title: Identifying Prepubertal Children with Risk for Suicide Using Deep Neural Network Trained on Multimodal Brain Imaging-Derived Phenotypes

abstract: Suicide is among the leading causes of death in youth worldwide. Early identification of children with high risk for suicide is key to effective screening and prevention strategies. Brain imaging can show functional or structural abnormalities related to youth suicidality, but literature is scarce. Here we tested the extent to which brain imaging is useful in predicting suicidal risk in children. In the largest to date, multi-site, multi-ethnic, epidemiological developmental samples in the US (N = 6,172; the ABCD study), we trained and validated machine learning models and deep neural networks on the multimodal brain imaging derived phenotypes (morphometry, white matter connectivity, functional activation, and connectivity) along with behavioral and self-reported psychological questionnaire data. The model trained on diffusion white matter connectomes showed the best performance (test AUC-ROC = 74.82) with a one percentage increase compared with the baseline model trained on behavioral and psychological data (test AUC-ROC = 74.16). Models trained on other MRI modalities showed similar but slightly lower performances. Model interpretation showed the important brain features involved in attention, emotion regulation, and motor coordination, such as the anterior cingulate cortex, temporal gyrus, and precentral gyrus. It further showed that the interaction of brain features with depression and impulsivity measures contributed to the optimal prediction of youth suicidality. This study demonstrates the potential utility of a multimodal brain imaging approach to youth suicidality prediction and uncovers the relationships of the psychological and multi-dimensional and multi-modal neural features to youth suicidality.

category: psychiatry and clinical psychology


title: Willingness to take the Covid-19 vaccines and associated factors at a tertiary institution community in Johannesburg, South Africa

abstract:
BackgroundSA is aiming to achieve herd immunity against Covid-19 by the first quarter of 2022. The success of the Covid-19 vaccination roll-out depends primarily on the willingness of the population to take the vaccines.

AimThis study examined the willingness to take the Covid-19 vaccine, along with the factors of concern, efficacy, and preferences of the individual which may increase the willingness to be vaccinated.

SettingThis study was conducted at the University of the Witwatersrand, Johannesburg, amongst adult students and academic and professional staff.

MethodsWe conducted a cross-sectional online study from 27 July - 14 August 2021. We performed descriptive and inferential analysis to determine the factors associated with willingness to take the Covid-19 vaccine.

Results2364 participants responded to a survey link and 82% were students, 66.8% were in the 18-29 years age band, females represented 64.0% and 49.2% were black people. 1965 (83.3%) were willing to receive a Covid-19 vaccine, the most preferred vaccines were Pfizer (41%) and J&J (23%), local pharmacy (29%) and GP (17%) were the preferred places for vaccination and the trusted sources of information on Covid-19 vaccines were the general practitioners (40.6%) and specialists (19,2%). Perceptions that vaccines are safe (aOR=31.56, 95%CI: 16.02-62.12 for affirmative agreement) and effective (aOR=5.92, 95%CI: 2.87-12.19 for affirmative agreement) were the main determinants for willingness to taking a COVID-19 vaccine

ConclusionIt is imperative to reinforce the message of Covid-19 vaccine safety and efficacy and to include the GPs and the community pharmacies in the vaccination roll-out in SA.

category: public and global health


title: Quantitative chest CT combined with plasma cytokines predict outcomes in COVID-19 patients

abstract: Despite extraordinary international efforts to dampen the spread and understand the mechanisms behind SARS-CoV-2 infections, accessible predictive biomarkers directly applicable in the clinic are yet to be discovered. Recent studies have revealed that diverse types of assays bear limited predictive power for COVID-19 outcomes. Here, we harness the predictive power of chest CT in combination with plasma cytokines using a machine learning approach for predicting death during hospitalization and maximum severity degree in COVID-19 patients. Patients (n=152) from the Mount Sinai Health System in New York with plasma cytokine assessment and a chest CT within 5 days from admission were included. Demographics, clinical, and laboratory variables, including plasma cytokines (IL-6, IL-8, and TNF-) were collected from the electronic medical record. We found that chest CT combined with plasma cytokines were good predictors of death (AUC 0.78) and maximum severity (AUC 0.82), whereas CT quantitative was better at predicting severity (AUC 0.81 vs 0.70) while cytokine measurements better predicted death (AUC 0.70 vs 0.66). Finally, we provide a simple scoring system using plasma IL-6, IL-8, TNF-, GGO to aerated lung ratio and age as novel metrics that may be used to monitor patients upon hospitalization and help physicians make critical decisions and considerations for patients at high risk of death for COVID-19.

category: radiology and imaging


title: A novel framework based on deep learning and ANOVA feature selection method for diagnosis of COVID-19 cases from chest X-ray Images

abstract: The new coronavirus (known as COVID-19) was first identified in Wuhan and quickly spread worldwide, wreaking havoc on the economy and peoples everyday lives. Fever, cough, sore throat, headache, exhaustion, muscular aches, and difficulty breathing are all typical symptoms of COVID-19. A reliable detection technique is needed to identify affected individuals and care for them in the early stages of COVID-19 and reduce the viruss transmission. The most accessible method for COVID-19 identification is RT-PCR; however, due to its time commitment and false-negative results, alternative options must be sought. Indeed, compared to RT-PCR, chest CT scans and chest X-ray images provide superior results. Because of the scarcity and high cost of CT scan equipment, X-ray images are preferable for screening. In this paper, a pre-trained network, DenseNet169, was employed to extract features from X-ray images. Features were chosen by a feature selection method (ANOVA) to reduce computations and time complexity while overcoming the curse of dimensionality to improve predictive accuracy. Finally, selected features were classified by XGBoost. The ChestX-ray8 dataset, which was employed to train and evaluate the proposed method. This method reached 98.72% accuracy for two-class classification (COVID-19, healthy) and 92% accuracy for three-class classification (COVID-19, healthy, pneumonia).


title: Early intervention with a glycerol throat spray containing cold-adapted cod trypsin after self-diagnosis of the common cold: a randomised prospective, parallel group and single-blind methods trial (Glycerol-cod trypsin spray in common cold)

abstract:
BackgroundA glycerol throat spray containing cold-adapted cod trypsin (GCTS) deactivates common cold virus in vitro and decreases pharyngeal rhinovirus load after inoculation in humans. We relied on early self-diagnosis and evaluated two different scales to detect a treatment effect in naturally occurring common colds.

MethodsAdults were enrolled in this randomised, prospective, parallel group, single-blind study to begin treatment six times daily at first sign of a common cold or were assigned to a non-treated group. Jacksons symptom scale and the 9-item Wisconsin Upper Respiratory Symptom Survey (WURSS)-21 quality of life (QoL) domain were recorded daily by subjects and area under the curve over 12 days (AUC1-12) calculated.

ResultsTreatment resulted in reduced symptoms with an AUC1-12 of 45.1 {+/-} 32.5 for Jackson scores compared to 53.8 {+/-} 35.7 in the controls (p=0.023). AUC1-12 for the 9-item WURSS-21 QoL domain was likewise improved, 113.6 {+/-} 107.7 and 152.7 {+/-} 126.3 (p=0.006), respectively. During the first four days fewer of the treated subjects (35.3%) used rescue medication than did the control group (50.4%, p=0.014).

ConclusionsReduction in common cold symptoms was seen with treatment with a glycerol throat spray containing cold-adapted cod trypsin. This effect was best detected with the 9-item WURSS-21 QoL domain.

category: respiratory medicine


title: Vitamin D Status: A U-shaped relationship for SARS-CoV-2 seropositivity in UK healthcare workers

abstract:
BackgroundVitamin D has numerous mechanistic roles within the immune system. There is increasing evidence to suggest Vitamin D deficiency may increase individuals risk of COVID-19 infection and susceptibility. We aimed to determine the relationship between severity of vitamin D deficiency and sufficiency and COVID-19 infection within healthcare workers.

MethodsThe study included an observational cohort of healthcare workers who isolated due to COVID-19 symptoms from 12th to 22nd May 2020, from the University Hospitals Birmingham NHS Foundation Trust (UHBFT). This was part of the COVID-19 convalescent immunity study (COCO). Data collected included SARS-CoV-2 seroconversion status, serum 25(OH)D3 levels as well as age, body mass index (BMI), sex, ethnicity, job role, and co-morbidities. Participants were grouped into four vitamin D (VD) categories. 1) Severe VD deficiency (VD <30 nmol/L); 2) VD deficiency (30 nmol/L [≤] VD <50 nmol/L); 3) VD insufficiency (50 nmol/L [≤] VD <75 nmol/L); 4) VD sufficiency (VD [≥]75 nmol/L).

ResultsWhen VD levels were compared against COVID-19 seropositivity rate, a U-shaped curve was identified in the total population. This trend repeated when split into subgroups of age, sex, ethnicity, BMI, and co-morbidity status. Significant difference was identified in the COVID-19 seropositivity rate between VD groups between multiple VD groups in the total population, males, females, BAME, BMI<30 (kg/m2), 0 and +1 comorbidities; the majority of which were differences when the severely VD deficient category were compared to the other group. A significantly larger proportion of those within the Black, Asian, minority ethnic (BAME) group (vs. white ethnicity) were severely vitamin D deficient (P <0.00001). A significantly higher proportion of the 0-comorbidity subgroup were vitamin D deficient in comparison to the 1+ comorbidity subgroup (P = 0.046).

ConclusionsFurther investigation of the U-shaped curves is required to determine whether high VD levels can have a detrimental effect on susceptibility to COVID-19 infection. Future randomised clinical trials of VD supplementation could potentially identify  optimal VD levels. This would allow for targeted therapeutic treatment for those at-risk such as in the BAME group.


title: Cell-type specific cis-eQTLs in eight brain cell-types identifies novel risk genes for human brain disorders

abstract: Most expression quantitative trait loci (eQTL) studies to date have been performed in heterogeneous brain tissues as opposed to specific cell types. To investigate the genetics of gene expression in adult human cell types from the central nervous system (CNS), we performed an eQTL analysis using single nuclei RNA-seq from 196 individuals in eight CNS cell types. We identified 6108 eGenes, a substantial fraction (43%, 2620 out of 6108) of which show cell-type specific effects, with strongest effects in microglia. Integration of CNS cell-type eQTLs with GWAS revealed novel relationships between expression and disease risk for neuropsychiatric and neurodegenerative diseases. For most GWAS loci, a single gene colocalized in a single cell type providing new clues into disease etiology. Our findings demonstrate substantial contrast in genetic regulation of gene expression among CNS cell types and reveal genetic mechanisms by which disease risk genes influence neurological disorders.

category: neurology


title: Axillary microbiota is associated with cognitive impairment in Parkinson's disease patients

abstract:
IntroductionCognitive impairment (CI) is among the most common non-motor symptoms of Parkinsons disease (PD) with substantially negative impact on patient management and outcome. The development and progression of CI exhibits high interindividual variability which requires better diagnostic and monitoring strategies. PD patients often display sweating disorders resulting from autonomic dysfunction which has been associated with CI. As the axillary microbiota is known to change with humidity level and sweat composition, we hypothesized that axillary microbiota of PD patients shifts in association with CI progression thus can be used as proxy for classification of CI stages in PD.

MethodsWe compared the axillary microbiota compositions of 103 PD patients (55 PD patients with dementia (PDD) and 48 PD patients with mild cognitive impairment (PD-MCI)) and 26 cognitively normal healthy controls (HC).

ResultsWe found that axillary microbiota profiles differentiate HC, PD-MCI and PDD groups based on differential ranking analysis and detected an increasing trend in the log ratio of Corynebacterium to Anaerococcus in progression from HC to PDD. In addition, phylogenetic factorization revealed that the depletion of Anaerococcus, Peptoniphilus and W5053 genera is associated with PD-MCI and PDD. Moreover, functional predictions suggested significant increase of myo-inositol degradation, ergothioneine biosynthesis, propionate biosynthesis, menaquinone biosynthesis, and the proportion of aerobic bacteria and biofilm formation capacity in parallel to CI.

ConclusionOur results suggest that alterations in axillary microbiota are associated with CI in PD. Thus, axillary microbiota holds potential to be exploited as a non-invasive biomarker in the development of novel strategies.


title: PAGEANT: Personal Access to Genome and Analysis of Natural Traits

abstract: GWASs have identified numerous genetic variants associated with a wide variety of diseases, yet despite the wide availability of genetic testing the insights that would enhance the interpretability of these results are not widely available to members of the public. As a proof of concept and demonstration of technological feasibility, we developed PAGEANT (Personal Access to Genome & Analysis of Natural Traits), usable through Graphical User Interface or command line-based version, aiming to serve as a protocol and prototype that guides the overarching design of genetic reporting tools. PAGEANT is structured across five core modules, summarized by five Qs: (1) Quality assurance of the genetic data; (2) Qualitative assessment of genetic characteristics; (3) Quantitative assessment of health risk susceptibility based on polygenic risk scores and population reference; (4) Query of third-party variant databases (e.g., ClinVAR and PharmGKB); and (5) Quick Response code of genetic variants of interest. Literature review was conducted to compare PAGEANT with academic and industry tools. For 2,504 genomes made publicly available through the 1,000 Genomes Project, we derived their genomic characteristics for a suite of qualitative and quantitative traits. One exemplary trait is susceptibility to COVID-19, based on the most up-to-date scientific findings reported.

category: genetic and genomic medicine


title: Genomic epidemiology reveals how restriction measures shaped the SARS-CoV-2 epidemic in Brazil

abstract: Brazil has experienced some of the highest numbers of COVID-19 cases and deaths globally and from May 2021 made Latin America a pandemic epicenter. Although SARS-CoV-2 established sustained transmission in Brazil early in the pandemic, important gaps remain in our understanding of virus transmission dynamics at the national scale. Here, we describe the genomic epidemiology of SARS-CoV-2 using near-full genomes sampled from 27 Brazilian states and a bordering country - Paraguay. We show that the early stage of the pandemic in Brazil was characterised by the co-circulation of multiple viral lineages, linked to multiple importations predominantly from Europe, and subsequently characterized by large local transmission clusters. As the epidemic progressed under an absence of effective restriction measures, there was a local emergence and onward international spread of Variants of Concern (VOC) and Variants Under Monitoring (VUM), including Gamma (P.1) and Zeta (P.2). In addition, we provide a preliminary genomic overview of the epidemic in Paraguay, showing evidence of importation from Brazil. These data reinforce the usefulness and need for the implementation of widespread genomic surveillance in South America as a toolkit for pandemic monitoring that provides a means to follow the real-time spread of emerging SARS-CoV-2 variants with possible implications for public health and immunization strategies.


title: Genomic epidemiology reveals the impact of national and international restrictions measures on the SARS-CoV-2 epidemic in Brazil


title: SPECIFIC DETECTION OF SARS-COV-2 VARIANTS B.1.1.7 (ALPHA) AND B.1.617.2 (DELTA) USING A ONE-STEP QUANTITATIVE PCR ASSAY

abstract: In this report, we describe the development of an RT-qPCR assay, termed Alpha Delta assay, which can detect SARS-COV-2 (SC-2) and distinguish between the Alpha (B.1.1.7) and Delta (B.1.617.2) variants. The Alpha- and Delta-specific reactions in the assay target mutations that are strongly linked to the target variant. The Alpha reaction targets the D3L substitution in N gene, and the Delta reaction targets the spike gene 156-158 mutations. Additionally, we developed a second Delta-specific assay, used as a confirmatory test for the Alpha Delta assay that targets the 119-120 deletion in the Orf8 gene. Both reactions have similar sensitivities of 15-25 copies per reaction, similar to the sensitivity of commercial SC-2 detection tests. The Alpha Delta assay and the Orf8-119del assay were successfully used to classify clinical samples that were subsequently analyzed by whole genome sequencing. Lastly, we show that the Alpha Delta and Orf8-119del assays correctly identified the presence of Alpha and Delta lineages RNA in wastewater samples. This study provides a rapid, sensitive and cost-effective tool for detecting and classifying two worldwide dominant SC-2 variants. It also highlights the importance of a timely diagnostic response to the emergence of new SC-2 variants with significant consequences on global health.

category: infectious diseases


title: Transmission of SARS-CoV-2 associated with cruise ship travel: protocol for a systematic review (Version 1)

abstract:
BackgroundMaritime and river travel, including cruise ships, have been implicated with spreading viruses through infected passengers and crew. Given the novelty of the SARS-CoV-2 infection, early cruise ship travel transmission models of spread are based on what is known of the dynamics of other respiratory viral infections. Our objective is to provide a rapid summary and evaluation of relevant data on SARS-CoV-2 transmission aboard cruise ships, report policy implications, and highlight research gaps requiring attention.

MethodsWe will search LitCovid, medRxiv, Google Scholar, and the WHO Covid-19 database using COVID-19, SARS-CoV-2, transmission, and cruise ship appropriate synonyms. We will also search the reference lists of included studies for additional relevant studies. We will include studies reporting onboard SARS-CoV-2 transmission from passengers and/or crew to passengers and/or crew. We will consider any potential transmission mode. We will assess study quality based on five criteria and report important findings. The outcome will consist of the onboard cruise ships transmission of SARS-CoV-2. We will provide a narrative summary of the data and report the outcomes, including quantitative estimates where feasible and relevant. Where possible, compatible datasets may be pooled for meta-analysis.

Expected resultsWe will present the evidence in three distinct packages: study description, methodological quality assessment and data extracted. We will summarize the evidence and will draw conclusions as to the quality of the evidence.


title: Inferring age-specific differences in susceptibility to and infectiousness upon SARS-CoV-2 infection based on Belgian social contact data

abstract: Several important aspects related to SARS-CoV-2 transmission are not well known due to a lack of appropriate data. However, mathematical and computational tools can be used to extract part of this information from the available data, like some hidden age-related characteristics. In this paper, we present a method to investigate age-specific differences in transmission parameters related to susceptibility to and infectiousness upon contracting SARS-CoV-2 infection. More specifically, we use panel-based social contact data from diary-based surveys conducted in Belgium combined with the next generation principle to infer the relative incidence and we compare this to real-life incidence data. Comparing these two allows for the estimation of age-specific transmission parameters. Our analysis implies the susceptibility in children to be around half of the susceptibility in adults, and even lower for very young children (preschooler). However, the probability of adults and the elderly to contract the infection is decreasing throughout the vaccination campaign, thereby modifying the picture over time.


title: Effect of SARS-CoV-2 vaccination on symptoms from post-acute COVID syndrome: results from the national VAXILONG survey

abstract:
IntroductionFew data are available concerning the effect of SARS-CoV-2 vaccination on the persistent symptoms associated with COVID-19, also called long-COVID or post-acute COVID-19 syndrome (PACS).

Patients and methodsWe conducted a nationwide online survey among adult patients with PACS as defined by symptoms persisting over 4 weeks following a confirmed or probable COVID-19, without any identified alternative diagnosis. Information concerning PACS symptoms, vaccine type and scheme and its effect on PACS symptoms were studied.

ResultsSix hundred and twenty surveys were completed and 567 satisfied the inclusion criteria and were analyzed. Respondents were 83.4% of women of median age 44 (IQR 25-75: 37-50). Initial infection was proven in 365 patients (64%) and 5.1% had been hospitalized to receive oxygen. 396 patients had received at least one injection of SARS-CoV-2 vaccine at the time of the survey, after a median of 357 [198-431] days following the initially-reported SARS-CoV-2 infection. Among the 380 patients who reported persistent symptoms at the time of SARS-CoV-2 vaccination, 201 (52.8%) reported variation of symptoms following the injection, without difference based on the type of vaccine used. After a complete vaccination scheme, 93.3% (28/30) of initially seronegative patients reported a positive anti-SARS-CoV-2 IgG.

170 PACS patients had not been vaccinated. The most common reasons for postponing SARS-CoV-2 vaccine were a fear of worsening PACS symptoms (55.9%) and the idea that vaccination was contraindicated because of PACS (15.6%).

ConclusionOur study suggests that SARS-CoV-2 vaccination is well tolerated in the majority of PACS patients and has good immunogenicity. Disseminating these reassuring data might prove crucial to increase vaccine coverage in patients with PACS.


title: Distribution and associated factors of hepatic iron -- a population-based imaging study

abstract:
ContextHepatic iron overload can cause severe organ damage. Therefore, an early diagnosis is crucial, and identification of modifiable risk factors could help to prevent manifestations of iron-driven complications.

ObjectiveTo investigate the sex-specific distribution of hepatic iron content (HIC) in a population-based sample, and to identify relevant associated factors from a panel of markers.

MethodsWe analysed N=353 participants from a cross-sectional, population-based cohort in Southern Germany (KORA FF4) who underwent whole-body magnetic resonance imaging. HIC was assessed by single-voxel spectroscopy with a high-speed T2-corrected multi-echo technique. A large panel of markers, including anthropometric, genetic and laboratory values as well as behavioural risk factors were assessed. Relevant factors associated with HIC were identified by variable selection based on LASSO regression with bootstrap resampling.

ResultsHIC in the study sample (mean age at examination was 56.0 years, 58.4% were men) was significantly lower in women (mean{+/-}SD: 39.2{+/-}4.1 s-1) than in men (41.8{+/-}4.7 s-1, p<0.001). Relevant factors associated with HIC were HbA1c and prediabetes for men, and visceral adipose tissue and age for women. Hepatic fat, alcohol consumption, and a genetic risk score for iron levels were associated with HIC in both sexes.

ConclusionThere are sex-specific associations of HIC with markers of body composition, glucose metabolism and alcohol consumption.

category: endocrinology


title: Trans-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes

abstract: Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy (GenDIP) Consortium assembled genome-wide association studies (GWAS) of diverse ancestry in a total of 5,485 women with GDM and 347,856 without GDM. Through trans-ancestry meta-analysis, we identified five loci with genome-wide significant association (p<5x10-8) with GDM, mapping to/near MTNR1B (p=4.3x10-54), TCF7L2 (p=4.0x10-16), CDKAL1 (p=1.6x10-14), CDKN2A-CDKN2B (p=4.1x10-9) and HKDC1 (p=2.9x10-8). Multiple lines of evidence pointed to genetic contributions to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D; and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomisation analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.


title: Genetic evidence supports the development of SLC26A9 targeting therapies for the treatment of lung disease

abstract:
BackgroundOver 400 variants in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) are CF-causing. CFTR modulators target variants to improve lung function, but marked variability in response exists and current therapies do not address all CF-causing variants highlighting unmet needs. Alternative epithelial ion channel/transporters such as SLC26A9 could compensate for CFTR dysfunction, providing therapeutic targets that may benefit all individuals with CF.

MethodWe investigate the relationship between rs7512462, a marker of SLC26A9 activity, and lung function pre- and post-treatment with CFTR modulators in Canadian and US CF cohorts, in the general population, and in those with chronic obstructive pulmonary disease (COPD).

ResultsRs7512462 CC genotype is associated with greater lung function in CF individuals with minimal function variants (for which there are currently no approved therapies; p=0.008); and for gating (p=0.033) and p.Phe508del/ p.Phe508del (p=0.006) genotypes upon treatment with CFTR modulators. In parallel, human nasal epithelia with CC and p.Phe508del/p.Phe508del after Ussing chamber analysis of a combination of approved and experimental modulator treatments show greater CFTR function (p=0.0022). Beyond CF, rs7512462 is associated with lung function in a meta-analysis of the UK Biobank and Spirometa Consortium (min p=2.74x0-44) and provides p=0.0891 in an analysis of COPD case-control status in the UK Biobank defined by spirometry.

ConclusionThese findings support SLC26A9 as a therapeutic target to improve lung function for all people with CF and in individuals with other obstructive lung diseases.

category: epidemiology


title: Antimicrobial consumption in pediatric intensive care units during the first year of COVID-19 pandemic

abstract:
IntroductionThe absence of standardized treatment for critical children admitted in pediatric intensive care units (PICUs) with COVID could lead to an increase in antimicrobial consumption, as indirect effect.

AimTo describe trends of antimicrobial consumption in two PICUs before and during the COVID pandemic year.

MethodsWe did a retrospective study in children admitted in two PICUs of Rio de Janeiro city, between March 2019 and March 2021. The first year represented the pre-pandemic period and the last one the pandemic period. Trends of antimicrobial consumption were measured by days of therapy (DOT/1000 patient-days) and analyzed by linear regression for antibiotics, antivirals and antifungals

ResultsNumber of patients-days in the PICU 1 was 3495 in the pre-pandemic period and 3600 in the pandemic period. The overall DOT/1000 PD of antibiotics, antivirals and antifungal was 15,308.1, 942.8 and 1,691.1, respectively in the pre-pandemic period and 13,481.5, 1,335.4 and 1,243.7, respectively in pandemic period. It was verified trend of reduction of antibiotic and antifungals and increase in antivirals consumption. Number of patients-days in the PICU 2 was 5029 in the pre-pandemic period and 4557 in the pandemic period and the overall DOT/1000 PD of antibiotics, antivirals and antifungal was 16,668.5, 1,385 and 1,966.7, respectively in the pre-pandemic period and 10,896.5, 830.7 and 677.3 in pandemic period. It was verified trend of reduction of antibiotic, antivirals and antifungals consumption.

ConclusionTrends of antimicrobial consumption reduction were verified for antibiotics and antifungals in two PICUs and reduction for antiviral in one of them

category: pediatrics


title: Nutrition Policies in Germany: A Systematic Assessment with the Food Environment Policy Index (Food-EPI)

abstract:
ObjectiveTo systematically assess Germanys nutrition policies, to benchmark them against international best practices, and to identify priority policy actions to improve population-level nutrition in Germany.

DesignWe applied the Food Environment Policy Index (Food-EPI), a methodological framework developed by the INFORMAS network. Qualitative content analysis of laws, directives and other documents formed the basis of a multi-staged, structured consultation process.

SettingGermany.

ParticipantsThe expert consultation process included 55 experts from academia, public administration, and civil society.

ResultsGermany lags behind international best practices in several key policy areas. For 18 policy indicators, the degree of implementation compared to international best practices was rated as very low, for 21 as low, for 8 as intermediate, and for none as high. In particular, indicators on food taxation, regulation of food marketing, and retail and food service sector policies were rated as very low to low. Identified priority actions included the binding implementation of nutrition standards for schools and kindergartens, a reform of the value added tax on foods and beverages, a sugar-sweetened beverage tax and stricter regulation of food marketing directed at children.

ConclusionsThe results show that Germany makes insufficient use of the potential of evidence-informed health-promoting nutrition policies. Adopting international best practices in key policy areas could help to reduce the burden of nutrition-related chronic disease and related inequalities in nutrition and health in Germany. Implementation of relevant policies requires political leadership, a broad societal dialogue, and evidence-informed advocacy by civil society, including the scientific community.

category: nutrition


title: Breastfeeding infants receive neutralizing antibodies and cytokines from mothers immunized with a COVID-19 mRNA vaccine

abstract:
ObjectiveTo evaluate the immune response to COVID-19 mRNA-based vaccines present in breastmilk and the transfer of the immune response to the breastfeeding child.

MethodsA prospective cohort study enrolled 30 lactating women who received an mRNA-based COVID-19 vaccine between January and April 2021. Women provided serial milk samples, which included milk expressed before vaccination, milk expressed across 2-3 weeks after the first dose, and milk expressed across 3 weeks after the second dose. Women also were asked to provide their blood, spotted on cards (dried blood spots; DBS) 19 days after the first dose and 21 days after the second dose. Stool samples from the breastfed infants were collected 21 days after mothers received their second dose. Pre-pandemic samples of milk, DBS cards, and infant stool from prior studies were also utilized. Milk and infant stool samples were tested by ELISA for receptor-binding domain (RBD)-specific IgA and IgG. Milk samples were tested for the presence of neutralizing antibodies against the spike and four variants of concern (VOCs): D614G, B.1.1.7 (alpha), B.1.351 (beta), and P.1 (gamma). Milk samples were also tested by electrochemiluminescence assay for levels of 10 cytokines.

ResultsMilk from COVID-19-immunized women neutralized the spike and four VOCs and this response is primarily IgG-driven. The immune response in milk also included significantly elevated levels of interferon-{gamma} (IFN-{gamma}). The immune response to maternal vaccination was reflected in breastfed babies; anti-RBD IgG and anti-RBD IgA was detected in 33% and 30% of infant stool samples, respectively. Levels of anti-RBD antibodies in infant stool correlated with maternal vaccine side-effects.

ConclusionHumoral and cellular immune responses to mRNA-based COVID-19 vaccination are present in the breastmilk of most women. The milk anti-RBD antibodies can neutralize SARS-CoV-2 spike and VOCs. Importantly, we describe for the first time the transfer of anti-RBD antibodies to breastfed infants, with the potential to confer passive immunity against SARS-CoV-2.

category: obstetrics and gynecology


title: Flying Without a Net: Space Radiation Cancer Risk Predictions without a Gamma-Ray Basis

abstract: It is well known that the spatial distribution of ionization in cells and tissue from heavy ions and other high linear energy transfer (LET) radiation leads to qualitative and quantitative differences in biological effects compared to low LET radiation such as gamma-rays. However, models used to estimate risks involve extensive use of gamma-ray data, including low LET radiation epidemiology, the role of gamma-rays in estimates of quality factors (QF), and the dose and dose-rate reduction effectiveness factor (DDREF). In tumor induction studies, high LET radiation typically have demonstrable dose responses in many animal strains and tissue, while gamma-ray exposures often lead to a weak or poorly determined dose response at low to moderate doses (<2 Gy) leading to large uncertainties in QF estimates. Here we consider an alternate risk prediction approach, avoiding low epidemiology, the QF and DDREF, by formulating a fluence based track structure model of excess relative risk (ERR) with parameters estimated from animal studies with heavy ions and neutrons for the induction for lung and breast cancer in females and liver cancer in males. The ERR model is applied directly with cancer rates for the US population to predict lifetime risks to astronauts at solar minimum. Results for male liver and female breast cancer risk show that the ERR model agrees fairly well with estimates of a QF model with estimates of non-targeted effects (NTE), and is about 2-fold higher than the QF model that ignores NTE. The effective damage area derived by the ERR model for breast and liver tumors is several times that of a mammalian cell nucleus, which suggests NTE likely contribute to cancer risk. For female lung cancer risk, the ERR model predicts 2-fold and 5-fold lower risk compared to the QF models with or without NTE, respectively. We suggest that the direct ERR approach when coupled with improved experimental models of tissue specific cancers representing human risks would lead to large reductions in the uncertainties in space radiation risk projections by avoiding low LET uncertainties.


title: Colorectal cancer is associated with the presence of cancer driver mutations in normal colon

abstract:
While somatic mutations in colorectal cancer (CRC) are well characterized, little is known about the accumulation of cancer mutations in the normal colon prior to cancer. Here we have developed and applied an ultra-sensitive, single-molecule mutational test based on CRISPR-DS technology, which enables mutation detection at extremely low frequency (<0.001) in normal colon from patients with and without CRC. We found oncogenic KRAS mutations in the normal colon of about one third of patients with CRC but in none of the patients without CRC. Patients with CRC also carried more TP53 mutations than patients without cancer, and these mutations were more pathogenic and formed larger clones, especially in patients with early onset CRC. Most mutations in normal colon were different from the driver mutations in tumors suggesting that the occurrence of independent clones with pathogenic KRAS and TP53 mutations is a common event in the colon of individuals that develop CRC.

SIGNIFICANCEOur results suggest a prevalent process of somatic mutation and evolution in the normal colon of patients with CRC, which can be detected by ultra-sensitive sequencing of driver genes and potentially employed clinically for CRC risk prediction.

category: oncology


title: Clinical indicants and electrophysiological patterns of sciatic nerve in patients after total hip replacement

abstract:
BackgroundThe incidence of sciatic nerve (SN) damage after a total hip replacement (THR) is 10 percent. The underdiagnosis of paucisymptomatic sciatic neuropathy may lead to the unsatisfactory outcome of the treatment in these patients featured by frequent chronic pain syndrome. This research was aimed at the evaluation of the dynamics of clinical and electrophysiological patterns in SN after THR.

Material and methodsThe research involved 16 individuals 45 to 68 years old with primary idiopathic coxarthrosis who underwent THR in the Scientific Research Institute of Traumatology, Orthopedics and Neurosurgery, Federal State Budgetary Educational Institution of Higher Education  V.I. Razumovsky Saratov State Medical University, the Russian Federation Ministry of Healthcare. We compared the findings of clinical and neurologic examinations (VAS, muscle strength, and sensitivity evaluation) as well as ENMG before surgeries and 14 days after them.

ResultsIn the evaluation of the clinical score in 9 patients, we observed some negative changes featured by paresthesia around the area of the SN innervation. The analysis of changes in ENMG findings revealed the decrease in M-response amplitudes of both peroneal and tibial nerves by more than 10 percent of the age-appropriate normal value; this was more prominent in patients who had undergone the lengthening of extremities in more than 3 cm.

ConclusionTHR is associated with a higher risk of traction and entrapment changes in SN that lead to the progress of their neuropathies in the post-operative period.

ReviewersAssoc. Prof. Ulyanov V.Yu., MD, DSc;

Assoc. Prof. Gulyaev D.A., MD, DSc

category: orthopedics


title: Structural Variants Are a Major Component of the Missing Heritability of Autism Spectrum Disorder

abstract: The heritability of autism spectrum disorder (ASD), based on 680,000 families and five countries, is estimated to be nearly 80%, yet we lack genetic markers that adequately explain it. It is increasingly clear that genomic structural variants (SVs) are a major component of the "missing heritability" for many complex phenotypes. Here we use a novel method to identify SVs based on non-Mendelian inheritance patterns in pedigrees using parent-child genotypes from ASD families and demonstrate that the genes that the ASD-specific SVs overlap recapitulate the known molecular biology of ASD including dendritic spinogenesis, axon guidance, and chromatin modification. We further define fine-grained biological pathways that strongly implicate aberrant early development of the cerebellum. Importantly, using these previously excluded variants, we identify the ACMSD gene in the kynurenine pathway as significantly associated with non-verbal cases of ASD and we then use an explainable artificial intelligence approach to define subgroups for future diagnosis and deployment of personalized medicine.


title: Artificial Intelligence for the Diagnosis and Treatment of Diabetes Kidney Disease: a systematic review

abstract:
BackgroundDiabetic nephropathy (DN) is a serious microvascular complication that affects 40% of diabetes patients. In the last decade, artificial intelligence (AI) has been widely used in both structured and unstructured clinical data to improve the treatment of patients/potential patients with DN.

MethodsThis systematic review aims to cover all applications of AI in the clinical use of DN or related topics. Studies were searched in four open-access databases (Pubmed, IEEE Xplore, DBLP Computer Science Bibliography, and ACM digital library). Finally, the author manually searched the reference list of included studies in the study for additional relevant articles.

ResultsFinally, a total of 24 original peers reviewed articles were included in this study. Through a manual data extraction, the summary of key information such as applied AI algorithm, main outcomes, performance evaluation etc. was taken. Then the included studies underwent a quality assessment criterion, assessing the reproducibility, generalizability etc. Most of the included studies revealed that the AI frameworks outperformed conventional statistical methods. A summary of the limitations, such as lack of data availability or external validation of the framework, in the included studies, was also included.

ConclusionThe rapid advancement of the AI framework and the exponential data generation in healthcare can be utilized and applied in clinical practices. The aid of AI can be instrumental in the treatment of DN.

category: health informatics


title: Impact Of Adaptive Natural Killer Cells, KLRC2 Genotype And Cytomegalovirus Reactivation On Late Mortality In Patients With Severe Covid-19 Lung Disease

abstract:
ObjectiveCOVID-19 infection results in severe lung disease in a small but significant number of infected patients. The etiopathogenesis in a subset of such patients, who continue to have progressive pulmonary disease following virus clearance remains unexplored.

MethodsWe investigated the role of NKG2C+/NKG2A- adaptive natural killer (ANK) cells, KLRC2 genotype and cytomegalovirus reactivation in 22 such patients.

ResultsThe median duration of virus positivity was 23 days and the median duration of hospitalisation was 48 days. The overall survival at 60 days in this group was 50%. Older age and comorbidities impacted survival negatively. CMV viremia was documented in 11 patients, with a survival of 25% vs 80% in those without viremia with viral load correlating with mortality. ANK cells were markedly depressed in all patients at day 15. However, persistently low ANK cells at 30 days along with an inversely high NKG2C-/NKG2A+ inhibitory NK cells significantly correlated with high CMV viremia as well as mortality, irrespective of KLRC2 genotype. Day 30 ANK cells were significantly lower in KLRC2 deletion group. IFN-gamma and Perforin release were severely compromised in all patients at day +15, with significant improvement in the survivors at day +30, but not in those with adverse outcome.

ConclusionPatients with severe lung disease even after negative SARS-CoV-2 status, with persistently reduced and functionally compromised ANK cells, are more likely to have CMV reactivation and an adverse outcome, independent of KLRC2 genotype.


title: The GenoDiabMar registry. A collaborative research platform of "real world" type 2 diabetes patients.

abstract:
The GenoDiabMar registry is a prospective study aims to provide data on demographic, biochemical and clinical changes, from a "real-world" population of Type 2 DM (T2D) patients. This registry is addressed to find new biomarkers related to the micro and macrovascular complications of T2D, especially focused on diabetic nephropathy. The registry includes longitudinal serum and urine samples, DNA bank, as well as data on 227 metabolomics profiles, 77 Immunoglobulin G glycomics traits and others emerging biomarkers. 650 patients aged 69.56 {+/-}9.31 with different grades of chronic kidney disease; (G1-2 50.3%, G3 31.4%, G4 10.8% and G5 7.5%) were followed up for 4.96 ({+/-}0.43) years. Regardless of albuminuria, women lost 0.93 (0.40-1.46) glomerular filtration units per year less than men. 17% of the participant experienced rapid progression of renal function, 75.2% men, with differential risk factors between sexes; severe macroalbuminuria >300mg/g for men OR[IQ] 2.40 [1.29:4.44] and concomitant peripheral vascular disease 3.32 [1.10:9.57] for women. An overall mortality of 23% was detected (38% due to Cardiovascular aetiology).

This cohort is postulated as a great tool for scientific collaboration for studies, whether they are focused on T2D, or whether they are interested in comparing differential markers between diabetic and non-diabetic populations.


title: Comparison of endoscopic activity before and during the covid pandemic at a tertiary care hospital in South Punjab

abstract:
IntroductionCoronavirus disease 2019 (COVID-19) has resulted in dramatic changes to health-care delivery. Endoscopic activity has had frequent disruptions during this pandemic. The objective of the study was to see the influence of pandemic over the endoscopic activity.

MethodsThis retrospective analysis of endoscopic activity was undertaken at Nishtar Hospital Multan. Procedural analysis was done in the three months immediately after covid lockdown (1st April till 30th June 2020) and was compared to a similar period one year back.

ResultsFive hundred and fifty-four (68.5%) patients underwent endoscopic procedures during the three months of pre-COVID era, while this number reduced to half (n=255, 31.5%) patients during the covid pandemic. Even though the absolute number of Esophagogastroduodenoscopies (EGDs) reduced during the pandemic, patients were more likely to undergo EGDs during the COVID pandemic in contrast to the era before the pandemic (79% versus 66%, p = 0.002). The most common indication for EGD was upper gastrointestinal bleeding (UGIB). The percentage of EGDs done for UGIB rose from almost 60% to 80% during the covid pandemic (p < 0.001). The most common findings were esophageal varices and portal gastropathy (non-significant difference during and before the pandemic). Percentage of ERCPs done for obstructive jaundice doubled during the COVID pandemic (33% versus 65%, p = 0.002).The most common indication for sigmoidoscopy or colonoscopy was lower gastrointestinal bleeding. However, no significant difference was found before and during the covid pandemic (41.7% and 45.8% respectively, p=0.72). Internal hemorrhoids were the most common endoscopic finding. Colon cancer diagnosis reduced from 10% to undetected during the pandemic period.

ConclusionCOVID pandemic resulted in considerable reduction in all type of endoscopic procedures. Majority of procedures were done for emergency indications like gastrointestinal bleeding. Rates of cancer detection was significantly reduced.

category: gastroenterology


title: Predicting Axillary Lymph Node Metastasis in Early Breast Cancer Using Deep Learning on Primary Tumor Biopsy Slides

abstract:
ObjectivesTo develop and validate a deep learning (DL) based primary tumor biopsy signature for predicting axillary lymph node (ALN) metastasis preoperatively in early breast cancer (EBC) patients with clinically negative ALN.

MethodsA total of 1058 EBC patients with pathologically confirmed ALN status were enrolled from May 2010 to August 2020. A deep learning core-needle biopsy (DL-CNB) model was built on the attention based multiple instance learning (AMIL) framework to predict ALN status utilizing the deep learning features, which were extracted from the cancer areas of digitized whole-slide images (WSIs) of breast CNB specimens annotated by two pathologists. Accuracy, sensitivity, specificity, receiver operating characteristic (ROC) curves, and areas under the receiver operating characteristic curve (AUCs) were analyzed to evaluate our model.

ResultsThe best performing DL-CNB model with VGG16_BN as the feature extractor achieved an AUC of 0.816 (95% confidence interval (CI): 0.758, 0.865) in predicting positive ALN metastasis in the independent test cohort. Furthermore, our model incorporating the clinical data, which was called DL-CNB+C, yielded the best accuracy of 0.831 (95%CI: 0.775, 0.878), especially for patients younger than 50 years (AUC: 0.918, 95%CI: 0.825, 0.971). The interpretation of DL-CNB model showed that the top signatures most predictive of ALN metastasis were characterized by the nuclei features including density (p=0.015), circumference (p=0.009), circularity (p=0.010), and orientation (p=0.012).

ConclusionOur study provides a novel deep learning-based biomarker on primary tumor CNB slides to predict the metastatic status of ALN preoperatively for patients with early breast cancer.

category: pathology


title: Microstructural deficits in the thalamus of major depressive disorder

abstract: Macroscopic structural abnormalities in the thalamus and thalamic circuits have been shown to contribute to the neuropathology of major depressive disorder (MDD). However, cytoarchitectonic properties underlying these macroscopic abnormalities remain unknown. The purpose of this study was to identify systematic deficits of brain architecture in depression, from structural brain network organization to microstructural properties. A multi-modal neuroimaging approach including diffusion, anatomical and quantitative magnetic resonance imaging (MRI) was used to examine structural-related alternations in 56 MDD patients compared with 35 age- and sex-matched controls. Structural networks were constructed and analyzed using seed-based probabilistic tractography. Morphometric measurements, including cortical thickness and voxel-based morphometry (VBM), were evaluated across the whole brain. A conjunction analysis was then conducted to identify key regions showing common structural alternations across modalities. The microstructural properties, macromolecular tissue volume (MTV) and T1 relaxation times of identified key regions were then calculated. Results showed multiple alterations of structural connectivity within a set of subcortical areas and their connections to cortical regions in MDD patients. These subcortical regions included the putamen, thalamus and caudate, which are predominately involved in the limbic-cortical-striatal-pallidal-thalamic network (LCSPT). Structural connectivity was disrupted within and between large-scale networks, mainly including subcortical networks, default mode networks and salience/ventral attention networks. Consistently, these regions also exhibited widespread volume reductions in MDD patients, specifically the bilateral thalamus, left putamen and right caudate. Importantly, the microstructural properties, T1 relaxation time of left thalamus were increased and negatively correlated with its gray matter volume in MDD patients. The present work to date sheds light on the neuropathological disruptions of LCSPT circuit in MDD, providing the first multi-modal neuroimaging evidence for the macro-micro structural abnormalities of the thalamus in patients with MDD. These findings have implications in understanding the abnormal changes of brain structures across development of MDD.

category: psychiatry and clinical psychology


title: Leaders gender and the fight against COVID-19: investigation, replication, and a possible explanation

abstract:
ObjectivesTo investigate the alleged relationship between leaders gender and COVID-19 related cases and deaths in different countries across the globe.

Study designThe relationship between leaders gender and percent of women in parliament to COVID-19 cases and death per million was investigated in three time points (10 months) across 180 countries, controlling for possible covariates.

MethodsThree different types of analyses were run: (1) Six basic t-tests; (2) Two repeated-measure ANOVA tests analyzing change over time; (3) Six stepwise regression analyses for both leaders gender and the percentage of women in parliament.

ResultsOur findings suggest that, contrary to some research and popular media headlines, and in-line with recent academic research, leadership gender is not a significant factor in explaining the variation between countries in the fight against the COVID-19 pandemic.

ConclusionsWe suggest that this alleged relationship may stem from an illusory correlation. We argue that the uncertainty, stress, and anxiety that prevail in these times of global pandemic may be the breeding ground for judgmental biases of this sort.

category: public and global health


title: Impact of Recent Job Loss on Sleep, Energy Consumption and Diet

abstract:
To examine how sleep quality and sleep duration affect caloric intake among those experiencing involuntary job loss.

MethodsAdequate sleep and self reported dietary recall data from the Assessing Daily Activity Patterns through Occupational Transitions (ADAPT) study was analysed. Primary sleep indices used were total sleep time, time spent in bed after final awakening, and sleep quality as measured by the Daily Sleep Diary (DSD). Mean Energy consumption (MEC) was the primary nutritional index. Secondary indices included diet quality using the Health Eating Index 2015 (HEI), and self-reported intake of protein, carbohydrates and fats.

ResultsThe study participants were comprised mainly of women (61%) and non-Hispanic white. The participants had at least 2 years of college education and mean body mass index of 30.2{+/-}8.08 (kg/m 2). The average time in bed was 541.8{+/-}77.55 minutes and total sleep time was 461.1{+/-}56.49 minutes. Mean sleep efficiency was 91{+/-}6%, self-reported sleep quality was 2.40{+/-}0.57 (0-4 scale, 4 = very good), and minutes earlier than planned morning awakening were 14.36{+/-}24.15. Mean HEI score was 47.41{+/-}10.92. Although the MEC was below national average for both men and women, male sex was associated with higher MEC. In a fully adjusted model sleep quality was positively associated with MEC.

ConclusionDaily overall assessments of sleep quality among recently unemployed persons were positively associated with mean energy consumption. Additionally, the diet quality of unemployed persons was found to unhealthier than the average American and consistent with the relationship between poor socioeconomic status and lower diet quality.


title: Improving reproducibility of proton MRST by optimally averaging temperatures measured from multiple references: theoretical and empirical approaches

abstract:
PurposeIn 1H MRS-based thermometry of brain, averaging temperatures measured from more than one reference peak offers several advantages including improving the reproducibility, i.e., precision, of the measurement. This paper proposes theoretically and empirically optimal weighting factors to improve the weighted average of temperatures measured from three references.

MethodsWe first proposed concepts of equivalent noise and equivalent signal-to-noise ratio in terms of frequency measurement and a concept of relative frequency that allows the combination of different peaks in a spectrum for improving the precision of frequency measurement. Based on these, we then derived a theoretically optimal weighting factor and proposed an empirical weighting factor, both involving equivalent noise levels, for a weighted average of temperatures measured from three references, i.e., the singlets of NAA, Cr, and Ch, in 1H MR spectrum. We assessed these two weighting factors by comparing their errors in measurement of temperatures with the errors of temperatures measured from individual references; we also compared these two new weighting factors with two previously proposed weighting factors. These errors were defined as the standard deviations (SDs) in repeated measurements or in Monte Carlo studies.

ResultsBoth the proposed theoretical and empirical weighting factors outperformed the two previously proposed weighting factors as well as the three individual references in all phantom and in vivo experiments. In phantom experiments with 4 Hz or 10 Hz line broadening, the theoretical weighting factor outperformed the empirical one, but the latter was superior in all other repeated and Monte Carlo tests performed on phantom and in vivo data.

ConclusionThe proposed weighting factors are superior to the two previously proposed weighting factors and can improve the reproducibility of temperature measurement using the 1H MRS-based thermometry.

category: radiology and imaging


title: Reliability of multi-modal MRI-derived brain phenotypes for multi-site assessment of neuropsychiatric complications of SARS-CoV-2 infection

abstract:
BackgroundMagnetic resonance imaging (MRI) of the brain could be a key diagnostic and research tool for understanding the neuropsychiatric complications of COVID-19. For maximum impact, multi-modal MRI protocols will be needed to measure the effects of SARS-CoV2 infection on the brain by diverse potentially pathogenic mechanisms, and with high reliability across multiple sites and scanner manufacturers.

MethodsA multi-modal brain MRI protocol comprising sequences for T1-weighted MRI, T2-FLAIR, diffusion MRI (dMRI), resting-state functional MRI (fMRI), susceptibility-weighted imaging (swMRI) and arterial spin labelling (ASL) was defined in close approximation to prior UK Biobank (UKB) and C-MORE protocols for Siemens 3T systems. We iteratively defined a comparable set of sequences for General Electric (GE) 3T systems. To assess multi-site feasibility and between-site variability of this protocol, N=8 healthy participants were each scanned at 4 UK sites: 3 using Siemens PRISMA scanners (Cambridge, Liverpool, Oxford) and 1 using a GE scanner (Kings College London). Over 2,000 Imaging Derived Phenotypes (IDPs) measuring both data quality and regional image properties of interest were automatically estimated by customised UKB image processing pipelines. Components of variance and intra-class correlations were estimated for each IDP by linear mixed effects models and benchmarked by comparison to repeated measurements of the same IDPs from UKB participants.

ResultsIntra-class correlations for many IDPs indicated good-to-excellent between-site reliability. First considering only data from the Siemens sites, between-site reliability generally matched the high levels of test-retest reliability of the same IDPs estimated in repeated, within-site, within-subject scans from UK Biobank. Inclusion of the GE site resulted in good-to-excellent reliability for many IDPs, but there were significant between-site differences in mean and scaling, and reduced ICCs, for some classes of IDP, especially T1 contrast and some dMRI-derived measures. We also identified high reliability of quantitative susceptibility mapping (QSM) IDPs derived from swMRI images, multi-network ICA-based IDPs from resting-state fMRI, and olfactory bulb structure IDPs from T1, T2-FLAIR and dMRI data.

ConclusionThese results give confidence that large, multi-site MRI datasets can be collected reliably at different sites across the diverse range of MRI modalities and IDPs that could be mechanistically informative in COVID brain research. We discuss limitations of the study and strategies for further harmonization of data collected from sites using scanners supplied by different manufacturers. These protocols have already been adopted for MRI assessments of post-COVID patients in the UK as part of the COVID-CNS consortium.


title: Neuroanatomical correlates of working memory performance in Neurofibromatosis 1

abstract:
BackgroundNeurofibromatosis 1 (NF1) is a single-gene neurodevelopmental disorder associated with cognitive and behavioural impairments, particularly with deficits in working memory. This study investigates the cerebral volumetric differences in adolescents with NF1 as compared to typically developing controls and how working memory task performance is associated with these differences.

Methods31 adolescents aged 11-17 years were compared to age and sex-matched controls. NF1 subjects were assessed using detailed measurement of working memory at baseline followed by a 3T MR scan. A voxel-based morphometry approach was used to estimate the total and regional gray matter volumetric differences between the NF1 and control groups. The working memory metrics were subjected to a principal component analysis (PCA) approach. Finally, we examined how the components derived from PCA correlated with the changes in gray matter volume in the NF1 group, after adjusting for age, sex and total intracranial volume.

ResultsThe NF1 cohort showed increased gray matter volumes in the thalamus, globus pallidus, caudate, putamen, dorsal midbrain and cerebellum bilaterally as compared to controls. The PCA yielded three independent behavioural components reflecting high memory load, low memory load and auditory working memory. Correlation analyses revealed that increased volume of the inferior lateral parietal cortex was associated with poorer performance on the high working memory load tasks. Increased volume of posterior cingulate cortex, a key component of the default mode network (DMN) was significantly associated with poorer performance on low working memory load tasks.

DiscussionThis is the first study to examine the neuroanatomical correlates of working memory in NF1 adolescents. Consistent with prior literature we show larger subcortical brain volumes in in the NF1 cohort. The strong association between posterior cingulate cortex volume and performance on low memory load conditions supports previously suggested hypotheses of deficient DMN structural development, which in turn may contribute to the cognitive impairments in NF1.


title: Increased Akkermansia abundance is associated with increased colonic mucosal ω-3 fatty acids and decreased colonic mucosal PGE2 concentrations following healthy dietary pattern interventions

abstract: Both increased dietary intake of {omega}-3 polyunsaturated fatty acids (PUFA) and subsequent increases in colonic mucosal {omega}-3 PUFA concentrations have been linked to improved gut barrier function and decreased risks of metabolic diseases and cancer. In addition, increased dietary {omega}-3 PUFA has been linked to eubiosis in mouse studies. Increased {omega}-3 PUFA function in part to reduce cyclooxygenase-(COX) mediated prostaglandin E2 (PGE2) production, a biomarker of cancer risk linked to compromised gut barrier function. We analyzed data from a dietary intervention study in individuals at increased risk of colon cancer to determine whether changes in the mucosal microbiome composition were associated with changes in colonic mucosal {omega}-3/ {omega}-6 PUFA ratio. Microbiome analyses of colonic biopsies before and after the dietary intervention from 86 participants were done by sequencing the V4 region of the 16S rRNA gene. Multivariable linear regression models were used to evaluate further whether changes in Akkermansia was associated with changes in each colonic tissue variable: {omega}-3/{omega}-6 PUFA ratios, PGE2 concentrations, and expression of COX-1 and COX-2. The median dietary intake and mucosal {omega}-3/{omega}-6 PUFA ratio increased after intervention. Greater increases in mucosal {omega}-3/{omega}-6 PUFA ratios after intervention were significantly associated with several changes in taxon abundance, including increased Akkermansia muciniphilia relative abundance. An increased abundance of Akkermansia muciniphilia also was associated significantly with decreased PGE2 concentrations but not with changes in COX expression. Further studies are warranted to elucidate mechanisms by which Akkermansia may affect or is affected by these pathways and the relative importance of individual dietary components.


title: Explainable Transformer-Based Neural Network forthe Prediction of Survival Outcomes in Non-SmallCell Lung Cancer (NSCLC)

abstract: In this paper, we introduce the "Clinical Transformer" - a recasting of the widely used transformer architecture as a method for precision medicine to model relations between molecular and clinical measurements, and the survival of cancer patients. Although the emergence of immunotherapy offers a new hope for cancer patients with dramatic and durable responses having been reported, only a subset of patients demonstrate benefit. Such treatments do not directly target the tumor but recruit the patients immune system to fight the disease. Therefore, the response to therapy is more complicated to understand as it is affected by the patients physical condition, immune system fitness and the tumor. As in text, where the semantics of a word is dependent on the context of the sentence it belongs to, in immuno-therapy a biomarker may have limited meaning if measured independent of other clinical or molecular features. Hence, we hypothesize that the transformer-inspired model may potentially enable effective modelling of the semantics of different biomarkers with respect to patients survival time. Herein, we demonstrate that this approach can offer an attractive alternative to the survival models utilized in current practices as follows: (1) We formulate an embedding strategy applied to molecular and clinical data obtained from the patients. (2) We propose a customized objective function to predict patient survival. (3) We show the applicability of our proposed method to bioinformatics and precision medicine. Applying the clinical transformer to several immuno-oncology clinical studies, we demonstrate how the clinical transformer outperforms other linear and non-linear methods used in current practice for survival prediction. We also show that when initializing the weights of a domain-specific transformer by the weights of a cross-domain transformer, we further improve the predictions. Lastly, we show how the attention mechanism successfully captures some of the known biology behind these therapies.


title: Genome-wide association study of liking of physical activity in the UK Biobank

abstract: A lack of physical activity (PA) is one of the most pressing health issues facing society today. Our individual propensity for PA is partly influenced by genetic factors. Stated liking of various PA behaviors may capture additional dimensions of PA behavior that are not captured by other measures, and contribute to our understanding of the genetics of PA behavior. Here, in over 157,000 individuals from the UK Biobank, we sought to complement and extend previous findings on the genetics of PA behavior by performing genome-wide association studies of self-reported liking of several PA-related behaviors plus an additional derived trait of overall PA-liking. We identified a total of 19 unique genome-wide significant loci across all traits, only four of which overlap with loci previously identified for PA behavior. The PA-liking traits were genetically correlated with self-reported (rg: 0.38 - 0.80) and accelerometry-derived (rg: 0.26 - 0.49) PA measures, and with a wide range of health-related traits and dietary behaviors. Replication in the Netherlands Twin Register (NTR; n>7,300) and the TwinsUK (n>1,300) study revealed directionally consistent associations. Polygenic risk scores (PRS) were then trained in UKB for each PA-liking trait and for self-reported PA behavior. The PA-liking PRS significantly predicted the same liking trait in NTR. The PRS for liking of going to the gym predicted PA behavior in NTR (r2 = 0.40%) nearly as well as the one constructed based on self-reported PA behavior (r2 = 0.42%). Combining the two PRS into a single model increased the r2 to 0.59%, suggesting that although these PRS correlate with each other, they are also capturing distinct dimensions of PA behavior. In conclusion, we have identified the first loci associated with PA-liking, and extended and refined our understanding of the genetic basis of PA behavior.


title: Advancing our understanding of skeletal muscle across the lifecourse: protocol for the MASS_Lifecourse Study and characteristics of the first 80 participants

abstract:
IntroductionSarcopenia, the age-related loss of skeletal muscle strength and mass, carries a significant burden for affected individuals. There has been little investigation of sarcopenia using experimental medicine techniques to study human muscle tissue in detail. The aim of the Muscle Ageing Sarcopenia Studies Lifecourse (MASS_Lifecourse) study is to recruit up to 160 participants, equally divided between females and males between ages 45 and 85 years for detailed phenotyping of skeletal muscle health. Here we describe the protocol for the study and the characteristics of the first 80 participants.

MethodsWe are recruiting participants from three sources in the north-east of England. Study fieldwork comprises a home visit (or videocall) for consent and assessment of health, cognition, lifestyle, and wellbeing. This is followed by a visit to a clinical research facility for assessment of sarcopenia status and collection of samples including a vastus lateralis muscle biopsy. We produced descriptive statistics for the first 80 participants, including expressing their grip strength relative to normative data in the form of Z-scores.

ResultsThe first 80 participants (53.8% female) covered the target ages, ranging from 48 to 84 years. They were regularly physically active, reported good physical function and had a prevalence sarcopenia (including probable sarcopenia) of 11.3% based on the revised European consensus. Their grip strength was similar to that in the general population, with a mean Z-score of 0.09 standard deviations (95% CI: -1.64, 1.83) above that expected.

ConclusionsThe MASS_Lifecourse study combines comprehensive health and lifestyle data with a range of biological samples including skeletal muscle. The findings from planned analyses should contribute to improvements in the diagnosis, treatment, and prevention of sarcopenia.

category: geriatric medicine


title: Markerless Video Analysis of Spontaneous Bodily Movements in 4-Month-Old Infants Predicts Autism-like Behavior in 18-Month-Olds.

abstract: Early intervention is now considered the core treatment strategy for autism spectrum disorders (ASD). Thus, it is of significant clinical importance to establish a screening tool for the early detection of ASD in infants. To achieve this goal, in a longitudinal design, we analysed spontaneous bodily movements of 4-month-old infants and assessed their ASD-like behaviours at 18 months of age. Infants at high risk for ASD at 18 months of age exhibited less rhythmic and weaker bodily movement patterns at 4 months of age than low-risk infants. When the observed bodily movement patterns were submitted to a machine learning-based analysis, linear and non-linear classifiers successfully predicted ASD-like behaviour at 18 months of age based on the bodily movement patterns at 4 months of age, at the level acceptable for practical use. This suggests the utility of the proposed method for the early screening of infants at risk for ASD.


title: Differential immunogenicity of homologous versus heterologous boost in Ad26.COV2.S vaccine recipients.

abstract:
Protection offered by COVID-19 vaccines wanes over time, requiring an evaluation of different boosting strategies to revert such a trend and enhance the quantity and quality of Spike-specific humoral and cellular immune responses. These immunological parameters in homologous or heterologous vaccination boosts have thus far been studied for mRNA and ChAdOx1 nCoV-19 vaccines, but knowledge on individuals who received a single dose of Ad26.COV2.S is lacking.

We studied Spike-specific humoral and cellular immunity in Ad26.COV2.S vaccinated individuals (n=55) who were either primed with Ad26.COV2.S only (n=13), or boosted with a homologous (Ad26.COV2.S, n=28) or heterologous (BNT162b2, n=14) second dose. We compared our findings with the results found in individuals vaccinated with a single (n=16) or double (n=44) dose of BNT162b2. We observed that a strategy of heterologous vaccination enhanced the quantity and breadth of both, Spike-specific humoral and cellular immunity in Ad26.COV2.S vaccinated. In contrast, the impact of homologous boost was quantitatively minimal in Ad26.COV2.S vaccinated and Spike-specific antibodies and T cells were narrowly focused to the S1 region. Although a direct association between quantity and quality of immunological parameters and in vivo protection has not been demonstrated, the immunological features of Spike-specific humoral and cellular immune responses support the utilization of a heterologous strategy of vaccine boost in individuals who received Ad26.COV2.S vaccination.


title: Genome Recombination between Delta and Alpha Variants of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

abstract: Prominent genomic recombination has been observed between the Delta and Alpha variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) isolated from clinical specimens in Japan. It is necessary to intensively study such marked genetic variations and characterize the emerging variants after careful verification of their lineage and clade assignment.


title: The impact of heating, ventilation, and air conditioning design features on the transmission of viruses, including the 2019 novel coronavirus: a systematic review of ultraviolet radiation

abstract:
Respiratory viruses are capable of transmitting via an aerosol route. Emerging evidence suggests that SARS-CoV-2 which causes COVID-19 can be spread through airborne transmission, particularly in indoor environments with poor ventilation. Heating, ventilation, and air conditioning (HVAC) systems can play a role in mitigating airborne virus transmission. We conducted a systematic review of the scientific literature examining the effectiveness of HVAC design features in reducing virus transmission--here we report results for ultraviolet (UV) radiation. Following international standards for systematic reviews, we conducted a comprehensive search and synthesized findings from 32 relevant studies published between 1936 and 2020. Research demonstrates that: viruses and bacteriophages are inactivated by UV radiation; increasing UV dose is associated with decreasing survival fraction of viruses and bacteriophages; increasing relative humidity is associated with decreasing susceptibility to UV radiation; UV dose and corresponding survival fraction are affected by airflow pattern, air changes per hour, and UV device location; and UV radiation is associated with decreased transmission in both animal and human studies. This comprehensive synthesis of the scientific evidence examining the impact of UV radiation on virus transmission can be used to guide implementation of systems to mitigate airborne spread and identify priorities for future research.

Practical ImplicationsIn-duct ultraviolet germicidal irradiation (UVGI) addresses virus transmission throughout the heating, ventilation, and air conditioning (HVAC) system of a building as a whole; whereas, upper-room UVGI addresses virus transmission in one room of that building. The susceptibility of a virus is often determined from the relationship between UV dose and survival fraction of the virus, and can be affected by relative humidity. Modelling studies revealed that practical implementation of UVGI in HVAC systems should consider airflow patterns, air changes per hour, and UV device location. Future field studies of UVGI systems could address an existing research gap and provide important information on system performance in real-world situations.


title: SARS-CoV-2 vaccine antibody response and breakthrough infections in patients receiving dialysis

abstract:
BackgroundPatients receiving dialysis are a sentinel population for groups at high risk for death and disability from COVID-19. Understanding correlates of protection post-vaccination can inform immunization and mitigation strategies.

MethodsMonthly since January 2021, we tested plasma from 4791 patients receiving dialysis for antibodies to the receptor-binding domain (RBD) of SARS-CoV-2 using a high-throughput assay. We qualitatively assessed the proportion without a detectable RBD response and among those with a response, semiquantitative median IgG index values. Using a nested case-control design, we matched each breakthrough case to five controls by age, sex, and vaccination-month to determine whether peak and pre-breakthrough RBD IgG index values were associated with risk for infection post-vaccination.

ResultsAmong 2563 vaccinated patients, the proportion without a detectable RBD response increased from 6.6% [95% CI 5.5-8.1] in 14-30 days post-vaccination to 20.2% [95% CI 17.1-23.8], and median index values declined from 92.7 (95% CI 77.8-107.5) to 3.7 (95% CI 3.1-4.3) after 5 months. Persons with SARS-CoV-2 infection prior-to-vaccination had higher peak index values than persons without prior infection, but values equalized by 5 months (p=0.230). Breakthrough infections occurred in 56 patients, with samples collected a median of 21 days pre-breakthrough. Peak and pre-breakthrough RBD values <23 (equivalent to <506 WHO BAU/mL) were associated with higher odds for breakthrough infection (OR: 3.7 [95% CI 2.0-6.8] and 9.8 [95% CI 2.9-32.8], respectively).

ConclusionsThe antibody response to SARS-CoV-2 vaccination wanes rapidly, and in persons receiving dialysis, the persisting antibody response is associated with risk for breakthrough infection.


title: Modeling and analysis of COVID-19 infected persons during repeated waves in Japan

abstract: A model for estimating the number of COVID-19 infected persons (infecteds) is proposed based on the exponential function law of the SIR model. This model is composed of several equations expressing the number of infecteds, considering the onset after an incubation period, infectivity, wavy infection persistence with repeated infection spread and convergence with insufficient quarantine. This model is applied to the infection in Japan, which is currently suffering from the 5th wave, and the initial number of infecteds and various related parameters are calculated by curve fitting of the cumulative number of infecteds to the total cases in the database. As a minimum boundary of the number of infecteds for the infection continuation up to the 5th wave, the initial number of infecteds at the outbreak of infection is more than an order of magnitude higher than the actual initial cases. A convergence ratio (cumulative number of infecteds / total cases) at the end of the first wave is obtained as 1.5. The quarantine rate and social distancing ratio based on the SIQR model are evaluated, and the social distancing ratio increases sharply just after the governments declaration of emergency. The quarantine rate closely equals the positive rate by PCR tests, meaning that the number of infecteds, which had been unknown, is on the order of almost the same as the number of tests.


title: Vaccine effectiveness against SARS-CoV-2 transmission to household contacts during dominanceof Delta variant (B.1.617.2), August-September 2021, the Netherlands

abstract: We estimated vaccine effectiveness against onward transmission by comparing secondary attack rates among household members between vaccinated and unvaccinated index cases, based on source and contact tracing data collected when Delta variant was dominant. Effectiveness of full vaccination of the index against transmission to fully vaccinated household contacts was 40% (95% confidence interval (CI) 20-54%), which is in addition to the direct protection of vaccination of contacts against infection. Effectiveness of full vaccination of the index against transmission to unvaccinated household contacts was 63% (95%CI 46-75%). We previously reported effectiveness of 73% (95%CI 65-79%) against transmission to unvaccinated household contacts for the Alpha variant.


title: Differentiation of SARS-CoV-2 naturally infected and vaccinated individuals in an inner-city emergency department

abstract:
BackgroundEmergency Departments (EDs) can serve as surveillance sites for infectious diseases. Our purpose was to determine the burden of SARS-CoV-2 infection and prevalence of vaccination against COVID-19 among patients attending an urban ED in Baltimore City.

MethodsUsing 1914 samples of known exposure status, we developed an algorithm to differentiate previously infected, vaccinated, and unexposed individuals using a combination of antibody assays. We applied this testing algorithm to 4360 samples ED patients obtained in the springs of 2020 and 2021. Using multinomial logistic regression, we determined factors associated with infection and vaccination.

ResultsFor the algorithm, sensitivity and specificity for identifying vaccinated individuals was 100% and 99%, respectively, and 84% and 100% for naturally infected individuals. Among the ED subjects, seroprevalence to SARS-CoV-2 increased from 2% to 24% between April 2020 and March 2021. Vaccination prevalence rose to 11% by mid-March 2021. Marked differences in burden of disease and vaccination coverage were seen by sex, race, and ethnicity. Hispanic patients, though 7% of the study population, had the highest relative burden of disease (17% of total infections) but similar vaccination rates. Women and White individuals were more likely to be vaccinated than men or Black individuals (adjusted odds ratios [aOR] 1.35 [95% CI: 1.02, 1.80] and aOR 2.26 [95% CI: 1.67, 3.07], respectively).

ConclusionsIndividuals previously infected with SARS-CoV-2 can be differentiated from vaccinated individuals using a serologic testing algorithm. SARS-CoV-2 exposure and vaccination uptake frequencies reflect gender, race and ethnic health disparities in this urban context.

SummaryUsing an antibody testing algorithm, we distinguished between immune responses from SARS-CoV-2-infected and vaccinated individuals. When applied to blood samples from an emergency department in Baltimore, disparities in disease burden and vaccine uptake by sex, race, and ethnicity were identified.


title: Effectiveness of the BNT162b2 (Pfizer-BioNTech) and the ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccines for reducing susceptibility to infection with the Delta variant(B.1.617.2) of SARS-CoV-2

abstract:
BackgroundFrom January to May 2021 the alpha variant (B.1.1.7) of SARS-CoV-2 was the most commonly detected variant in the UK, but since then the Delta variant (B.1.617.2), first detected in India, has become the predominant variant. The UK COVID-19 vaccination programme started on 8th December 2020. Most vaccine effectiveness studies to date have focused on the alpha variant. We therefore aimed to estimate the effectiveness of the BNT162b2 (Pfizer-BioNTech) and the ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccines in preventing infection with respect to the Delta variant in a UK setting.

MethodsWe used anonymised public health record data linked to infection data (PCR) using the Combined Intelligence for Population Health Action resource. We then constructed an SIR epidemic model to explain SARS-CoV-2 infection data across the Cheshire and Merseyside region of the UK.

ResultsWe determined that the effectiveness of the Oxford-AstraZeneca vaccine in reducing susceptibility to infection is 39% (95% credible interval [34,43]) and 64% (95% credible interval [61,67]) for a single dose and a double dose respectively. For the Pfizer-BioNTech vaccine, the effectiveness is 20% (95% credible interval [10,28]) and 84% (95% credible interval [82,86]) for a single-dose and a double dose respectively.

ConclusionVaccine effectiveness for reducing susceptibility to SARS-CoV-2 infection shows noticeable improvement after receiving two doses of either vaccine. Findings also suggest that a full course of the Pfizer-BioNTech provides the optimal protection against infection with the Delta variant. This would advocate for completing the full course programme to maximise individual protection and reduce transmission.


title: Nutritional deficiency recapitulates intestinal injury associated with environmental enteric dysfunction in patient-derived Organ Chips

abstract: Environmental Enteric Dysfunction (EED) is a chronic inflammatory condition of the intestine characterized by villus blunting, compromised intestinal barrier function, and reduced nutrient absorption. Here, we show that key genotypic and phenotypic features of EED-associated intestinal injury can be reconstituted in a human intestine-on-a-chip (Intestine Chip) microfluidic culture device lined by organoid-derived intestinal epithelial cells from EED patients and cultured in niacinamide- and tryptophan-deficient (-N/-T) medium. Exposure of EED Intestine Chips to -N/-T deficiencies resulted in transcriptional changes similar to those seen in clinical EED patient samples including congruent changes in six of the top ten upregulated genes. Exposure of EED Intestine Chips or chips lined by healthy intestinal epithelium (healthy Intestine Chips) to -N/-T medium resulted in severe villus blunting and barrier dysfunction, as well as impairment of fatty acid uptake and amino acid transport. EED Intestine Chips exhibited reduced secretion of cytokines at baseline, but their production was significantly upregulated compared to healthy Intestine Chips when exposed to -N/-T deficiencies. The human Intestine Chip model of EED-associated intestinal injury may be useful for analyzing the molecular, genetic, and nutritional basis of this disease and can serve as a preclinical model for testing potential EED therapeutics.


title: COVID-19 and Mental Health: Predicted Mental Health Status is Associated with Clinical Symptoms and Pandemic-Related Psychological and Behavioral Responses

abstract:
BackgroundThe COVID-19 pandemic led to dramatic threats to health and social life. Study objectives - develop a prediction model leveraging subsample of known Patient/Controls and evaluate the relationship of predicted mental health status to clinical outcome measures and pandemic-related psychological and behavioral responses during lockdown (spring/summer 2020).

MethodsOnline cohort study conducted by National Institute of Mental Health Intramural Research Program. Convenience sample of English-speaking adults (enrolled 4/4-5/16/20; n=1,992). Enrollment measures: demographics, clinical history, functional status, psychiatric and family history, alcohol/drug use. Outcome measures (enrollment and q2 weeks/6 months): distress, loneliness, mental health symptoms, and COVID-19 survey. NIMH IRP Patient/Controls survey responses informed assignment of Patient Probability Scores (PPS) for all participants. Regression models analyzed the relationship between PPS and outcome measures.

OutcomesMean age 46.0 ({+/-}14.7), female (82.4%), white (88.9 %). PPS correlated with distress, loneliness, depression, and mental health factors. PPS associated with negative psychological responses to COVID-19. Worry about mental health (OR 1.46) exceeded worry about physical health (OR 1.13). PPS not associated with adherence to social distancing guidelines but was with stress related to social distancing and worries about infection of self/others.

InterpretationMental health status (PPS) was associated with concurrent clinical ratings and COVID-specific negative responses. A focus on mental health during the pandemic is warranted, especially among those with mental health vulnerabilities. We will include PPS when conducting longitudinal analyses of mental health trajectories and risk and resilience factors that may account for differing clinical outcomes.

FundingNIMH (ZIAMH002922); NCCIH (ZIAAT000030)


title: Molecular phenotypes associated with antipsychotic drugs in the human caudate nucleus

abstract: Antipsychotic drugs are the current first-line of treatment for schizophrenia and other psychotic conditions. However, their molecular effects on the human brain are poorly studied, due to difficulty of tissue access and confounders associated with disease status. Here we examine differences in gene expression and DNA methylation associated with positive antipsychotic drug toxicology status in the human caudate nucleus. We find no genome-wide significant differences in DNA methylation, but abundant differences in gene expression. These gene expression differences are overall quite similar to gene expression differences between schizophrenia cases and controls. Interestingly, gene expression differences based on antipsychotic toxicology are different between brain regions, potentially due to affected cell type differences. We finally assess similarities with effects in a mouse model, which finds some overlapping effects but many differences as well. As a first look at the molecular effects of antipsychotics in the human brain, the lack of epigenetic effects is unexpected, possibly because long term treatment effects may be relatively stable for extended periods.


title: Examining the Association between the COVID-19 Pandemic and Self-Harm Death Counts in Four Canadian Provinces

abstract: Governments implemented lockdowns and other physical distancing measures to stop the spread of SARS-CoV-2 (COVID-19). Resulting unemployment, income loss, poverty, and social isolation, coupled with daily reports of dire news about the COVID-19 pandemic, could serve as catalysts for increased self-harm deaths (SHD). This ecological study examined whether observed SHD counts were higher than predicted SHD counts during the pandemic period in the Canadian provinces of Alberta, British Columbia, Ontario, and Quebec. The study also explored whether SHD counts during the pandemic were affected by lockdown severity (measured using the lockdown stringency index [LSI]) and COVID-19 case numbers. We utilized publicly available SHD data from January 2018 through November 2020, and employed AutoRegressive Integrated Moving Average (ARIMA) modelling, to predict SHD during the COVID-19 period (March 21 to November 28, 2020). We used Poisson and negative binomial regression to assess ecological associations between the LSI and COVID-19 case numbers, controlling for seasonality, and SHD counts during the COVID-19 period. On average, observed SHD counts were lower than predicted counts during this period (p < 0.05 [except Alberta]). Additionally, LSI and COVID-19 case numbers were not statistically significantly associated with SHD counts.


title: Effects of Side-Effect Risk Framing Strategies on COVID-19 Vaccine Intentions in the United States and the United Kingdom: A Randomized Controlled Trial

abstract: Fear over side-effects is one of the main drivers of COVID-19 vaccine hesitancy. We conducted a pre-registered randomized controlled trial among 8998 individuals to examine the effects of different ways of framing and presenting vaccine side-effects on individuals willingness to get vaccinated. We found that adding a descriptive risk label ("very low risk") next to the numerical side-effect and providing a comparison to motor vehicle mortality increased participants willingness to take the COVID-19 vaccine by 3.0 percentage points (p = 0.003) and 2.4 percentage points (p = 0.049), respectively. These effects were independent and additive and combining both framing strategies increased willingness to receive the vaccine by 6.1 percentage points (p < 0.001). Mechanistically, we find evidence that these framing effects operate by increasing individuals perceptions of how safe the vaccine is. Our results reveal that low-cost side-effect framing strategies can meaningfully affect vaccine intentions at a population level.


title: Effects of Side-Effect Risk Framing Strategies on COVID-19 Vaccine Intentions: A Randomized Controlled Trial


title: Young womens knowledge and attitudes towards cervical cancer screening at a selected higher education institution in Lesotho

abstract:
BackgroundIn Lesotho, cervical cancer is the most common female cancer and leading cause of death amongst women. In 2019, the annual number of new cancer cases was 477 and 346 women died from cancer related complications in Lesotho.

AimThe aim of this study was to assess the knowledge and attitudes of young women towards cervical cancer screening at a selected higher education institution in Lesotho.

MethodsA quantitative cross-sectional research design was used to collect data using an interviewer administered semi-structured questionnaire from 80 young women who were randomly selected. Permission to conduct the study was sought and granted from relevant authorities. Informed consent was sought from the respondents who were identified using codes and participated voluntarily.

ResultsFifty percent (n=40) of the women did not know cervical cancer screening tests, 70% (n=56) did not know about the frequency of screening, whilst 75% (n=60) knew that human papilloma virus (HPV) vaccine is be used to prevent cervical cancer. Additionally, 95% (n=76) had not screened for cervical cancer, 65% (n=52) perceived cervical cancer screening as painful, and 95% (n=76) needed more information on cervical cancer screening.

ConclusionsThe practice of cervical cancer screening is low and there is a high need for health education and incorporating regular cervical cancer screening in health care services to increase the uptake amongst young women. Many participants were hesitant to screen as they perceived the procedure to be painful and this suggests the need for reassurance and counselling on cervical cancer screening techniques.

category: sexual and reproductive health


title: Urine extracellular vesicles capture kidney transcriptome and hyperglycemia linked mRNA signatures for type 1 diabetic kidney disease

abstract: Diabetic kidney disease (DKD) is a severe complication of type 1 diabetes (T1D), which lacks non-invasive early biomarkers. Although less explored, mRNAs in urinary extracellular vesicles (uEV) could reflect changes in the kidney transcriptome during DKD development. We performed genome-wide mRNA sequencing of >100 uEV samples from two T1D cohorts with 24-hour and overnight urine collections. Our uEV pipeline allowed reproducible detection of >10,000 mRNAs bearing overall similarity to kidney transcriptome. uEV from T1D DKD groups showed significant upregulation of 13 genes, prevalently expressed by proximal tubular cells within the kidney. Strikingly, six genes involved in cellular stress responses including protection against oxidative stress (GPX3, NOX4, MSRB, MSRA, HRSP12 and CRYAB) correlated with hyperglycemia and long-term changes in kidney function independent of albuminuria status. The study identified genes associated with glycemic stress in T1D DKD and confirmed the utility of uEV in capturing pathological gene expression signatures from kidney.

category: nephrology


title: Analytical performance of a highly sensitive system to detect gene variants using next-generation sequencing for lung cancer companion diagnostics

abstract: Companion diagnostics, which predict the efficacy of molecular targeted agents based on genetic information, are indispensable for the treatment of advanced non-small cell lung carcinoma. Recent increase in the number of molecular targeted agents and the corresponding target genes have led to the demand for the simultaneous testing of multiple genes. Although gene panels using next-generation sequencing (NGS panels) are ideal for this purpose, conventional panels require high tumor content, and biopsy samples often do not meet this requirement. We developed a new NGS panel called a compact panel, to accommodate biopsy samples without the restriction of tumor content. The compact panel is characterized by high sensitivity, with detection limits for mutations of 0.14%, 0.20%, 0.48%, 0.24%, and 0.20% for EGFR exon 19 deletion, L858R, T790M, BRAF V600E, and KRAS G12C, respectively. Mutation detection also has a high quantitative ability, with correlation coefficients ranging from 0.966 to 0.992. The panel detected fusions in samples whose tumor cell content was as low as 1%. The compact panel exhibited good concordance with approved tests as follows: EGFR positive, 100.0 (95% confidence interval 95.5-100); EGFR negative, 90.9 (82.2-96.3); ALK positive, 96.7 (83.8-99.9); ALK negative, 98.4 (97.2-99.2); ROS1 positive, 100 (66.4-100); ROS1 negative, 99.0 (97.1-99.2); MET positive, 98.0 (89.0-100); MET negative 100 (92.8-100). The analytical performance demonstrated that the compact panel can handle various types of biopsy samples obtained by routine clinical practice, without requiring strict pathological monitoring like in case of conventional NGS panels.