title: Urinary collagen-derived peptides as sensitive markers for bone resorption and bisphosphonate treatment in kidney transplant patients

abstract: Kidney transplant recipients (KTR) are at increased risk of fractures. Total urinary hydroxyproline excretion used to be a marker for bone resorption (BR) but faded into the background when more specific markers like Beta-CrossLaps (CTX) became available. Proteomic studies identified numerous hydroxyproline-containing urinary collagen peptides but their origin remains unknown. We followed the hypothesis that some of the urinary collagen peptides are associated with BR and are markers for pathophysiological changes in bone metabolism of KTR. Clinical and laboratory data including serum levels of CTX in 96 KTR from two French centers (Strasbourg, n=38; Paris-Necker, n=58) were correlated with the signal intensity of urinary peptides identified by capillary electrophoresis (CE) coupled to mass spectrometry (MS) and tandem-MS. The effect of oral bisphosphonates on urinary peptides was studied in an independent group of 11 KTR. Eighty-two urinary peptides were identified to be significantly correlated with serum CTX levels in both cohorts. Statistical association with parameters other than BR markers were not significant. Collagen -1(I) chain (COL1A1) was the most frequently identified peptide source. COL1A1 peptides associated with BR were significantly more hydroxylated than those showing no association (55.9% versus 45,2%, p<0.0003 by a {chi}2-test). From the 82 urinary peptides correlated to CTX, 17 were significantly associated with bisphosphonate treatment. All of these 17 peptides showed a marked reduction in their excretion levels after 410 {+/-} 344 days of bisphosphonate treatment compared to baseline levels. We studied the cleavage sites of these COL1A1 peptides and observed a signature of Cathepsin K and Matrix Metallopeptidase 9. This study provides strong evidence for the occurrence of collagen peptides in the urine of KTR that are associated with BR and that are sensitive to bisphosphonate treatment. Their assessment might become a valuable tool to monitor bone status in KTR.

category: transplantation


title: Machine learning analysis reveals biomarkers for the detection of neurodegenerative diseases

abstract:
It is critical to identify biomarkers for neurodegenerative diseases (NDDs) to advance disease diagnosis and accelerate drug discovery for effective treatment of patients. In this work, we retrieved genotyping and clinical data from 1223 UK Biobank participants to identify genetic and clinical biomarkers for NDDs, including Alzheimers disease (AD), Parkinsons disease (PD), motor neuron disease (MND), and myasthenia gravis (MG). Using a machine learning modelling approach and Monte Carlo randomisation, we identified 16 informative clinical variables for predicting AD, PD, MND, and MG. In a multinomial model, these clinical variables could correctly predict the diagnosis of one of the four diseases with an accuracy of 88.3%. In addition to clinical biomarkers, we also explored genetic biomarkers. In a genome-wide association study of AD, PD, MND, and MG patients, we identified single nucleotide polymorphisms (SNPs) implicated in several craniofacial disorders such as apnoea and branchiootic syndrome. We found evidence for shared genetic risk loci across NDDs, including SNPs in cancer-related genes and SNPs known to be associated with non-brain cancers such as Wilms tumour, leukaemia, and pancreatic cancer. Our analysis supports current knowledge regarding the ageing-related degeneration/cancer shift.

Significance statementThis study highlights the potential for hypothesis-free mathematical modelling of easily measured clinical variables to identify diagnostic biomarkers for neurodegenerative diseases (NDDs). Prior to this study, the focus in NDD research has surrounded toxic species such as amyloid beta and -synuclein, but this approach has not enjoyed success at clinical trial. Here, we studied Alzheimers disease, Parkinsons disease, motor neuron disease, and myasthenia gravis by constructing and inspecting a multinomial based on demographics and blood and urine biochemistry. Cognitive measures were important for the predictive power of the model. Model weights correctly indicated multiple trends reported in the literature. Separately, genome-wide association indicated a shared risk profile between NDD and cancer, which has also been reported in the literature.

category: neurology


title: Patterns of Polysubstance use among Adults in Malaysia - A Latent Class Analysis

abstract:
IntroductionPolysubstance use is the use of more than one non-prescribed licit or illicit substance at one time. This is a common phenomenon, but little is known about the severity and the various substances used by adults in Malaysia.

ObjectiveTo determine the pattern of polysubstance use and its associated factors among general adults in Malaysia.

MethodologyThis was a secondary data analysis from the National Health and Morbidity Survey (NHMS) 2019), a cross-sectional population survey with a two-stage stratified random sampling design. A total of 10,472 Malaysians aged 18 years and above participated in this survey. Polysubstance use was defined as concurrent use of more than one substance, either alcohol, tobacco, or drugs (opioid, marijuana, amphetamine/ methamphetamine or kratom). A latent class analysis (LCA) was used to identify the membership of polysubstance groups. The association of class membership with demographic profiles was examined using Multinomial Logistic Regression analysis.

ResultsFit indices (AIC =16458.9, BIC = 16443.6) from LCA supported 3 classes solution: i) Combination of tobacco and alcohol (Tob+Alc) use (2.4%), ii) multi-drug use including kratom (0.3%) and iii) non/negligible user (97.3%). The multinomial model showed young adults (18-40 years) had a higher likelihood of being polysubstance users both for Tob+Alc class (OR=4.1) and multi-drug class (OR=3.9) compared to older age ([≥]60 years). Chinese (OR = 18.9), Indian (OR =23.3), Indigenous Sabah & Sarawak (OR =34.6) and others ethnicity (OR =8.9) showed higher odds of being Tob+Alc users than Malays. The greater odds of Tob+Alc. use for male (OR =35.5), working group (OR =1.5) and low education level group (OR=3.2).

ConclusionOur study highlights patterns and demographics related to the use of polysubstance among adults in Malaysia. These results would help formulate specific prevention programmes for these high risk groups.

category: addiction medicine


title: Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains

abstract: Attention deficit hyperactivity disorder (ADHD) is a prevalent childhood psychiatric disorder, with a major genetic component. Here we present a GWAS meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, which is more than twice the number previously reported. Fine-mapping risk loci highlighted 76 potential risk genes enriched in genes expressed in brain, particularly the frontal cortex, and in early brain development. Overall, ADHD was associated with several brain specific neuronal sub-types and especially midbrain dopaminergic neurons. In a subsample of 17,896 exome-sequenced individuals, we identified increased load of rare protein-truncating variants in cases for a set of risk genes enriched with likely causal common variants, suggesting implication of SORCS3 in ADHD by both common and rare variants. We found ADHD to be highly polygenic, with around seven thousand variants explaining 90% of the SNP heritability. Bivariate gaussian mixture modeling estimated that more than 90% of ADHD influencing variants are shared with other psychiatric disorders (autism, schizophrenia and depression) and phenotypes (e.g. educational attainment) when both concordant and discordant variants are considered. Additionally, we demonstrated that common variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions including attention.

category: psychiatry and clinical psychology


title: Intraocular water movement visualization using 1H-MRI with eye drops of O-17 labeled saline: a first-in-human study

abstract:
BackgroundVisualization of aqueous humor flow in the human eye is difficult because gadolinium, a magnetic resonance imaging (MRI) contrast agent, does not readily cross the blood-retinal and blood-aqueous barriers of capillaries that supply water to the eye. The proton (1H) of oxygen-17 water (H217O) has a very short transverse relaxation time (T2), and the T2-weighted (T2W) 1H-MRI signal intensity of a region with H217O is lower than that with only H2 16O.

PurposeTo observe the distribution of H217O in the human eye, and the flow into and out of the anterior chamber of H217O, using dynamic T2W 1H-MRI.

Materials and MethodsSeven ophthalmologically normal adult volunteers under 40 years old participated in this study. During dynamic imaging, the subject self-administered 10 mol% H217O saline (0.92-1.37 mL) to their right eye for 1 min. Time-series images were created by subtracting the image before the eye drops from each of the images obtained after the eye drops. The "normalized signal intensity of the right anterior chamber" (rAC) in each image was obtained by dividing the signal intensity of the right anterior chamber region-of-interest by that of the left. Changes in transverse relaxation rate and H217O concentration (PO17) were calculated from the rAC. The inflow and outflow constants of H217O in the right anterior chamber were also determined.

ResultsDecreased signal intensity after the H217O eye drops was observed in the anterior and posterior chambers, but not in the vitreous body. The rAC signal intensity decreased after the eye drops, and then recovered to close to rAC(0) at 40 min. The inflow and outflow constants were 0.53 {+/-} 0.19 and 0.055 {+/-} 0.019 min-1, respectively, and the peak value of PO17 was 0.19 {+/-} 0.04% (mean {+/-} SD).

ConclusionH217O saline eye drops distributed in the human anterior and posterior chambers. Further, the eye drops smoothly flowed into, and slowly out of, the anterior chamber.

SummaryO-17 water dropped into human eyes as a T2-weighted MRI contrast agent was distributed in the anterior and posterior chambers, with smooth flow into, and slow outflow from, the anterior chamber.

Key findingsIn seven healthy volunteers, dynamic T2-weighted 1H-MRI showed that the signal intensity in the anterior chamber decreased smoothly after H217O eye drops and then slowly recovered, reaching a value close to that observed before the eye drops, after 40 minutes, with inflow and outflow constants of H217O of 0.53 {+/-} 0.19 min-1 and 0.055 {+/-} 0.019 min-1, respectively. The signal changes were limited to the anterior and posterior chambers and were not observed in the vitreous body.

category: radiology and imaging


title: Adherence to prophylaxis and bleeding outcome: a multicenter Nigerian study

abstract:
BackgroundIn Nigeria, low-dose prophylaxis is the standard of care as it reduces bleeding, development of target joints, arthropathy, and improvement of quality of life. Non-adherence or poor adherence can prevent the achievement of these outcomes. The levels and determinants of (non-)adherence among persons with haaemophilia (PWH) in Sub-Saharan Africa have not been evidenced.

ObjectiveTo evaluate self-reported adherence among PWH, provide evidence of determinants/predictors of adherence and establish the associations between nonadherence and presence of target joints and annualized bleed rate.

MethodologyA cross-sectional survey of 42 participants on low-dose prophylaxis recruited during outpatient appointments in 5 haemophilia treatment centers in Nigeria. We used the validated Haemophilia Regimen Treatment Adherence Scale-Prophylaxis (VERITAS -Pro), 24 questions on six subscales (time, dose, plan, remember, skip, and communicate) questionnaire. The options of VERITAS -Pro were represented in a 5 Likert scale and the possible subscale ranged from 4 points (most adherent) to 20 points (least adherent) and the possible total score ranged from 24 (most adherent) to 120 (least adherent) the cutoff for overall adherence put at > 61 to indicate nonadherence. Information on the presence of target joints, the number of target joints, and annualized bleeding rates were collected from medical files.

ResultsThe mean age of the participants was 9.79 (6.29) years, with 96.6% having hemophilia A and 79.3% having target joints. Overall adherence to the prophylaxis regimen was 81.0%. The mean total VERITAS-Pro for the adherent group and the non-adherent group was 37.35 {+/-}9.08 and 63.0{+/-} 6.37, respectively. The mean subscale scores for the adherent group ranged from 0.67 (communication) to 8.68 (planning), while the mean subscale scores range from 1.0 communication to 13.88 (planning) for the nonadherent group. The mean difference of all except the dosing subscale was statistically significant with p<0.05. Only the skipping subscale showed a statistically significant positive correlation with ABR in the non-adherent group p=0.02.

ConclusionsThe findings indicate that adherence was very good, and most were in communication with their treatment centers. The skipping subscale was significantly associated with ABR for the nonadherent group. Interventions aimed at improving adherence are the key to better treatment outcomes. A multicenter study was needed to assess the reason for poor adherence.

category: hematology


title: Heated tobacco products and a telemedicine smoking cessation programme: A retrospective study

abstract:
ObjectivesJapan is one of the largest markets for heated tobacco products (HTP), and the number of HTP users, including dual users, is burgeoning. However, it is not yet clear whether a telemedicine smoking cessation programme is helpful for nicotine-dependent people who use HTPs.

MethodsWe retrospectively evaluated the effectiveness of a telemedicine smoking cessation programme for nicotine-dependent tobacco product users, comparing short- and long-term continuous abstinence rates (CAR) from 9 to 24 weeks (CAR9-24) and 9 to 52 weeks (CAR9-52). We divided programme participants into 1) exclusively cigarette users, 2) exclusively HTP users, and 3) dual users. Using logistic regression with inverse probability weighting, an adjusted odds ratio (aOR) with a 95% confidence interval (CI) for CAR was calculated to compare the differences among the three groups.

ResultsWe analysed 733 telemedicine smoking cessation programme participants (exclusively cigarette users, 52%; exclusively HTP users, 31%; and dual-users, 16%) dating August 2018 to October 2020. HTP users had higher CARs than the exclusively cigarettes group in CAR9-24 (aOR, 1.12; CI, 1.02-1.23; p=0.02) and CAR9-52 (aOR 1.09; CI, 0.99-1.19; p=0.08). Conversely, dual users had lower CARs than the exclusively cigarettes group in the CAR9-24 (aOR, 0.85; CI, 0.76-0.95; p=0.004) and CAR9-52 (aOR, 0.88; CI, 0.79-0.97; p=0.01).

ConclusionsExclusively HTP users achieved higher CARs, whereas dual users had lower CARs than exclusively cigarette users over short- and long-term periods. A telemedicine smoking cessation programme may be a reasonable option for exclusively HTP users.

Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABSTelemedicine smoking cessation programmes can be helpful for some nicotine-dependent people.

What this study addsExclusively HTP users had higher continuous abstinence rates (CARs) than the exclusively cigarettes group. Conversely, dual users had lower CARs than the exclusively cigarettes group. A telemedicine smoking cessation programme may be a reasonable option for exclusive HTP users.

How this study might affect research, practice, or policyIn addition to conventional combustible cigarettes, the number of HTP users, including dual users, is burgeoning in Japan. This study could add an effective and alternative option for HTP users to remotely quit smoking in the era of COVID-19 and beyond.

category: respiratory medicine


title: City-wide wastewater genomic surveillance through the successive emergence of SARS-CoV-2 Alpha and Delta variants

abstract: Genomic surveillance of SARS-CoV-2 has been essential to provide an evidence base for public health decisions throughout the SARS-CoV-2 pandemic. Sequencing data from clinical cases has provided data crucial to understanding disease transmission and the detection, surveillance, and containment of outbreaks of novel variants, which continue to pose fresh challenges. However, genomic wastewater surveillance can provide important complementary information by providing estimates of variant frequencies which do not suffer from sampling bias, and capturing all variants circulating in a population. Here we show that genomic SARS-CoV-2 wastewater surveillance can detect fine-scale differences within urban centres, specifically within the city of Liverpool, UK, during the emergence of Alpha and Delta variants between November 2020 and June 2021. Overall, the correspondence between wastewater and clinical variant frequencies demonstrates the reliability of wastewater surveillance. Yet, discrepancies between the two approaches when the Alpha variant was first detected emphasises that wastewater monitoring can also capture missing information resulting from asymptomatic cases or communities less engaged with testing programmes, as found by a simultaneous surge testing effort across the city.

category: infectious diseases


title: Meta-analyses on SARS-CoV-2 Viral Titers in Wastewater and Their Correlations to Epidemiological Indicators

abstract:
BackgroundRecent applications of wastewater-based epidemiology (WBE) have demonstrated its ability to track the spread and dynamics of COVID-19 at the community level. Despite the growing body of research, quantitative synthesis of SARS-CoV-2 titers in wastewater generated from studies across space and time using diverse methods has not been performed.

ObjectiveThe objective of this study is to examine the correlations between SARS-CoV-2 viral titers in wastewater across studies, stratified by key covariates in study methodologies. In addition, we examined the associations of proportions of positive detections (PPD) in wastewater samples and methodological covariates.

MethodsWe systematically searched the Web of Science for studies published by February 16th, 2021, performed a reproducible screen, and employed mixed-effects models to estimate the levels of SARS-CoV-2 viral titers in wastewater samples and their correlations to case prevalence, sampling mode (grab or composite sampling), and the fraction of analysis (FOA, i.e., solids, solid-supernatant mixtures, or supernatants/filtrates)

ResultsA hundred and one studies were found; twenty studies (1,877 observations) were retained following a reproducible screen. The mean of PPD across all studies was 0.67 (95%-CI, [0.56, 0.79]). The mean titer was 5,244.37 copies/mL (95%-CI, [0; 16,432.65]). The Pearson Correlation coefficients (PCC) between viral titers and case prevalences were 0.28 (95%-CI, [0.01; 0.51) for daily new cases or 0.29 (95%-CI, [-0.15; 0.73]) for cumulative cases. FOA accounted for 12.4% of the variability in PPD, followed by case prevalence (9.3% by daily new cases and 5.9% by cumulative cases) and sampling mode (0.6%). Among observations with positive detections, FOA accounted for 56.0% of the variability in titers, followed by sampling mode (6.9%) and case prevalence (0.9% by daily new cases and 0.8% by cumulative cases). While sampling mode and FOA both significantly correlated with SARS-CoV-2 titers, the magnitudes of increase in PPD associated with FOA were larger. Mixed-effects model treating studies as random effects and case prevalence as fixed effects accounted for over 90% of the variability in SARS-CoV-2 PPD and titers.

InterpretationsPositive pooled means and confidence intervals in PCC between SARS-CoV-2 titers and case prevalence indicators provide quantitative evidence reinforcing the value of wastewater-based monitoring of COVID-19. Large heterogeneities among studies in proportions of positive detections, titers, and PCC suggest a strong demand in methods to generate data accounting for cross-study heterogeneities and more detailed metadata reporting. Large variance explained by FOA suggesting FOA as a direction that needs to be prioritized in method standardization. Mixed-effects models accounting for study level variations provide a new perspective to synthesize data from multiple studies.

category: epidemiology


title: Balanced chromosomal rearrangements offer insights into coding and noncoding genomic features associated with developmental disorders

abstract: Balanced chromosomal rearrangements (BCRs), including inversions, translocations, and insertions, reorganize large sections of the genome and contribute substantial risk for developmental disorders (DDs). However, the rarity and lack of systematic screening for BCRs in the population has precluded unbiased analyses of the genomic features and mechanisms associated with risk for DDs versus normal developmental outcomes. Here, we sequenced and analyzed 1,420 BCR breakpoints across 710 individuals, including 406 DD cases and the first large-scale collection of 304 control BCR carriers. We found that BCRs were not more likely to disrupt genes in DD cases than controls, but were seven-fold more likely to disrupt genes associated with dominant DDs (21.3% of cases vs. 3.4% of controls; P = 1.60x10-12). Moreover, BCRs that did not disrupt a known DD gene were significantly enriched for breakpoints that altered topologically associated domains (TADs) containing dominant DD genes in cases compared to controls (odds ratio [OR] = 1.43, P = 0.036). We discovered six TADs enriched for noncoding BCRs (false discovery rate < 0.1) that contained known DD genes (MEF2C, FOXG1, SOX9, BCL11A, BCL11B, and SATB2) and represent candidate pathogenic long-range positional effect (LRPE) loci. These six TADs were collectively disrupted in 7.4% of the DD cohort. Phased Hi-C analyses of five cases with noncoding BCR breakpoints localized to one of these putative LRPEs, the 5q14.3 TAD encompassing MEF2C, confirmed extensive disruption to local 3D chromatin structures and reduced frequency of contact between the MEF2C promoter and annotated enhancers. We further identified six genomic features enriched in TADs preferentially disrupted by noncoding BCRs in DD cases versus controls and used these features to build a model to predict TADs at risk for LRPEs across the genome. These results emphasize the potential impact of noncoding structural variants to cause LRPEs in unsolved DD cases, as well as the complex interaction of features associated with predicting three-dimensional chromatin structures intolerant to disruption.

category: genetic and genomic medicine


title: Mask up! Testing strategies to increase mask usage in Kenya

abstract:
BackgroundCOVID-19 continues to pose a major threat to countries around the world, and non-pharmaceutical interventions such as social distancing and face coverings remain important to reduce transmission, especially in settings with low vaccination rates. Despite a nationwide mask mandate in Kenya during the pandemic, proper masking remained low in Siaya County. We conducted a pilot study with the Siaya County Ministry of Health to improve mask adoption within Ugunja subcounty, and present initial findings on mask usage effects.

MethodsThe study took place across 72 villages in Ugunja subcounty, which were randomly assigned to receive: (i) free mask and education on mask usage; (ii) only education on mask usage; or (iii) no mask or education by community health workers. A "role model" intervention was also cross-randomized across half of the villages, along with SMS messages reinforcing a variety of messages around masking. The intervention was administered in January 2021. Data collection was done via phone survey and direct observation of mask usage.

FindingsPreliminary analysis of the pilot study suggests providing free face masks may improve compliance, particularly in settings with higher COVID-19 risks. Two weeks to three months after the intervention, the free mask and education arm increased directly-observed correct mask usage by 3.1 percentage points (95% confidence interval 1.9, 6.0) on a control mean of 6.8 percent. Some treatment arms also improved COVID-19 knowledge and mask attitudes.

InterpretationInterventions designed to increase adoption of health measures can be successful, but behavioral change is challenging and may require more intensive treatment.

category: public and global health


title: Systematic analysis and prediction of genes associated with disorders on chromosome X

abstract: Disease gene discovery on chromosome (chr) X is challenging owing to its unique modes of inheritance. We undertook a systematic analysis of human chrX genes. We observe a higher proportion of disorder-associated genes and an enrichment of genes involved in cognition, language, and seizures on chrX compared to autosomes. We analyze gene constraints, exon and promoter conservation, expression and paralogues, and report 127 genes sharing one or more attributes with known chrX disorder genes. Using a neural network trained to distinguish disease-associated from dispensable genes, we classify 235 genes, including 121 of the 127, as having high probability of being disease-associated. We provide evidence of an excess of variants in predicted genes in existing databases. Finally, we report damaging variants in CDK16 and TRPC5 in patients with intellectual disability or autism spectrum disorders. This study predicts large-scale gene-disease associations that could be used for prioritization of X-linked pathogenic variants.


title: Reliability of citations of medRxiv preprints in articles published on COVID-19 in the world leading medical journals

abstract:
BackgroundPreprints have been widely cited during the COVID-19 pandemics, even in the major medical journals. However, since subsequent publication of preprint is not always mentioned in preprint repositories, some may be inappropriately cited or quoted. Our objectives were to assess the reliability of preprint citations in articles on COVID-19, to the rate of publication of preprints cited in these articles and to compare, if relevant, the content of the preprints to their published version.

MethodsArticles published on COVID in 2020 in the BMJ, The Lancet, the JAMA and the NEJM were manually screened to identify all articles citing at least one preprint from medRxiv. We searched PubMed, Google and Google Scholar to assess if the preprint had been published in a peer-reviewed journal, and when. Published articles were screened to assess if the title, data or conclusions were identical to the preprint version.

ResultsAmong the 205 research articles on COVID published by the four major medical journals in 2020, 60 (29.3%) cited at least one medRxiv preprint. Among the 182 preprints cited, 124 were published in a peer-reviewed journal, with 51 (41.1%) before the citing article was published online and 73 (58.9%) later. There were differences in the title, the data or the conclusion between the preprint cited and the published version for nearly half of them. MedRxiv did not mentioned the publication for 53 (42.7%) of preprints.

ConclusionsMore than a quarter of preprints citations were inappropriate since preprints were in fact already published at the time of publication of the citing article, often with a different content. Authors and editors should check the accuracy of the citations and of the quotations of preprints before publishing manuscripts that cite them.

Key pointsO_LIMajor medical journals cite preprints in their articles on COVID
C_LIO_LI41% of the preprint cited were in fact already published when the citing article was published online and the published version should have been cited instead
C_LIO_LI40% of them displayed difference in the data when comparing to the published version and 10% in the conclusions
C_LIO_LIDifferences in content between the preprint and the published version are also common for preprints published after the publication of the citing article
C_LI


title: Comparative transmission of SARS-CoV-2 Omicron (B.1.1.529) and Delta (B.1.617.2) variants and the impact of vaccination: national cohort study, England

abstract:
BackgroundThe SARS-CoV-2 Omicron variant (B.1.1.529) has rapidly replaced the Delta variant (B.1.617.2) to become dominant in England. This epidemiological study assessed differences in transmissibility between the Omicron and Delta using two methods and data sources.

MethodsOmicron and Delta cases were identified through genomic sequencing, genotyping and S-gene target failure in England from 5-11 December 2021. Secondary attack rates for Omicron and Delta using named contacts and household clustering were calculated using national surveillance and contact tracing data. We used multivariable logistic regression was used to control for factors associated with transmission.

FindingsAnalysis of contact tracing data identified elevated secondary attack rates for Omicron vs Delta in household (15.0% vs 10.8%) and non-household (8.2% vs 3.7%) settings. The proportion of index cases resulting in residential clustering was twice as high for Omicron (16.1%) compared to Delta (7.3%). Transmission was significantly less likely from cases, or in named contacts, in receipt of three compared to two vaccine doses in household settings, but less pronounced for Omicron (aRR 0.78 and 0.88) compared to Delta (aRR 0.62 and 0.68). In non-household settings, a similar reduction was observed for Delta cases and contacts (aRR 0.84 and 0.51) but only for Omicron contacts (aRR 0.76, 95% CI: 0.58-0.93) and not cases in receipt of three vs two doses (aRR 0.95, 0.77-1.16).

InterpretationOur study identified increased risk of onward transmission of Omicron, consistent with its successful global displacement of Delta. We identified a reduced effectiveness of vaccination in lowering risk of transmission, a likely contributor for the rapid propagation of Omicron.

FundingStudy funded by the UK Health Security Agency.


title: Early-life exposure to the Chinese famine of 1959-61 and type 2 diabetes in adulthood: a systematic review and meta-analysis

abstract:
BackgroundThe Chinese famine of 1959-61 has been widely interpreted as an important driver of current and future type 2 diabetes (T2D) epidemics. We conducted a systematic review and meta-analysis of prenatal famine exposure and type 2 diabetes (T2D) in China to summarize study characteristics, examine impacts of control selections and other selected characteristics on study results, identify other characteristics influencing results, and formulate recommendations for future studies.

MethodsWe searched English and Chinese databases for studies that examined the relationship between T2D and prenatal exposure to the Chinese famine up to February 8th, 2022. From included studies, we extracted information on the number of T2D cases and populations at risk among individuals born during the famine (famine births), before the famine (pre-famine births), and after the famine (post-famine births). We compared risk of T2D in famine births to different controls: post-famine births, pre- and post-famine births combined, and pre-famine births. Heterogeneity across studies was assessed, and random-effects models were used to calculate summary estimates. Meta-regressions were used to examine the relationship between effect estimates and age differences. Subgroup analyses were performed based on selected characteristics, including participants sex, age, T2D measurement, famine intensity, residence, and publication language.

FindingsIn total, 23 studies met our inclusion criteria. Sample sizes ranged from below 300 to over 350,000. All studies defined famine exposure based on participants date of birth, and 18 studies compared famine births to controls of post-famine births to estimate famine effects on T2D. Famine and post-famine births had an age difference of three years and over in each study. Using post-famine births as controls, a random-effects model shows an increased risk of T2D (OR 1.50, 95% CI 1.34-1.68) among famine births. In contrast, a marginally increased risk of T2D (OR 1.12, 95% CI 1.02-1.24) can be observed using pre- and post-famine births combined as controls, and a decreased risk (OR 0.89, 95% CI 0.79-1.00) using pre-famine births as controls. Studies with larger age differences between comparison groups had larger famine effects. Effect estimates comparing famine births to pre- and post-famine births combined depend on none of above selected characteristics. Studies showed a large variation in sampling sources, famine intensity assessment, and confounding adjustment.

InterpretationCurrent estimates of a positive relation between prenatal exposure to the Chinese famine and adult T2D are mainly driven by uncontrolled age differences between famine births and post-famine controls. Marginal or no effects remain after controlling for the differences in most Chinese famine studies. It remains an open question to what extent the famine is related to current T2D patterns in China. Studies with more rigorous methods including age-balanced controls and robust famine intensity measures will be needed to quantify this relationship.

FundingNone.


title: ProBioQuest: a database and semantic analysis engine for literature, clinical trials, and patents related to probiotics

abstract:
The use of probiotics to improve health via the modulation of gut microbiota has gained wide attention. The growing volume of investigations of probiotic microorganisms and commercialized probiotic products has created the need for a database to organize the health-promoting functions driven by probiotics reported in academic articles, clinical trials, and patents. Currently, no such database is available. We constructed ProBioQuest to collect up-to-date literature related to probiotics from PubMed.gov, ClinicalTrials.gov, and Patents View. More than 2.8 million articles were collected by the end of 2021: PubMed.gov: 2 656 818; Clinical Trials.gov: 205 349; Patents View: 32 536. Automated information technology-assisted procedures enabled us to collect the data continuously, providing the most up-to-date information. Statistical functions and semantic analyses are provided on the website as an advanced search engine, which contributes to the semantic tool of this database for information search and analyses. The semantic analytical output provides categorised search results and functions to enhance further analysis. A keyword bank is included which can display multiple tables of contents. Users can select keywords from different displayed categories to achieve easy filtered searches. Additional information on the searched items can be browsed via the link-out function. ProBioQuest is not only useful to scientists and health professionals, but also to dietary supplement manufacturers and the general public. In this paper, the method we used to build this database-web system is described. Applications of ProBioQuest for several literature-based analyses of probiotics are included as examples of the various uses to which this search engine can be put. ProBioQuest can be accessed free of charge at http://kwanlab.bio.cuhk.edu.hk/PBQ/.

Database URLhttp://kwanlab.bio.cuhk.edu.hk/PBQ/


title: Targeted transcutaneous cervical spinal cord stimulation promotes upper limb recovery in spinal cord and peripheral nerve injury

abstract: Long-term recovery of volitional control of the upper limb is a major unmet need in people with paralysis. Recently, it has been demonstrated that spinal cord stimulation, when paired with intense physical therapy, can restore volitional control of upper limb in spinal cord injury (SCI). Epidural stimulation of the spinal cord has traditionally been demonstrated to be highly effective in restoring movement, potentially due to the ability of targeted activation of specific motoneuron pools. However, transcutaneous spinal cord stimulation (tSCS) has recently shown equally promising results. In this study, we use a custom designed electrode patch and stimulator to enable targeted stimulation of specific spinal segments. We show that targeted transcutaneous stimulation of the cervical spinal cord can substantially and rapidly improve volitionally evoked muscle activity and force, even with minimal physical therapy, in two individuals with SCI. We also show, for the first time, the effectiveness of tSCS in restoring strength and dexterity in an individual with paralysis of the hand due to a peripheral injury.


title: Gaining Control of Combination Cancer Treatment Risk by Incorporating Cost and Value Data into the Drug Selection Process at the Point-of-Care

abstract:
The use of combination drug therapies (e.g., immunotherapies, chemotherapies and drugs having distinct mechanisms of action) for the treatment of cancer is now widespread; as well, the repositioning of FDA- approved treatments for off-label indications. While much is known about their clinical effectiveness, there exists no study of the relative cost of novel multi-drug combinations vs. monotherapies or examinations as to how knowledge about comparative therapy costs may be leveraged by doctors, health systems and payers to identify therapies that are likely to be more effective, less wasteful and a financial value. We found that

O_LIcombination multi-drug cancer regimens are often far less expensive than traditional monotherapies,
C_LIO_LInovel, multi-drug combinations are often better financial values than traditional monotherapies, and
C_LIO_LIhaving treatment cost and value data, at the point of care, enables the prompt selection of more cost- effective medications and the avoidance of expensive low-value therapies that are financially wasteful.
C_LI

We conclude that the effectiveness of value-based purchasing models may be amplified if providers and payers use comparative treatment cost data to augment and enhance their drug-selection decision making.

Study HighlightsO_ST_ABSWhat Is The Current Knowledge On The Topic ?C_ST_ABS{ballotcheck} We know that the effectiveness of targeted multi-drug combination therapies in the treatment of cancer is long established, 1-4 that few clinicians are aware of the cost of the medications they prescribe, or which are more cost-effective, deliver a better return-on-investment or represent a financial value, 8 and that it is intuitive to infer that a combination of multiple high-cost medications is far more costly than a monotherapy.

What Question Did This Study Address ?{ballotcheck} Although studies on the clinical impact of multi-drug cancer treatments abound, 1-4 there are no examinations of the relative cost or value of combination therapies vs. that of traditional monotherapies, or how knowledge of how this data can be used in practice. A systematic method to calculate, evaluate and compare the relative cost of 1-, 2- and 3-drug combination cancer therapies is presented that can be used by providers, health systems and payers to better manage their oncology special pharmacy spend and drive better outcomes.

What Does This Study Add To Our Knowledge ?{ballotcheck} We show that multi-drug cancer therapies are not necessarily more costly than monotherapies; and that furnishing providers and payers with comparative treatment cost and value data to augment their complex medication selection decision making enables them to identify drugs that are a value, avoid those that are wasteful and create better targeted novel combination cancer therapies that represent a genuine value.

How Might This Change Combination Therapy Drug Selection Or Value-Based Oncology Management ?{ballotcheck} Clinicians have the tools, information and data with which to confidently develop novel drug combinations that customize molecular targeting, reduce waste and lower treatment costs. Payers now have a framework within which to drive value-based purchasing to gain control of their oncology specialty drug risk. Cancer patients will benefit from more personalized, efficient and effective therapies and less financial toxicity.

category: health economics


title: Relative Virulence of SARS-CoV-2 Among Vaccinated and Unvaccinated Individuals Hospitalized with SARS-CoV-2

abstract:
BackgroundThe rapid development of safe and effective vaccines against the SARS-CoV-2 virus has been a singular scientific achievement. Confounding due to health seeking behaviours and differential testing by vaccination status may bias analyses towards an apparent increase in infection severity following vaccination. We sought to determine whether risks of intensive care unit (ICU) admission and death were diminished significantly by vaccination, even in individuals for whom vaccination failed to prevent hospitalization.

MethodsWe used data from Ontario, Canadas Case and Contact Management database, merged to a provincial vaccination dataset (COVaxON) to create a time-matched cohort of individuals who were hospitalized with SARS-CoV-2 infection. Each vaccinated individual was matched to up to five unvaccinated individuals based on test date of positive SARS-CoV-2 infection. Risk of ICU admission and death were evaluated using multivariable conditional logistic regression. Unmatched exploratory analyses were performed to identify sources of heterogeneity in vaccine effects.

ResultsIn 20,064 individuals (3,353 vaccinated and 16,711 unvaccinated) hospitalized with infection due to SARS-CoV-2 between January 1st, 2021 and January 5th, 2022, vaccination with 1, 2, or 3 doses significantly reduced the risk of ICU admission and death. An inverse dose-response relationship was observed between vaccine doses received and both outcomes (adjusted odds ratio (aOR) for ICU admission per additional dose: 0.66, 95% CI 0.62 to 0.71; aOR for death per additional dose: 0.78, 95% CI 0.72 to 0.84). The reduction in risk was greater for ICU admission than for death (P for heterogeneity <0.05), but no significant differences in risk were seen based on infecting variant of concern (VOC).

InterpretationWe identified a decrease in the risk of ICU admission and death in vaccinated individuals compared to unvaccinated, time-matched controls, even when vaccines failed to prevent infection sufficiently severe to cause hospitalization. Even with diminished efficacy of vaccines against infection with novel VOCs, vaccines remain an important tool for reduction of ICU admission and mortality.


title: Natural Trajectory of Recovery of COVID-19 Associated Olfactory Loss

abstract:
ImportancePrevalence of post-viral olfactory loss has increased dramatically due to the frequency and severity of olfactory dysfunction associated with infection by the SARS-CoV-2 virus.

ObjectiveTo determine the trajectory of COVID-19 olfactory loss over a six-month period. A key secondary objective is to assess predictive factors associated with the recovery of olfaction.

DesignLongitudinal repeated-measures study that enrolled from May 5, 2020 to February 2, 2021, with the last date of data collection on June 15, 2021.

SettingBarnes-Jewish HealthCare/Washington University School of Medicine facilities (Saint Louis, Missouri, USA).

ParticipantsIndividuals who tested positive for SARS-CoV-2 by real-time polymerase chain reaction on nasopharyngeal swab and indicated olfactory loss on COVID-19 screening questionnaire. Individuals were excluded if they had previously diagnosed history of olfactory loss, neurodegenerative disorders, less than 18 years of age, admitted to hospital service, unable to read, write, and understand English, or lacked computer or internet access.

Interventions/ExposuresWatch and wait for spontaneous recovery.

Main Outcome(s) and Measure(s)Participants completed olfactory assessments every 30 days for six months. Each assessment consisted of the University of Pennsylvania Smell Identification Test (UPSIT), an objective "scratch-and-sniff" test, and Clinical Global Impressions (CGI), a subjective Likert rating scale.

ResultsThe mean age was 41 years old (SD = 16). 39 (80%) were female and 42 (86%) white. At baseline assessment of objective olfaction, 18 (36%) participants had anosmia or severe hyposmia. Subjective, complete recovery at six months was 81% (95% CI 74% to 88%). Likelihood of recovery was associated with age less than 50 years (aHR = 8.1 (95% CI 1.1 to 64.1)) and mild olfactory loss at baseline (UPSIT = 30-33 for males and 31-34 for females) (aHR 6.2 (95% CI 1.2 to 33.0)).

Conclusions and RelevanceThe trajectory of olfactory recovery among adults with COVID-19 olfactory loss illustrated rapid recovery within 2-3 weeks of infection, and by six months 81% had recovered based on self-report. Age less than 50 years old and mild severity of olfactory loss at baseline were associated with increased likelihood of recovery of olfaction. These findings can be used to inform shared decision-making with patients.


title: The SARS-CoV2 envelope is distinct from host membranes, exposes pro-coagulant lipids, and can be inactivated in vivo by surfactant-containing oral rinses.

abstract: The lipid envelope of SARS-CoV2 is an essential component of the virus, however its molecular composition is unknown. Addressing this knowledge gap could support the design of anti-viral agents, and further understanding of viral interaction with extracellular host proteins, infectivity, pathogenicity, and innate immune system clearance. Lipidomics analysis of SARS-CoV2 particles generated from Vero or A549 cells revealed that the virus envelope comprised mainly of phospholipids (PL), primarily phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI), with very little cholesterol, sphingolipids or other lipids, indicating significant differences from host membranes. Unlike healthy cellular membranes, procoagulant aminoPL (aPL), specifically PE and phosphatidylserine (PS), were present on the external side at levels far exceeding those seen on activated platelets. As a result, purified virions directly promoted coagulation. To investigate whether these differences enabled the viral envelope to be selectively targeted at relevant sites in vivo, we tested whether non-toxic oral rinses containing lipid disrupting chemicals could reduce viral infectivity. Products containing PL-disrupting surfactant solutions (cetylpyridinium chloride (CPC) or ethyl lauroyl arginate) met EN14476 virucidal standards in vitro, however products containing essential oils, PVP-I, or Chlorhexidine did not, nor did rinses containing components that altered the critical micelle concentration of CPC. This result was recapitulated in vivo, where a 30-second oral rinse with CPC-mouthwash eliminated live virus in the oral cavity of COVID19 patients for at least 1hr, while PVP-Iodine and saline mouthwashes were ineffective. Thus, the SARS-CoV2 lipid envelope is distinct from the host plasma membrane which may enable design of selective anti-viral approaches, it exposes PE and PS which may influence thrombosis, pathogenicity, and inflammation, and can be selectively targeted in vivo by specific oral rinses.


title: Validation of the RT-LAMP assay in a large cohort of nasopharyngeal swab samples shows that it is a useful screening method for detecting SARS-CoV-2 and its VOC variants

abstract: The COVID-19 pandemic is challenging the global supply chain and equipment needed for mass testing with RT-qPCR, the gold standard for SARS-CoV-2 diagnosis. Here, we propose the RT-LAMP assay as an additional strategy for rapid virus diagnosis. However, its validation as a diagnostic method remains uncertain. In this work, we validated the RT-LAMP assay in 1,266 nasopharyngeal swab samples with confirmed diagnosis by CDC 2019-nCoV RT-qPCR. Our cohort was divided, the first (n=984) was used to evaluate two sets of oligonucleotides (S1 and S3) and the second (n=281) to determine whether RT-LAMP could detect samples with several types of variants. This assay can identify positive samples by color change or fluorescence within 40 minutes and shows high concordance with RT-qPCR in samples with CT [≤]35. Also, S1 and S3 are able to detect SARS-CoV-2 with a sensitivity of 68.4% and 65.8%, and a specificity of 98.9% and 97.1%, respectively. Furthermore, RT-LAMP assay identified 279 sequenced samples as positive (99.3% sensitivity) corresponding to the Alpha, Beta, Gamma, Delta, Epsilon, Iota, Kappa, Lambda, Mu and Omicron variants. In conclusion, RT-LAMP is able to identify SARS-CoV-2 with good sensitivity and excellent specificity, including all VOC, VOI, VUM and FMV variants.

category: intensive care and critical care medicine


title: Medication Guideline Adherence Among Patients with Markedly Elevated Blood Pressure in A Real-World Setting

abstract:
ObjectiveTo evaluate medication guideline adherence among ambulatory patients with markedly elevated blood pressure (BP), overall and by patient characteristics.

DesignPopulation-based, retrospective cohort study.

SettingYale New Haven Health System.

ParticipantsAdult patients aged 18-85 years with markedly elevated BP (defined as two consecutive outpatient visits with systolic BP [≥]160 mmHg or diastolic BP [≥]100 mmHg) between October 1st, 2015 and December 31st, 2018.

Main outcome measuresWe assessed the number and class of antihypertensive drugs (previously taken and newly prescribed) prior to 90 days of the second visit with BP [≥]160/100 mmHg. Among patients treated with two-drug class regimens, we assessed the proportion of patients on guideline-recommended two drug classes, overall and stratified by documentation of prior myocardial infarction (MI), diabetes, chronic kidney disease (CKD), and uncomplicated hypertension (i.e., without MI, coronary artery disease, diabetes, CKD, and cerebrovascular disease).

ResultsWe identified 16,377 patients with markedly elevated BP. They had a mean age of 65.8 (SD: 14.5) years; 54.0% were female; and 69.4%, 19.6%, and 9.6% were White, Black, and Hispanic, respectively. Prior to 90 days of the second visit, 29.8% had no active antihypertensive drug prescription, 20.0% had one drug class prescribed, and 50.2% had two or more drug classes prescribed. Among patients prescribed one antihypertensive drug class, the most common drug class was angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), followed by calcium channel blocker (CCB). Among patients prescribed two antihypertensive drug classes, the most common treatment combinations were ACEI or ARB and thiazide diuretic (21.0%), followed by ACEI or ARB and CCB (20.6%). Guideline-recommended two-drug class combination therapy were prescribed in 54.3% of the treated population, with the highest proportion of 67.0% in patients with a prior MI and the lowest proportion of 48.2% among patients with CKD. Older age, lower body mass index, and lower BP were associated with lower prescription of guideline-recommended combination therapy.

ConclusionOnly half of patients with markedly elevated BP were prescribed guideline-recommended antihypertensive combination drugs. Major opportunities exist for improving the guideline adherence of antihypertensive drug prescription in this population.

What this Paper AddsO_ST_ABSSection 1: What is already known on this subject?C_ST_ABSHypertension affects nearly one in two adults in the United States, of whom 20% have markedly elevated blood pressure (BP; defined as BP [≥]160/100 mmHg). People with markedly elevated BP have increased risks of adverse cardiovascular and kidney events. Clinical guidelines recommend prescribing combination therapy with two or more antihypertensive agents for patients with markedly elevated BP.

Section 2: What this study addsThis study quantified the real-world medication guideline adherence among ambulatory patients with markedly elevated BP, using electronic health record data from a large health system in the United States. Prior to 90 days of the second visit with BP [≥]160/100 mmHg, nearly 30% of patients had no active antihypertensive drug prescription. Among patients prescribed at least one antihypertensive drug class, guideline-recommended two-drug class combination therapy were prescribed in 54% of patients, with the highest proportion of 67% in patients with a prior myocardial infarction and the lowest proportion of 48% among patients with chronic kidney disease. These findings highlight a large missed opportunity for improving the guideline adherence of antihypertensive drug prescription in this population.

category: cardiovascular medicine


title: Glycemic variability and all-cause mortality in a large prospective southern European cohort of patients with differences in glycemic status.

abstract:
BackgroundFew studies have analyzed the relationship between glucose variability (GV) and adverse health outcomes in patients with differences in glycemic status. The present study tests the hypothesis that GV predicts all-cause mortality regardless of glycemic status after simple (age and sex) and full adjustment (age, sex, cardiovascular disease, hypertension, use of aspirin, statins, GLP-1 receptor agonists, SGLT-2 inhibitors and DPP-4 inhibitors, baseline FPG and average HbA1c).

MethodsProspective cohort study with 795 normoglycemic patients, 233 patients with prediabetes, and 4,102 patients with type 2 diabetes. GV was measured using the coefficient of variation of fasting plasma glucose (CV-FPG) over 12 years of follow-up. The outcome measure was all-cause mortality.

ResultsA total of 1,223 patients (657 men, 566 women) died after a median of 9.8 years of follow-up, with an all-cause mortality rate of 23.35/1,000 person-years. In prediabetes or T2DM patients, the fourth quartile of CV-FPG exerted a significant effect on all-cause mortality after simple and full adjustment. A sensitivity analysis excluding participants who died during the first year of follow-up revealed the following results for the highest quartile in the fully adjusted model: overall, HR (95%CI) =1.54 (1.26-1.89); dysglycemia (prediabetes and T2DM), HR=1.41 (1.15-1.73); T2DM, HR=1.36 (1.10-1.67).

ConclusionWe found CV-FPG to be useful for measurement of GV. It could also be used for the prognostic stratification of patients with dysglycemia.


title: Effect of a single dose of oral iron on pancreatic beta-cell function in healthy individuals: a before-and-after (pre-post) study

abstract:
IntroductionAlthough in vitro and animal studies have shown that iron loading in pancreatic beta-cells impaired insulin secretion, no human studies have documented the acute effects of oral iron on beta-cell insulin secretory capacity. In this study, we determined beta-cell insulin secretory capacity at baseline and after a single oral dose of iron (ferrous sulphate, 120 mg elemental iron) in healthy male individuals.

MethodsFifteen healthy male volunteers underwent an oral glucose tolerance test (OGTT) to document baseline glucose tolerance and insulin secretion kinetics (baseline OGTT). One week later, the same subjects underwent a second OGTT, two hours after an oral dose of ferrous sulfate (120 mg of elemental iron) (post-iron OGTT). Changes in disposition index, insulin secretion kinetics, glucose tolerance, insulin clearance, and iron-related parameters in serum were determined.

ResultsCompared to baseline OGTT, the areas under the curve (AUC) for serum iron and transferrin saturation increased by 125% and 118% respectively, in the post-iron OGTT. The disposition index decreased by 20% (p=0.009) and the AUC for glucose concentrations increased by 5.7% (p<0.001) during the post-iron OGTT. The insulin secretion rate was marginally lower during the first hour (-3.5%, p=0.63), but became significantly higher during the second hour (22%, p=0.005) of the post-iron OGTT. Concentrations of glucose, insulin and C-peptide in blood were significantly higher at 120 min of the post-iron OGTT.

ConclusionThe decrease in disposition index and glucose tolerance observed after the oral dose of iron points to an acute iron-induced impairment in pancreatic beta-cell insulin secretory capacity.

category: endocrinology


title: Discovery of Novel Trans-Ancestry and Ancestry-Specific Gene Loci for Total Testosterone in a Multi-Ancestral Analysis of Men in the Million Veteran Program

abstract: Utilizing data from the Million Veteran Program (MVP), we investigated the genetic determinants underlying total testosterone levels via a multi-ancestral analysis of 124,593 individuals of European (n=88,385), African (n=25,235) and Hispanic (n=10,973) ancestry. We identified 46 trans-ancestry variants and 17 ancestry-specific variants, of which 14 trans-ancestry variants and 15 ancestry-specific variants are novel associations with testosterone. Results implicate genes regulating testosterone shared across ancestral groups, which include SHBG, JMJD1C, FXR2, SENP3, TNFSF12-TNFSF13 while implicating genes such as MSN, DMD, VSIG4, CHEK2, TKTL1 that may underlie ancestry-group differences in testosterone regulation. We also linked testosterone variants on the X chromosome with differential risk of chronic kidney disease and hereditary hemolytic anemias in African and Hispanic ancestry groups, respectively. Lastly, we constructed a polygenic score from our 46 trans-ancestry variants and associated it with testicular dysfunction, hyperlipidemia, gout and prostate cancer with stronger prostate cancer associations in Hispanic and African ancestry groups compared to the European ancestry group. These findings provide insight into ancestry-specific androgen regulation and identify novel variants for disease risk stratification in patients.


title: The acute lag effects of elevated ambient air pollution on stillbirth risk in Ulaanbaatar, Mongolia

abstract: Ulaanbaatar city (UB), the capital and the home to half of Mongolias total population, has experienced extreme seasonal air pollution in the past two decades with levels of fine particulate matter with an aerodynamic diameter less than 2.5 micrometers (PM2.5) exceeding 500 g/m3 during winter. Based on monitoring data, (PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2), and carbon monoxide (CO) exposures were estimated for residential areas across UB using Random Forest models. We collected individual-level data on 1093 stillbirths from UB hospital records (2010-2013) and a surveillance database (2014-2018). Using a time-stratified case-crossover design, we investigated whether short-term increases in daily ambient air pollutants with different exposure lags (2 to 6 days) before delivery were associated with stillbirth. We estimated associations using conditional logistic regression and examined individual-level characteristics for effect modification. During the cold season (Oct-Mar) we observed significantly elevated relative odds of stillbirth per interquartile range increase in mean concentrations of PM2.5 (odds ratio [OR]=1.35, 95% confidence interval [CI]=1.07-1.71), SO2 (OR=1.71, 95% CI=1.06-2.77), NO2 (OR=1.30, 95% CI=0.99-1.72), and CO (OR=1.44, 95% CI=1.17-1.77) 6 days before delivery after adjusting for apparent temperature with a natural cubic spline. The associations of pollutant concentrations with stillbirth were significantly stronger among those younger than 25, nulliparous, and without comorbidities or pregnancy complications during stratified analyses. There was a clear pattern of increased risk for women living in areas of lower socioeconomic status. We conclude that acute exposure to ambient air pollution before delivery may trigger stillbirth, and this risk is higher for certain subsets of women.


title: The effects of skin pigmentation on the accuracy of pulse oximetry in measuring oxygen saturation: a systematic review and meta-analysis

abstract:
BackgroundPulse oximetry was widely used in hospitals and at home to monitor blood oxygen during the COVID-19 pandemic. There have been concerns regarding potential bias in pulse oximetry measurements for people with dark skin. We aimed to assess the effects of skin pigmentation on the accuracy of oxygen saturation measurement by pulse oximetry (SpO2) compared with the gold standard SaO2 measured by CO-oximetry.

MethodsWe searched Ovid MEDLINE, Ovid Embase, and EBSCO CINAHL Plus (up to December 2021), as well as ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform (up to August 2021). We identified studies comparing SpO2 values in any population, in any care setting, using any type of pulse oximeter, with SaO2 by standard CO-oximetry; and measuring the impact of skin pigmentation or ethnicity on pulse oximetry accuracy. We performed meta-analyses for mean bias (the primary outcome in this review) and its standard deviations (SDs) across studies included for each subgroup of level of skin pigmentation and ethnicity. We calculated accuracy root-mean-square (Arms) and 95% limits of agreement based on pooled mean bias and pooled SDs for each subgroup.

ResultsWe included 32 studies (6505 participants); 27/32 (84.38%) in hospitals and none in peoples homes. Findings of 14/32 studies (43.75%) were judged, via QUADAS-2, at high overall risk of bias. Fifteen studies measured skin pigmentation and 22 referred only to ethnicity. Compared with standard SaO2 measurement, pulse oximetry probably overestimates oxygen saturation in people with dark skin (pooled mean bias 1.11%; 95% confidence interval 0.29% to 1.93%) and people described as Black/African American (pooled mean bias 1.52%; 0.95% to 2.09%) (moderate- and low-certainty evidence). These results suggest that, for people with dark skin, pulse oximetry may overestimate blood oxygen saturation by around 1% on average compared with SaO2. The bias of pulse oximetry measurements for people with other levels of skin pigmentation, or those from the White/Caucasian group is more uncertain. The data do not suggest overestimation in people from other ethnic groups such as those described as Asian, Hispanic, or mixed ethnicity (pooled mean bias 0.31%, 0.09% to 0.54%), but this evidence is low certainty. Whilst the extent of mean bias is small or negligible for all the subgroups of population evaluated, the associated imprecision is unacceptably large (with the pooled SDs > 1%). Nevertheless, when the extents of measurement bias and precision are considered jointly in Arms, pulse oximetry measurements for all the subgroups appear acceptably accurate (with Arms < 4%).

ConclusionsLow-certainty evidence suggests that pulse oximetry may overestimate oxygen saturation in people with dark skin and people whose ethnicity is reported as Black/African American, compared with SaO2, although the overestimation may be quite small in hospital settings. The clinical importance of any overestimation will depend on the particular clinical circumstance. Pulse oximetry measurements appear accurate but imprecise for all levels of skin pigmentation. The evidence relates to clinician-measured oximetry in health care environments and may not be reflected in home pulse oximetry where other factors may also influence accuracy.

Author summaryO_ST_ABSWhy was this study done?C_ST_ABSO_LIPulse oximetry was widely used in hospital and at home to measure blood oxygen levels during the COVID-19 pandemic.
C_LIO_LIThere was uncertainty as to whether skin pigmentation affects the accuracy of pulse oximetry measurements.
C_LI

What did the researchers do and find?O_LIWe assessed, via systematic review, the effects of skin pigmentation on the accuracy of pulse oximetry measurement (SpO2) compared with SaO2 measured by standard CO-oximetry.
C_LIO_LIIn people with dark skin, oxygen saturation measured in hospital by pulse oximetry may be overestimated by an average of 1% compared with gold standard SaO2, however, the evidence is of low certainty.
C_LIO_LIThe accuracy of pulse oximetry measured compared with standard SaO2 is quite uncertain for people with light or medium levels of skin pigmentation and for people from ethnic groups other than those described in papers as Black or African American.
C_LIO_LIPulse oximetry measurements appear to have acceptable overall accuracy (with Arms< 4%) for all subgroups of population evaluated whilst the variation of oximetry readings appear unacceptably wide (with the pooled SDs > 1%).
C_LI

What do these findings mean?O_LIHospital measured pulse oximetry may overestimate oxygen saturation in people with dark skin compared with SaO2 by approximately 1%.
C_LIO_LIThe implications of this finding in different clinical scenarios will vary but could be clinically important. Impacts are likely to be at the thresholds of being diagnosed as having hypoxaemia where even a small SpO2 overestimation could lead to clinically important hypoxaemia remaining undetected and untreated.
C_LIO_LIHow these findings extrapolate to community and home care settings is unclear.
C_LI


title: An optimized reference tissue method for quantification of tau protein depositions in diverse neurodegenerative disorders by PET with 18F-PM-PBB3 (18F-APN-1607)

abstract: Positron emission tomography (PET) with 18F-PM-PBB3 (18F-APN-1607) enables high-contrast detection of tau depositions in various neurodegenerative dementias, including Alzheimers disease (AD) and frontotemporal lobar degeneration (FTLD). A simplified method for quantifying the radioligand binding in target regions is to employ the cerebellum as a reference (CB-ref) on the assumption that the cerebellum has minimal tau pathologies. This procedure could be valid in AD, while FTLD disorders exemplified by progressive supranuclear palsy (PSP) are characterized by occasional tau accumulations in the cerebellum, hampering the application of CB-ref. The present study aimed to establish an optimal method for defining reference tissues on 18F-PM-PBB3-PET images of the AD and non-AD tauopathy brains. We developed a new algorithm to extract reference voxels with a low likelihood of containing tau deposits from gray matter (GM-ref) or white matter (WM-ref) by a bimodal fit to an individual, voxel-wise histogram of the radioligand retentions and applied it to 18F-PM-PBB3-PET data obtained from age-matched 40 healthy controls (HCs) and 23 AD, 40 PSP, and five other tau-positive FTLD patients. PET images acquired at 90-110 min after injection were averaged and co-registered to corresponding magnetic resonance imaging space. Subsequently, we generated standardized uptake value ratio (SUVR) images estimated by CB-ref, GM-ref and WM-ref respectively, and then compared the diagnostic performances. GM-ref and WM-ref covered a broad area in HCs and free of voxels located in regions known to bear high tau burdens in AD and PSP patients. GM-ref allowed the most robust separation of AD and PSP patients from HCs according to the area under the curves in receiver operating characteristic curve analyses. GM-ref also provided SUVR images with higher contrast than CB-ref in FTLD patients with suspected and confirmed corticobasal degeneration. The methodology for determining reference tissues as optimized here reinforces the accuracy of 18F-PM-PBB3-PET measurements of tau burdens in a wide range of neurodegenerative illnesses.


title: Hand Hygiene Products and Adverse Skin Reactions: A Comparison between Health Care and Non-Health Care Workers

abstract:
BackgroundSince December 2019, a deadly coronavirus epidemic has swept the globe. Due to the significant risk of infection, frontline health workers had to use Personal Protective Equipment, including hand hygiene products, to keep their hands hygienic. The present study aims to compare adverse skin responses between Health Care Worker (HCW) and Non-Health Care Worker (NHCW).

Materials and MethodsA descriptive, cross-sectional study of HCW and NHCW throughout the country was executed. A self-structured questionnaire was utilized to gather data from 404 HCWs and 826 NHCWs during a two-month period using multistage sampling. STATA (v16) was used to analyse the data.

Results41.87% of the study participants experienced adverse skin reactions, which were more prevalent among HCW (65.10%) than NHCW (30.51%). The most often reported skin condition was skin dryness (34.39%), followed by skin peeling (11.71%). Users of alcohol-based hand sanitizers (ABHS) were more likely to get itch (8.13%), whereas soap water users were more likely to suffer skin peeling (35.74%) and rash (7.46%). There was a significant (p<0.001) association between occupation and adverse skin responses, with HCW being 3.5 times more likely to have adverse skin manifestations than NHCW.

ConclusionThe research showed that health care workers had a greater prevalence of skin conditions than the overall population. Hand hygiene guidelines for frontline employees should be equipped with instructions on how to protect oneself from these adverse skin manifestations, since frequent use constitutes a significant risk factor. Above all, health care professionals and the general population should be educated on good hand hygiene practices.

category: occupational and environmental health


title: Risk of Ocular Adverse Events with Taxane Based Chemotherapy

abstract:
OBJECTIVETaxane based chemotherapy agents such as docetaxel and paclitaxel are used for a wide range of cancers. Although much has been published on adverse events related to taxanes, data on ocular outcomes with these very important drugs is scant. We sought to quantify the risk of three ocular adverse events: 1) epiphora, 2) cystoid macular edema (CME) and 3) optic neuropathy with taxane based chemotherapy agents by undertaking a large pharmacoepidemiologic study.

DESIGNNew users, retrospective cohort study design

SUBJECTS, PARTICIPANTS, CONTROLSWe created a cohort of new users of women matched by age (within one year) on docetaxel or paclitaxel and new users of tamoxifen as controls. Study members were followed to the first incidence of the three outcomes.

METHODSDescriptive statistics were used to examine demographics of the exposed and unexposed groups. A Cox model was constructed to compute crude and adjusted hazard ratios. Potential confounders for each outcome were adjusted for.

MAIN OUTCOME MEASURESFirst diagnosis of 1) epiphora, 2) cystoid macular edema (CME) or 3) optic neuropathy ascertained using international classification for diseases 9th or 10th division codes.

RESULTSFor the epiphora analysis there were 1,824 taxane users (PTX or DTX) and 16,395 tamoxifen users. The crude HR for this association was 7.32 (95%CI: 4.25-16.61) and adjusted HR was 5.15 (95% CI:2.79-9.54). For the CME analysis there were 1,909 taxane user and 16,524 tamoxifen users. The crude HR for CME comparing taxane users to tamoxifen users was 1.37 (95% CI: 0.72-2.60) and adjusted HR was 1.33 (95% CI: 0.70-2.53). For optic neuropathy there were 1,913 taxane users and 16,566 tamoxifen users. The crude HR was 4.43 (95% CI:1.10-17.82) and the adjusted HR was 4.44 (95% CI:1.04-18.87). When we restricted our analysis to only cases of toxic optic neuropathy the aged-matched HR remained elevated (HR=7.24, 95% CI: 1.13-46.36).

CONCLUSIONIn a cohort of women who were using taxane chemotherapy agents, there was an elevated risk for epiphora, optic neuropathy and a less precise increase in risk for cystoid macular edema. Ophthalmologists and oncologists should be aware of these adverse events in women with breast cancer who use these drugs.

category: ophthalmology


title: Effectiveness and safety of PRP on persistent olfactory dysfunction related to COVID-19: towards a new therapeutic hope

abstract:
Olfactory dysfunction (OD) is a well know symptom of coronavirus disease 2019 (COVID-19), accounting for 48 to 85% of patients. In 1 to 10% of cases, patients develop a chronic olfactory dysfunction (COD,) lasting more than 6 months. Recently, platelet-rich plasma (PRP) was used in patients with non-COVID-19 COD and authors reported encouraging results. In the present study, we investigated the usefulness and safety of PRP injection in 56 patients with COVID-19 COD.

Our results showed that PRP in the olfactory cleft can increase the olfactory threshold one month after the injection. Moreover, our results suggest that timing of treatment may be an important factor and that PRP is a safe treatment because no adverse effects were reported throughout the study

category: otolaryngology


title: Germline intergenic duplications at Xq26.1 underlie Bazex-Dupre-Christol syndrome, an inherited basal cell carcinoma susceptibility condition

abstract:
BackgroundBazex-Dupre-Christol syndrome (BDCS; MIM301845) is a rare X-linked dominant genodermatosis characterized by follicular atrophoderma, congenital hypotrichosis and multiple basal cell carcinomas (BCCs). Previous studies have linked BDCS to an 11.4 Mb interval on chromosome Xq25-27.1. However, the genetic mechanism of BDCS remains an open question.

MethodsTo investigate the genetic etiology of BDCS, we ascertained eight families with individuals affected with BDCS (F1-F8). Whole exome (F1 and F2) and genome sequencing (F3) were performed to identify putative disease-causing variants within the linkage region. Array-comparative genomic hybridization and quantitative PCR were used to explore copy number variations (CNV) in BDCS families, followed by long-range gap-PCR and Sanger sequencing to amplify duplication junction and define the precise head-tail junctions, respectively. Immunofluorescence was performed in hair follicles, BCCs and trichoepitheliomas from BDCS patients and sporadic BCCs to detect the expression of corresponding genes. The ACTRT1 variant (p.Met183Asnfs*17), previously proposed to cause BDCS, was evaluated with allele frequency calculator.

ResultsIn eight BDCS families, we identified overlapping 18-135kb duplications (six inherited and two de novo) at Xq26.1, flanked by ARHGAP36 and IGSF1. We detected ARHGAP36 expression near the control hair follicular stem cells compartment, and found increased ARHGAP36 levels in hair follicles in telogen, BCCs and trichoepitheliomas from patients with BDCS. ARHGAP36 was also detected in sporadic BCCs from individuals without BDCS. Our modelling showed the predicted ACTRT1 variants maximum tolerated minor allele frequency in control populations to be orders of magnitude higher than expected for a high-penetrant ultra-rare disorder, suggesting loss-of-function of ACTRT1 is unlikely to cause BDCS.

ConclusionsOur data support the pathogenicity of intergenic duplications at Xq26.1, most likely leading to dysregulation of ARHGAP36, establish BDCS as a genomic disorder, and provide a potential therapeutic target for both inherited and sporadic BCCs.


title: Modeling COVID-19 disease processes by remote elicitation of causal Bayesian networks from medical experts

abstract:
BackgroundCOVID-19 is a new multi-organ disease, caused by the SARS-CoV-2 virus, resulting in considerable worldwide morbidity and mortality. While many recognized pathophysiological mechanisms are involved, their exact causal relationships remain opaque. A better understanding is needed for predicting their progression, targeting therapeutic approaches, and improving patient outcomes. While many mathematical causal models describe COVID-19 epidemiology, none have been developed for its pathophysiology. The viruss rapid and extensive spread and therapeutic responses made this particularly difficult. Initially, no large patient datasets were publicly available, and their data remains limited. The medical literature was flooded with unfiltered, technical and sometimes conflicting pre-review reports. Clinicians in many countries had little time for academic consultations, and in-person meetings were unsafe.

Methods and FindingsIn early 2020, we began a major project to develop causal models of the pathophysiological processes underlying the diseases clinical manifestations. We used Bayesian network (BN) models, because they provide both powerful tools for calculation and clear maps of probabilistic causal influence between semantically meaningful variables, as directed acyclic graphs (DAGs). Hence, they can incorporate expert opinion and numerical data, and produce explainable results. Dynamic causal BNs, which represent successive "time slices" of the system, can capture feedback loops and long-term disease progression.

To obtain the likely causal structures, we used extensive elicitation of expert opinion in structured online sessions. Centered in Australia, with its exceptionally low COVID-19 burden, we managed to obtain many consultation hours. Groups of clinical and other subject matter specialists, all independent volunteers, were enlisted to filter, interpret and discuss the literature and develop a current consensus. We aimed to capture the experts understanding, so we encouraged discussion and inclusion of theoretically salient latent (i.e., unobservable) variables, documented supporting literature while noting controversies, and allowed experts to propose mechanisms by extrapolation from other diseases. Intermediary experts with some combined expertise facilitated the exchange of knowledge to BN modelers and vice versa. Our method was iterative and incremental: we systematically refined and checked the group output with one-on-one follow-up meetings with the original and new experts to validate previous results. In total, 35 experts contributed 126 face-to-face hours, and could review our products.

ConclusionsOur method demonstrates and describes an improved procedure for developing BNs via expert elicitation, which can be implemented rapidly by other teams modeling emergent complex phenomena. The results presented are two key models, for the initial infection of the respiratory tract and the possible progression to complications, as causal DAGs and BNs with corresponding verbal descriptions, dictionaries and sources. These are the first published causal models of COVID-19 pathophysiology, with three anticipated applications: (i) making expert knowledge freely available in a readily understandable and updatable form; (ii) guiding design and analysis of observational and clinical studies, by identifying potential mediators, confounders, and modifiers of treatment effects; (iii) developing and validating parameterized automated tools for causal reasoning and decision support, in clinical and policy settings. We are currently developing such tools for the initial diagnosis, resource management, and prognosis of COVID-19, parameterized using the ISARIC and LEOSS databases.


title: Effectiveness and durability of the mRNA vaccine-induced SARS-CoV-2-specific humoral and cellular immunity in severe asthma patients on biological therapy

abstract: The COVID-19 vaccines effectively elicit humoral and cellular immunity against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a healthy population. This immunity decreases several months after the vaccination. However, the efficacy of the vaccine-induced immunity and its durability in patients with severe asthma on biological therapy is unknown. In this study, we evaluated the effectiveness and durability of the mRNA vaccine-induced SARS-CoV-2-specific humoral and cellular immunity in severe asthma patients on biological therapy. The study included 37 patients with severe asthma treated with anti-IgE (omalizumab, n=18), anti-IL5 (mepolizumab, n=14; reslizumab, n=4), or anti-IL5R (benralizumab, n=1) biological therapy. All patients were vaccinated with two doses of BNT162b2 mRNA vaccine (Comirnaty) at a 6-week period between the doses. We found that the COVID-19 vaccination elicited SARS-CoV-2-specific humoral and cellular immunity, which significantly declined 6 months after the second dose of the vaccine. The type of biological treatment did not affect the vaccine-elicited immunity. However, the patients age negatively impacted the vaccine-induced humoral response. On the other hand, no such age-related impact was observed on the vaccine-elicited cellular immunity. Our findings showed that biological therapy of patients with severe asthma does not compromise the effectiveness and durability of the COVID-19 vaccine-induced immunity.

category: allergy and immunology


title: Its allowed us access to the outside world: A Qualitative Study of Lifespan Supported Mobility Device Use in Cerebral Palsy

abstract:
AimThe overarching aim of this research was to 1) Understand the mobility experiences, supported mobility device (SMD) use, and desired participation outcomes of people with cerebral palsy (CP) across the lifespan; and 2) Describe how perspectives of rehabilitation care and professional resources may influence mobility decision-making processes and outcomes. The aim of this study was to understand the lived experience of SMD provision and use with a focus group guide co-developed by stakeholders.

MethodsFocus groups were conducted with 164 participants (people with CP, caregivers, and healthcare providers) across four US cities. Sessions were audio-recorded, transcribed, and analyzed using constant comparison.

ResultsSix themes emerged. Five presented across all stakeholder groups: 1) The System is Broken; 2) Equipment is Simultaneously Liberating and Restricting; 3) Adaptation Across the Lifespan; 4) Designed for Transport, not for Living; and 5) Sharing Our Stories and Sharing Resources. One theme was specific to healthcare provider groups: Caught in the Middle.

InterpretationThis qualitative study underscores the simultaneous value and frustration associated with SMD, and the need to improve connections and resource networks within the CP community to improve SMD design and provision processes across device types and across the lifespan for people with CP.

What this paper addsO_LIOne of the largest qualitative data sets specific to supportive mobility devices across ages and functional levels.
C_LIO_LIResults indicate SMD is most often equated with freedom, participation, and independence.
C_LIO_LIFrustrations with SMD across the lifespan persist related to design, function, cost, and maintenance.
C_LIO_LIStakeholders in the CP community are seeking greater networking and resource-sharing to enhance SMD provision processes.
C_LIO_LIAccess to appropriate SMD across the lifespan and the need for systems improvement is critical.
C_LI

category: rehabilitation medicine and physical therapy


title: Association between sexual and reproductive health knowledge and protective sexual behaviors among young women in Nigeria

abstract:
BackgroundWhile the literature is replete with studies on young peoples risky sexual behaviors and their effects on HIV and STI acquisition, unintended pregnancy, and unsafe abortion, few studies have explored the practice of protective sexual behaviors and its association with sexual and reproductive health knowledge. We examined the association between sexual and reproductive health knowledge and protective sexual behaviors using data of young women in Nigeria.

MethodsData of 8,995 young women (aged 15-24) who were neither married nor living with a partner were obtained from the 2018 Nigeria Demographic and Health Survey (NDHS) and analyzed in this study. Protective sexual behaviors were measured using questions exploring sexual fidelity, condom use, having multiple partners, and abstinence, while sexual and reproductive health knowledge was measured with questions on fertility, fecundity, contraceptives, and HIV prevention. We fitted multinomial logistic regression to examine the association between sexual and reproductive health knowledge and protective sexual behaviors.

ResultsThe median score on sexual and reproductive health knowledge was five. The majority of the sample (71.5%) had no sexual experience, 6.6% abstained from sex in the past year, 7.2% used condoms and practiced sexual fidelity, 1.0% used condoms but did not practice sexual fidelity, 12.7% did not practice sexual fidelity but used condoms while 0.8% neither used condom nor practiced sexual fidelity. After controlling for important covariates, sexual and reproductive health knowledge was positively associated with "condom use and sexual fidelity" (uRRR = 1.28; CI = 1.04-1.60) relative to "not using condoms nor practicing sexual fidelity." However, the association between sexual and reproductive health knowledge and other categories of protective sexual behaviors, such as no sexual experience, abstinence in the past year, and sexual fidelity but no condom use, did not reach a significant level.

ConclusionWe found a high prevalence of protective sexual behavior among young women in Nigeria. Our study provides evidence in support of the association between sexual and reproductive health knowledge and a higher likelihood of practicing protective sexual behaviors. Intervention efforts can focus on providing sexual and reproductive health education to young people to equip them with information to safeguard their sexual health.

category: sexual and reproductive health


title: Natural Language Processing to Identify Patients with Cognitive Impairment

abstract:
INTRODUCTIONEarly detection of patients with cognitive impairment may facilitate care for individuals in this population. Natural language processing (NLP) is a potential approach to identifying patients with cognitive impairment from electronic health records (EHR).

METHODSWe used three machine learning algorithms (logistic regression, multilayer perceptron, and random forest) using clinical terms extracted by NLP to predict cognitive impairment in a cohort of 199 patients. Cognitive impairment was defined as a mini-mental status exams (MMSE) score <24.

RESULTSNLP identified 69 (35%) patients with cognitive impairment and ICD codes identified 44 (22%). Using MMSE as a reference standard, NLP sensitivity was 35%, specificity 66%, precision 41%, and NPV 61%. The random forest method had the best test parameters; sensitivity 95%, specificity 100%, precision 100%, and NPV 97%

DISCUSSIONNLP can identify adults with cognitive impairment with moderate test performance that is enhanced with machine learning.

category: geriatric medicine


title: Analytical Sensitivity of the SalivaDirect™ Assay on the Liberty16 for detecting SARS-CoV-2 B.1.1.529 Omicron

abstract: The newly emerged Omicron variant of SARS-CoV-2 has numerous mutations that are not found in other variants of concern (VOCs). Despite acquiring extended functions in adapting to the host-cell environment, the viral genetic variation exerts a potential negative impact on a molecular test, which in turn, compromises public health and safety. The Liberty16 has been clinically validated as a flexible and accessible device system for running the affordable SalivaDirect real time PCR detection assay for SARS-CoV-2 especially in low resource settings. Preliminary, based on in-silico sequence analysis, we found that Omicrons mutation at position 28,311 overlaps with the CDC 2019-nCoV_N1 probe binding region. In order to verify the performance of CDC 2019-nCoV-N1 primers-probe set in detecting the Omicron variant of SARS-CoV-2, plasmids containing Wuhan/WH01/2019 (wild-type) and B.1.1.529 (Omicron) sequences were serially diluted and subsequently directed for SalivaDirect RT-qPCR detection on Liberty16 using commercially procured reagents. Our findings provide analytical support for reports that the mutations in the Omicron variant have little or no impact on SalivaDirect assay in terms of amplification efficiency and detection sensitivity using either standard and the recently reported fast Liberty16 SalivaDirect thermal cycling protocols.


title: A novel SEIR-e model for disease transmission and pathogen exposure

abstract: In this study, we couple compartment models for indoor air quality and disease transmission to develop a novel SEIR-e model for disease transmission and pathogen exposure. In doing so, we gain insight into the contribution of people-people and people-pathogen interactions to the spread of transmissible diseases. A general modelling framework is used to assess the risk of infection in indoor environments due to people-pathogen interactions via inhalation of viral airborne aerosols, and contact with contaminated surfaces. We couple the indoor environment model with a standard disease transmission model to investigate how both people-people and people-pathogen interactions result in disease transmission. The coupled model is referred to as the SEIR-e model. To demonstrate the applicability of the SEIR-e model and the novel insights it can provide into different exposure pathways, parameter values which describe exposure due to people-people and people-pathogen interactions are inferred using Bayesian techniques and case data relating to the 2020 outbreak of COVID-19 in Victoria (Australia).


title: Ethnic inequities in multimorbidity among people with psychosis: A retrospective cohort study

abstract:
BackgroundResearch shows persistent ethnic inequities in mental health experiences and outcomes, with a higher incidence of illnesses among minoritised ethnic groups. People with psychosis have a higher risk of multiple long-term conditions (MLTC; multimorbidity). However, there is limited research regarding ethnic inequalities in multimorbidity in people with a schizophrenia spectrum disorder. This study investigates ethnic disparities in physical health multimorbidity in a cohort of people with psychosis.

MethodsIn this retrospective cohort study, using the Clinical Records Interactive Search (CRIS) system, we identified service-users of the South London and Maudsley NHS Trust with a schizophrenia spectrum disorder, and then additional diagnoses of diabetes, hypertension, low blood pressure, overweight or obesity, and rheumatoid arthritis. Multinomial logistic regression was then used to investigate ethnic inequities in odds of multimorbidity (psychosis plus one physical health condition), as well as multimorbidity severity (having one or two physical health conditions, or three or more conditions), compared with no additional health conditions (no multimorbidity). The regression models adjusted for age and duration of care and investigated the influence of gender and area-level deprivation.

ResultsOn a sample of 20,800 service-users with psychosis, aged 13-65, ethnic differences were observed in the odds for multimorbidity. Compared to White British people, higher odds of multimorbidity were found for people of Black African [aOR=1.41, 95%CI (1.23 - 1.56)], Black Caribbean [aOR=1.79, 95%CI (1.58 - 2.03)], and Black British [aOR=1.64, 95%CI (1.49 - 1.81)] ethnicity. Reduced odds were observed among people of Chinese [aOR=0.61, 95%CI (0.43 - 0.88)] and Other ethnicities [aOR=0.67, 95%CI (0.59 - 0.76)]. Increased odds for severe multimorbidity (three or more physical health conditions) were also observed for people of any Black background.

ConclusionsEthnic inequities are observed for multimorbidity among people with psychosis. Further research is needed to understand the aetiology and impact of these inequities. These findings support the provision of integrated health care interventions and public health preventive policies and actions.

category: psychiatry and clinical psychology


title: The public health impact of poor sleep on severe COVID-19, influenza and upper respiratory infections

abstract:
BackgroundPoor sleep is associated with an increased risk of infections and all-cause mortality, and acute sleep loss and disruption have been linked with inflammation and poorer immune control. Previous studies, however, have been unable to evidence causality between the chronic effects of poor sleep and respiratory infection risk. In light of the ongoing COVID-19 pandemic and potential future disease outbreaks, understanding the risk factors for these infections is of great importance.

AimOur goal was to understand if chronic poor sleep could be identified as a causal risk factor for respiratory infections including influenza, upper respiratory infections and COVID-19.

MethodsWe used population cohorts from the UK Biobank (N {approx} 231,000) and FinnGen (N {approx} 327,000) with ICD-10 based electronic health records and obtained diagnoses of insomnia, influenza and upper respiratory infections (URIs) from primary care and hospital settings. We computed logistic regression to assess association between poor sleep and infections, disease free survival hazard ratios, and used summary statistics from genome-wide association studies of insomnia, influenza, URI and COVID-19 to perform Mendelian randomization analyses and assess causality.

FindingsUtilizing 23 years of registry data and follow-up, we saw that insomnia diagnosis associated with increased risk for infections in FinnGen and in UK Biobank (FinnGen influenza HR = 5.32 [4.09, 6.92], P = 1.02x10-35, UK Biobank influenza HR = 1.54 [1.37, 1.73], P = 2.49x10-13). Mendelian randomization indicated that insomnia causally predisposed to influenza (OR = 1.59, P = 6.23x10-4), upper respiratory infections (OR = 1.71, P = 7.60x10-13), COVID-19 infection (OR = 1.08, P = 0.037) and risk of hospitalization from COVID-19 (OR = 1.47, P = 4.96x10-5).

ConclusionsOur findings indicate that chronic poor sleep is a causal risk factor for contracting respiratory infections, and in addition contributes to the severity of respiratory infections. These findings highlight the role of sleep in maintaining sufficient immune response against pathogens as suggested by earlier work. As the current COVID-19 pandemic has increased the number of people suffering from poor sleep, safe interventions such as sleep management and treating individuals with insomnia could be promoted to reduce infections and save lives.


title: Serological responses and six-month trajectories to COVID-19 Comirnaty and Spikevax booster vaccine, September 2021 to January 2022, London, United Kingdom

abstract: In contrast to the increasing levels of high avidity S antibody measured by the Roche assay in the first 6 months following natural infection, marked waning is seen post 2 or 3 doses of vaccine. Although the kinetics differ between those with vaccine-induced immunity compared to those infected prior to vaccination (hybrid immunity), waning rates appear to be similar following 2 or 3 doses of vaccine. These data should allow countries to optimise the timing of future doses of vaccine.


title: Accessibility and Disability Inclusion Among Top-Funded U.S. Undergraduate Institutions

abstract:
BackgroundThere is limited data to assess, track, or quantify accessibility and disability inclusion across universities.

ObjectiveThis study assessed disability inclusion and accessibility at the top 50 National Institutes of Health (NIH)-funded undergraduate programs in the United States. We hypothesized that there is no association between NIH funding and the University Disability Inclusion Score

MethodsA novel tool, the University Disability Inclusion Score assessed disability inclusion and accessibility using 10 indicators spanning 4 categories: (1) accessibility of built and virtual environment, (2) public image of disability inclusion, (3) accommodations processes and procedures, and (4) grievance policy. Based upon the total points (out of a total score of 100), each university was assigned a letter grade (A-F).

ResultsOf the top 50 NIH-funded institutions, 6% received an A grade on the Score, while 60% received D or F. The mean scores were 15.2 (SD=5) for accessibility of built and virtual environment (20 points), 10 (SD=3) for public image of disability inclusion (20 points), 30.6 (SD=10) for accommodations processes and procedures (50 points), and 8.1 (SD=3) for grievance policy (10 points).

ConclusionsOur findings suggest room for improvement in disability inclusion and accessibility among top university recipients of NIH funding. To provide an equitable academic experience, universities must prioritize disability inclusion.

category: health policy


title: COVID-19-related Smell and Taste Impairment with Widespread Diffusion of SARS-CoV-2 Omicron Variant

abstract:
BackgroundThe aim of this study was to estimate the prevalence of self-reported chemosensory dysfunction in a study cohort of subjects who developed a mild-to-moderate COVID-19 in the period from January 17, 2022 to February 4, 2022 (Omicron proxy period) and compared that with a historical series of patients tested positive for SARS-CoV-2 infection between March and April, 2020 (comparator period).

MethodsProspective study based on the sinonasal outcome tool 22 (SNOT-22), item "sense of smell or taste" and additional outcomes.

ResultsPatients characteristics and clinical presentations of COVID-19 were evaluated and compared in 779 patients, 338 of the study cohort and 441 of the historical series. The prevalence of self-reported chemosensory dysfunction during the proxy Omicron period (32.5%; 95% CI, 27.6-37.8) was significantly lower from that during the comparator period (66.9%; 95% CI, 62.3-71.3) (p<.001). 24.6% (95% CI, 20.1-29.5) of patients reported an altered sense of smell during the proxy Omicron period compared to 62.6% (95% CI, 57.9-67.1) during the comparator period (p<.001). Similarly, the prevalence of an altered sense of taste dropped from 57.4% (95% CI, 52.6-62.0) during the comparator period to 26.9% (95% CI, 22.3-32.0) during the proxy Omicron period (p<.001). The severity of chemosensory dysfunction was lower in proxy Omicron period compared to comparator period (p<.001).

ConclusionsThe prevalence and the severity of COVID-19 associated smell and taste dysfunction has dropped significantly with the advent of the Omicron variant.

category: infectious diseases