms and a negative serostatus prior to vaccination leads to immune responses comparable to naive individuals.

MeaningOur results support a two-dose primary series requirement for any individual with prior history of asymptomatic SARS-CoV-2 infection.


title: Declining Course of Humoral Immune Response in Initially Responding Kidney Transplant Recipients after Repeated SARS-CoV-2 Vaccination

abstract:
Immunogenicity of SARS-CoV-2 vaccines in kidney transplant recipients is limited, resulting in inadequately low serological response rates and low immunoglobulin (Ig) levels, correlating with reduced protection against death and hospitalization from COVID-19. We retrospectively examined the time course of anti-SARS-CoV-2 Ig antibody levels after up to five repeated vaccinations in 644 previously nonresponding kidney transplant recipients. Using anti SARS-CoV-2 IgG/IgA ELISA and the total Ig ECLIA assays, we compare antibody levels at 1 month with levels at 2 and 4 months, respectively. Additionally, we correlate the measurements of the used assays.

Between 1 and 2 months, and between 1 and 4 months, mean anti-SARS-CoV-2 Ig levels in responders decreased by 14% and 25%, respectively, depending on the assay. Absolute Ig values and time course of antibody levels and showed high interindividual variability. Ig levels decreased by at least 20% in 77 of 148 paired samples with loss of sufficient serological protection over time occurring in 18 out of 148 (12.2%).

IgG ELISA and total Ig ECLIA assays showed a strong positive correlation (Kendalls tau=0.78), yet the two assays determined divergent results in 99 of 751 (13.2%) measurements. IgG and IgA assays showed overall strong correlation but divergent results in 270 of 1.173 (23.0%) cases and only weak correlation of antibody levels in positive samples.

Large interindividual variability and significant loss of serological protection after 4 months supports repeated serological sampling and consideration of shorter vaccination intervals in kidney transplant recipients.

category: allergy and immunology


title: CAR+ and CAR- T cells differentiate into an NK-like subset that is associated with increased inflammatory cytokines following infusion

abstract:
Chimeric antigen receptor (CAR) T cells have demonstrable efficacy in treating B-cell malignancies. Factors such as product composition, lymphodepletion and immune reconstitution are known to influence functional persistence of CAR+ T cells. However, little is known about the determinants of differentiation and phenotypic plasticity of CAR+ T and immune cells early post-infusion. We report single cell multi-omics analysis of molecular, clonal, and phenotypic profiles of CAR+ T and other immune cells circulating in patients receiving donor-derived products. We used these data to reconstruct a differentiation trajectory, which explained the observed phenotypic plasticity and identified cell fate of CAR+ and CAR- T cells. Following lympho-depletion, endogenous CAR- CD8+ and {gamma}{square} T cells, clonally expand, and differentiate across heterogenous phenotypes, from a dominant resting or proliferating state into precursor of exhausted T cells, and notably into a terminal NK-like phenotype. In parallel, following infusion, CAR+ T cells undergo a similar differentiation trajectory, showing increased proliferation, metabolic activity and exhaustion when compared to circulating CAR- T cells. The subset of NK-like CAR+ T cells was associated with increasing levels of circulating proinflammatory cytokines, including innate-like IL-12 and IL-18. These results demonstrate that differentiation and phenotype of CAR+ T cells are determined by non-CAR induced signals that are shared with endogenous T cells, and condition the patients immune-recovery.

One Sentence SummaryCAR+ and CAR- CD8+ T cells share a differentiation trajectory terminating in an NK-like phenotype that is associated with increased inflammatory cytokines levels.

Graphical Abstract

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title: Impact of Total Hip Replacements on the Incidence of Hip Fractures in Norway During 1999-2019. A NOREPOS Study

abstract: The knowledge about why hip fracture rates in Norway have declined is sparse. Concurrent with decreasing hip fracture rates, the rates of total hip replacements (THRs) have increased. We wanted to investigate if hip fracture rates continued to decline, and whether the increase in THRs had any influence on this decline, assuming that living with a hip prosthesis precludes fracture of the operated hip. Information on hip fractures in Norway 1999-2019 was available from the Norwegian Epidemiologic Osteoporosis Studies (NOREPOS) hip fracture database and population size were available in official population tables from Statistics Norway. Primary THRs (for any cause except hip fracture) 1989-2019 were obtained from the Norwegian Arthroplasty Register. We calculated the annual age-standardized incidence rates of hip fracture by sex for the period 1999-2019. The hip fracture rates in a scenario with no hip prostheses were calculated by subtracting 0.5 persons from the population at risk for each prevalent hip prosthesis, considering that each person has two hips at risk of fracture. We estimated how much of the decline could be attributed to the increased prevalence of hip prostheses. From 1999 to 2019, age-standardized incidence rates of hip fracture decreased by 27% in women and 20% in men. The rates remained stable in those under 70 years and decreased in those 70 years and above. Excluding replaced hips from the population at risk led to higher incidence rates, and this impact was considerably larger at higher ages. The increased prevalence of hip prostheses over the period accounted for approximately 18% (20% in women and 11% in men) of the observed decline in hip fracture rates. In conclusion, the incidence of hip fractures continued to decline, and the increasing number of people living with hip prostheses contributed significantly to the observed declining time trends.

category: epidemiology


title: Lessons from a pandemic

abstract:
ObjectivesSeveral interventions have been used around the world trying to contain the SARS-Cov-2 pandemic, such as quarantine, prohibition of mass demonstrations, isolation of sick people, tracing of virus carriers, semi-containment, promotion of barrier gestures, development of rapid auto-tests and vaccines among others. We propose a simple model to evaluate the potential impact of such interventions.

MethodsA model for the reproduction number of an infectious disease including three main contexts of infection (indoor mass events, public indoor activities and household) and seven parameters is considered. We illustrate how these parameters could be obtained from the literature or from expert assumptions, and we apply the model to describe 20 scenarios that can typically occur during the different phases of a pandemic.

ResultsThis model provides a useful framework for better understanding and communicating the effects of different (combinations of) possible interventions, while encouraging constant updating of expert assumptions to better match reality.

ConclusionThis simple approach will bring more transparency and public support to help governments to think, decide, evaluate and adjust what to do during a pandemic.


title: Lymphoid Enhancer-Binding Factor 1 (LEF1) immunostaining as a surrogate of β-Catenin (CTNNB1) mutations

abstract:
Activating mutations affecting exon 3 of the {beta}-Catenin (CTNNB1) gene result in constitutive activation of WNT signalling and are a diagnostic hallmark of several tumour entities including desmoid-type fibromatosis or define clinically relevant subtypes such as in endometrioid carcinoma. In a diagnostic setting, {beta}-Catenin immunohistochemistry is widely used as a surrogate of CTNNB1 mutations, but is often difficult to assess in practice, given that the characteristic nuclear translocation may be focal or hard to distinguish from spillover of the normal membranous staining.

We therefore assessed Lymphoid Enhancer-Binding Factor 1 (LEF1) immunohistochemistry, a nuclear marker of WNT activation as a potential surrogate of CTNNB1 mutations. Across a variety of entities characterised by CTNNB1 mutations as a putative driver we found diffuse and strong expression of LEF1 in 77% of cases. In a cohort of endometrial carcinomas (n=255) LEF1 was accurate to predict CTNNB1 mutations in 85% (p<0.001), while {beta}-Catenin was accurate in 76% (p<0.001). Irrespective of tumour type, we found LEF1 immunostaining to be easier to interpret than {beta}-Catenin immunostaining in 54% of cases, more difficult in 1% and equally easy to interpret in the remainder.

We conclude that LEF1 immunostaining is a highly useful surrogate marker of CTNNB1 mutations in lesions which are driven by WNT signalling, favourably complementing {beta}-Catenin immunohistochemistry and outperforming the latter as a single marker.

category: pathology


title: Sleep problems effect on developmental trajectories in children with autism

abstract: The effect of sleep problems in 2-to 5-year-old children with ASD was investigated in the largest and the longest observational study to-date. Parents assessed the development of 7069 children quarterly for three years on five orthogonal subscales: receptive language, expressive language, sociability, sensory awareness, and health. Moderate and severe sleep problems were reported in 13% of children. Children with no sleep problems developed faster compared to matched children with sleep problems in all subscales. The greatest difference in trajectories was detected in the health subscale. When controlling for the health score (in addition to each subscale score at baseline as well as gender and severity), the effect of sleep problems decreased in all subscales except the combinatorial receptive language subscale (where the effect of sleep problems was increased), suggesting that sleep problems affect combinatorial language acquisition irrespective of the overall health. This study confirms a high prevalence of sleep problems in ASD children and points to the need for more systematic research as an initial step in developing treatment strategies.


title: Birth anthropometry among three Asian ethnic groups in Singapore -- new growth charts

abstract:
ObjectiveWe analyse birth anthropometry of Asian babies and its socioeconomic exposures, develop gestational age and gender-specific birth anthropometry charts and compare to the widely used Fenton chart.

DesignRetrospective observational study.

SettingDepartment of Neonatology at the National University Hospital in Singapore.

Population or sampleWe report data from 52 220 Chinese, Indian and Malay infants, born from 1991-1997 and from 2010-2017 in Singapore.

MethodsThe BW, length and head circumference are each modelled with maternal exposures using general additive model. Anthropometry charts are built using smoothed centile curve and compared with Fenton charts using binomial test.

Main outcome measuresBW, head circumference, crown-heel length.

ResultsIn contrast to the marked differences in birth anthropometry among these ethnic populations, when exposed to a uniform socioeconomic environment, their intrauterine growth and birth anthropometry were almost identical. From the gestational age specific anthropometric charts, until about late prematurity, Asian growth curves, as derived from our cohort, mirrored that of Fentons; thereafter, Asian babies showed a marked reduction in growth velocity.

ConclusionsThese findings suggest comparative slowing of intrauterine growth among Asian babies towards term gestation. This phenomenon may be explained by two possible postulations, firstly, restrictive effects of a smaller uterus of shorter Asian women towards term and secondly, early maturation and senescence of fetoplacental unit among Asians. In clinical practice the new birth anthropometry charts will more accurately identify true fetal growth restriction as well as true postnatal growth failure in preterm infants when applied to the appropriate population.

FundingSingapore Population Health Improvement Centre (NMRC/CG/C026/2017_NUHS).


title: Identification of novel nutrient-sensitive gene regulatory networks in amniotic fluid from fetuses with spina bifida using miRNA and transcription factor network analysis

abstract:
BackgroundNeural tube defects (NTDs) remain among the most common congenital anomalies. Contributing risk factors include genetics and nutrient deficiencies, however, a comprehensive assessment of nutrient-gene interactions in NTDs is lacking. We hypothesised that multiple nutrient-gene interactions would be evident in NTD-associated gene signatures.

MethodsWe applied a novel, nutrient-focused gene expression analysis pipeline to identify nutrient-sensitive gene regulatory networks in amniocyte gene expression data (GSE4182) from fetuses with NTDs (cases; n=3) and fetuses with no congenital anomalies (controls; n=5). Differentially expressed genes (DEGs) were identified and screened for having nutrient cofactors. Transcription factors (TFs) with nutrient cofactors that regulated DEGs, and nutrient-sensitive miRNAs that had a previous link to NTDs, were identified and used to construct DEG regulatory networks.

ResultsOf the 880 DEGs in cases (vs. controls), 10% had at least one nutrient cofactor. DEG regulatory network analysis revealed that 39% and 52% of DEGs in cases were regulated by 22 nutrient-sensitive miRNAs and 10 nutrient-dependent TFs, respectively. Zinc- and B vitamin-dependent genes and gene regulatory networks (Zinc: 10 TFs targeting 50.6% of DEGs; B vitamins: 4 TFs targeting 37.7% of DEGs, 9 miRNAs targeting 17.6% of DEGs) were dysregulated in cases. Two nutrient-dependent TFs predicted to target DEGs in cases (Tumor Protein 63 and Churchill Domain Containing 1) have not been previously linked to NTDs.

ConclusionsWe identified multiple novel nutrient-sensitive gene regulatory networks associated with NTDs, which may relate to NTD pathogenesis, and indicate new targets to explore for NTD prevention or to optimise fetal development.


title: Effect of MAOA DNA methylation on human in vivo protein expression measured by harmine PET in healthy and depressed individuals

abstract:
Epigenetic modifications, such as DNA methylation, are understood as an intermediary between environmental factors affecting disease risk and pathophysiologic changes to brain structure and function. Cerebral monoamine oxidase A (MAO-A) levels are altered in depression, as are DNA methylation levels within the MAOA gene, particularly in the promoter / exon I / intron I region. An effect of MAOA methylation on peripheral protein expression was shown, but the extent to which methylation affects brain MAO-A levels is not fully understood. Here, the influence of average and CpG site-specific MAOA promoter / exon I / intron I region DNA methylation on global MAO-A distribution volume (VT), an index of MAO-A density, was assessed via [11C]harmine positron emission tomography in 22 patients suffering from winter-type seasonal affective disorder and 30 healthy controls. No significant influence of MAOA DNA methylation on global MAO-A VT was found, despite correction for health status (patients vs. controls), sex, season (methylation analysis in spring / summer vs. fall / winter) and MAOA variable number of tandem repeat genotype (VNTR; high vs. low expression groups). However, in female subjects, season affected average DNA methylation, with higher levels in spring and summer (puncorr = 0.03). We thus did not find evidence for an effect of MAOA DNA methylation on brain MAO-A VT. In contrast to a previous study that demonstrated an effect of the methylation of a MAOA promoter region located further 5 on brain MAO-A, in the present study MAOA methylation appears to affect brain protein levels to a limited extent. The observed effect of season on methylation levels is in accordance with extensive evidence for seasonal effects within the serotonergic system.

Clinicaltrials.gov IdentifierNCT02582398

EUDAMED NumberCIV-AT-13-01-009583

category: psychiatry and clinical psychology


title: No woman should be left behind: A decomposition analysis of socioeconomic inequalities in unsafe abortion among women presenting for abortion care services in Lusaka and Copperbelt provinces of Zambia

abstract: This study measured socioeconomic-related unsafe abortion inequality among women presenting for abortion care services in Lusaka and the Copperbelt provinces of Zambia and decompose its causes. We conducted a cross-sectional study between August and September 2021. Unsafe abortion inequalities were assessed using corrected concentration index and Erreygers-type decomposition analysis was conducted to assess causes of unsafe abortion inequalities. Out of 362 women, the magnitude of unsafe abortion was 77(21.3%, [95% CI: 17.8, 24.9]). The corrected concentration index was -0.231 (95% CI: -0.309, -0.154), implying pro-poor inequality in unsafe abortion among women. Decomposition analysis showed that the major contributors of the unsafe abortion inequality were socioeconomic status (66.6%), marital status (6.3%), education (10.2%) and employment (3.7%). Also, history of unwanted pregnancy (5.1%), awareness of whether abortion is legal in Zambia (8.9%) and awareness that hospitals offered free abortion services (11.3%). The findings suggest that the unsafe abortion is a problem in Zambia and substantial inequality mainly due to socioeconomic factors. Stakeholders and policymakers should consider socioeconomic strategies to reduce unsafe abortion inequality promoting advocacy to increased access to legal safe abortion and use of modern contraceptives so that no woman is left behind in the prevention of unsafe abortion.

category: public and global health


title: Diagnostic accuracy of three computer-aided detection systems for detecting pulmonary tuberculosis on chest radiography when used for screening: analysis of an international, multicenter migrants screening study

abstract:
The aim of this study was to independently evaluate the diagnostic accuracy of three artificial intelligence (AI)-based computer aided detection (CAD) systems for detecting pulmonary tuberculosis (TB) on global migrants screening chest x-ray (CXR) cases.

Retrospective clinical data and CXR images were collected from the International Organization for Migration (IOM) pre-migration health assessment TB screening global database for US-bound migrants. A total of 2,812 participants were included in the dataset, of which 1,769 (62.9%) had accompanying microbiological test results. All CXRs were interpreted by three CAD systems (CAD4TB v6, Lunit INSIGHT v4.9.0, and qXR v2) offline and re-interpreted by two expert radiologists in a blinded fashion. The performance was evaluated using receiver operating characteristics curve (ROC), estimates of sensitivity and specificity at different CAD thresholds against both microbiological and radiological reference standards (MRS and RadRS, respectively).

The area under the curve against MRS was highest for Lunit (0.85; 95% CI 0.83-0.87), followed by qXR (0.75; 95% CI 0.72-0.77) and then CAD4TB (0.71; 95% CI 0.68-0.73). At a set specificity of 70%, Lunit had the highest sensitivity (54.5%; 95% CI 51.7-57.3); at a set sensitivity of 90%, specificity was also highest for Lunit (81.4%; 95% CI 77.9-84.6). The CAD systems performed comparable to sensitivity (98.3%), and except CAD4TB, to specificity (13.7 %) of expert radiologist. Similar trends were observed when using RadRS.

In conclusion, the study demonstrated that the three CAD systems had broadly similar diagnostic accuracy with regard to TB screening, and comparable accuracy to expert radiologist. Compared with different reference standards, Lunit performed better than both qXR and CAD4TB against MRS, and better than qXR against RadRS. Overall, these findings suggest that CAD systems could be a useful tool for TB screening programs in remote, high TB prevalent places where access to expert radiologists may be limited.

category: radiology and imaging


title: Single-cell RNA-sequencing reveals predictive features of response to pembrolizumab in Sezary syndrome

abstract: The PD-1 inhibitor pembrolizumab is effective in treating Sezary syndrome, a leukemic variant of cutaneous T-cell lymphoma. Our purpose was to investigate the effects of pembrolizumab on healthy and malignant T cells in Sezary syndrome and to discover characteristics that predict pembrolizumab response. Samples were analyzed before and after 3 weeks of pembrolizumab treatment by single-cell RNA-sequencing of 118,961 peripheral blood T cells isolated from six Sezary syndrome patients. T-cell receptor clonotyping, bulk RNA-seq signatures, and whole exome data were integrated to classify malignant T-cells and their underlying subclonal heterogeneity. We found that responses to pembrolizumab were associated with lower KIR3DL2 expression within Sezary T cells. Pembrolizumab modulated Sezary cell gene expression of T-cell activation associated genes. The CD8 effector populations included clonally expanded populations with a strong cytotoxic profile. Expansions of CD8 terminal effector and CD8 effector memory T-cell populations were observed in responding patients after treatment. We observed intrapatient Sezary cell heterogeneity including subclonal segregation of a coding mutation and copy number variation. Our study reveals differential effects of pembrolizumab in both malignant and healthy T cells. These data support further study of KIR3DL2 expression and CD8 immune populations as predictive biomarkers of pembrolizumab response in Sezary syndrome.