High-resolution portability of 245 polygenic scores when derived and applied in the same cohort The low portability of polygenic scores (PGS) across global populations is a major concern that must be addressed before PGS can be used for everyone in the clinic. Indeed, prediction accuracy has been shown to decay as a function of the genetic distance between the training and test cohorts. However, such cohorts differ not only in their genetic distance but also in their geographical distance and their data collection and assaying, conflating multiple factors. In this study, we examine the extent to which PGS are transferable between ancestries by deriving polygenic scores for 245 curated traits from the UK Biobank data and applying them in nine ancestry groups from the same cohort. By restricting both training and testing to the UK Biobank data, we reduce the risk of environmental and genotyping confounding from using different cohorts. We define the nine ancestry groups at a high-resolution, country-specific level, based on a simple, robust and effective method that we introduce here. We then apply two different predictive methods to derive polygenic scores for all 245 phenotypes, and show a systematic and dramatic reduction in portability of PGS trained in the inferred ancestral UK population and applied to the inferred ancestral Polish - Italian - Iranian - Indian - Chinese - Caribbean - Nigerian - Ashkenazi populations, respectively. These analyses, performed at a finer scale than the usual continental scale, demonstrate that prediction already drops off within European ancestries and reduces globally in proportion to PC distance, even when all individuals reside in the same country and are genotyped and phenotyped as part of the same cohort. Our study provides high-resolution and robust insights into the PGS portability problem.
Significant Sparse Polygenic Risk Scores across 813 traits in UK Biobank We present a systematic assessment of polygenic risk score (PRS) prediction across more than 1,500 traits using genetic and phenotype data in the UK Biobank. We report 813 sparse PRS models with significant (p < 2.5 x 10-5) incremental predictive performance when compared against the covariate-only model that considers age, sex, types of genotyping arrays, and the principal component loadings of genotypes. We report a significant correlation between the number of genetic variants selected in the sparse PRS model and the incremental predictive performance (Spearmans {rho} = 0.61, p = 2.2 x 10-59 for quantitative traits, {rho} = 0.21, p = 9.6 x 10-4 for binary traits). The sparse PRS model trained on European individuals showed limited transferability when evaluated on non-European individuals in the UK Biobank. We provide the PRS model weights on the Global Biobank Engine (https://biobankengine.stanford.edu/prs).

Author summaryPolygenic risk scores (PRSs), an approach to estimate genetic predisposition on disease liability by aggregating the effects across multiple genetic variants, has attracted increasing research interest. While there have been improvements in the predictive performance of PRS for some traits, the applicability of PRS models across a wide range of human traits has not been clear. Here, applying penalized regression using Batch Screening Iterative Lasso (BASIL) algorithm to more than 269,000 individuals of white British ancestry in UK Biobank, we systematically characterize PRS models across more than 1,500 traits. We report 813 traits with PRS models of statistically significant predictive performance. While the statistical significance does not necessarily directly translate into clinical relevance, we investigate the properties of the 813 significant PRS models and report a significant correlation between predictive performance and estimated SNP-based heritability. We find that the number of genetic variants selected in our sparse PRS model is significantly correlated with the incremental predictive performance in both quantitative and binary traits. Our transferability assessment of PRS models in UK Biobank revealed that the sparse PRS models trained on individuals of European ancestry had a lower predictive performance for individuals of African and Asian ancestry groups.
Thromboembolic risk in hospitalised and non-hospitalised Covid-19 patients: A self-controlled case series analysis of a nation-wide cohort ObjectiveAn unexpectedly large number of people infected with Covid-19 had experienced a thrombotic event. This study aims to assess the associations between Covid-19 infection and thromboembolism including myocardial infarction (MI), ischaemic stroke, deep-vein thrombosis (DVT), and pulmonary embolism (PE).

Patients and MethodsA self-controlled case-series study was conducted covering the whole of Scotlands general population. The study population comprised individuals with confirmed (positive test) Covid-19 and at least one thromboembolic event between March 2018 and October 2020. Their incidence rates during the risk interval (5 days before to 56 days after the positive test) and the control interval (the remaining periods) were compared intra-personally.

ResultsAcross Scotland, 1,449 individuals tested positive for Covid-19 and experienced a thromboembolic event. The risk of thromboembolism was significantly elevated over the whole risk period but highest in the 7 days following the positive test (IRR 12.01, 95% CI 9.91-14.56) in all included individuals. The association was also present in individuals not originally hospitalised for Covid-19 (IRR 4.07, 95% CI 2.83-5.85). Risk of MI, stroke, PE and DVT were all significantly higher in the week following a positive test. The risk of PE and DVT was particularly high and remained significantly elevated even 56 days following the test.

ConclusionConfirmed Covid-19 infection was associated with early elevations in risk with MI, ischaemic stroke, and substantially stronger and prolonged elevations with DVT and PE both in hospital and community settings. Clinicians should consider thromboembolism, especially PE, among people with Covid-19 in the community. Subgrouping School-Aged Children on the Autism Spectrum Based on Co-Occurring Psychiatric Symptoms BackgroundPhenotypic heterogeneity along the autism spectrum is compounded by co-occurring psychiatric conditions. Deriving subgroups of autistic individuals based on symptoms of these conditions could better our understanding of psychiatric symptom patterns existing within this population. This studys goals were to derive subgroups of school-aged autistic children based on co-occurring psychiatric symptoms while controlling for age and sex and to examine correlates of subgroup membership while controlling for the degree of ASD-related diagnostic features.

MethodLatent class models were estimated in a sample from the Simons Simplex Collection (n = 2,087) using "borderline/clinical" versus "normative" range data from five of the DSM-Oriented Scales from the CBCL/6-18 as indicator variables. We evaluated the predictive value of NVIQ < 70, atypical sleep duration, allergies/autoimmune conditions, gastrointestinal conditions, and neurological conditions on subgroup membership using multinomial logistic regression.

ResultsFour subgroups emerged: Low Psychiatric Symptoms (41.02%), Externalizing Symptoms (12.36%), Internalizing Symptoms (31.58%), and High Psychiatric Symptoms (15.05%). Key findings were that NVIQ < 70 was associated with decreased odds of belonging to the Internalizing Symptoms and High Psychiatric Symptoms subgroups over the Low Psychiatric Symptoms subgroup, while atypical sleep duration and gastrointestinal conditions were associated with increased odds of belonging to the Externalizing Symptoms and High Psychiatric Symptoms subgroups. Neurological conditions were also associated with increased odds of belonging to the Externalizing Symptoms subgroup.

ConclusionDistinct patterns of psychiatric symptoms exist within school-aged autistic children and are correlated with NVIQ < 70, atypical sleep duration, and medical conditions, providing insights for clinical practice and etiology-driven research. Relationship Between Patient Sex and Serum Tumor Necrosis Factor Antagonist Drug and Anti-Drug Antibody Concentrations in Inflammatory Bowel Disease; A Nationwide Cohort Study BackgroundAnti-drug antibodies to infliximab (ATI) and adalimumab (ATA) are associated with loss of response to tumor necrosis factor antagonist (anti-TNF) therapy in inflammatory bowel disease (IBD). We evaluated the relationship between patient sex and serum TNF antagonist drug and antibody concentrations in inflammatory bowel disease

MethodsA nationwide multicenter retrospective cohort study was conducted by evaluating patients charts from July 2018 until September 2021. The effect of patient sex on anti-drug antibodies and serum drug concentration in patients with IBD across 7 hospitals was investigated. A subgroup analysis also investigated the effect of anti-TNF combination therapy. Geometric means were calculated, and multiple linear regression was used to estimate the adjusted ratio of geometric means (RoGM) and their 95% confidence intervals (CI).

ResultsIn the total study sample (n = 1093), males receiving infliximab had higher anti-drug antibody concentrations (38.3 vs. 22.3 AU/ml; aRoGM = 1.72, 95% CI: 1.30-2.27, p-value <0.001) compared to females. Additionally, infliximab serum drug concentrations among males were lower compared to females (2.6 vs. 4.1 ug/ml; aRoGM = 0.62, 95% CI: 0.44-0.88, p-value = 0.007). In the subgroup analysis (n = 359), male compared to female patients on combination therapy with infliximab and immunomodulators had similar anti-drug antibody concentrations (30.2 vs. 21.9 AU/ml; aRoGM = 1.38, 95% CI: 0.79-2.40, p-value = 0.254). There was no difference in the anti-drug antibody and serum drug concentrations among males and females on adalimumab.

ConclusionIn patients receiving infliximab, anti-drug antibodies were higher in males than females. Consistent with this, serum drug concentrations were lower in males than females on infliximab. There was no difference in anti-drug antibody and serum drug concentrations among males and females on adalimumab. In addition, no difference in anti-drug antibodies between males and females receiving anti-TNF combination therapy was observed. A User Preference Analysis Of Commercial Breath Ketone Sensors To Inform The Development Of Portable Breath Ketone Sensors For Diabetes Management In Young People BackgroundPortable breath ketone sensors may help people with Type 1 Diabetes Mellitus (T1DM) avoid episodes of diabetic ketoacidosis; however the design features preferred by users have not been studied. We aimed to elucidate breath analysis and design preferences associated with commercial breath ketone devices among young people with T1DM aged 12-16 years and their parents in order to inform the development of a breath ketone sensor prototype for diabetes management.

Research Designs and MethodsTwo commercially available breath ketone sensors, designed for ketogenic diet monitoring, were explored over one week by ten young people with T1DM to get an insight into breath measurements. Participants interacted with the devices at least twice daily for five days, taking breath ketone, blood ketone and blood glucose measurements. Semi-structured interviews were conducted post-testing with the young participants and their caregivers to elicit preferences related to breath analysis and to inform the co-design of a diabetes breath ketone sensor prototype. To validate the results from a professional healthcare perspective, we interviewed two diabetes educators working in pediatric care about their perspective of young people using breath ketone sensors.

ResultsParticipants acknowledged the non-invasiveness of breath sensors as compared to blood testing. Affordability, reliability and accuracy were identified as prerequisites for breath ketone sensors used for diabetes management. Design features valued by young people included portability, ease of use, sustainability, readability and suitability for use in public. The time required to use breath sensors was similar to that for blood testing. The requirement to maintain a 10-second breath exhalation posed a challenge for users. Diabetes educators highlighted the ease of use of breath devices especially for young people with insufficient blood ketone testing.

ConclusionsBreath ketone sensors for diabetes management bear potential to facilitate ketone testing in young people. Our study affirms features for young people that drive usability of breath sensors among this population, and provides a model of user preference assessment.

Highlights/new findingsO_LIPortable breath ketone sensors potentially offer a non-invasive alternative to blood ketone testing in diabetes management, especially for young people with diabetes.
C_LIO_LIA user preference assessment of portable non-medical breath ketone devices among young people with Type 1 Diabetes Mellitus demonstrates the key values associated with breath ketone devices for diabetes management.
C_LIO_LIThe time to test for breath ketones was similar to that of blood ketone testing.
C_LIO_LIYoung people can and should be engaged in co-creation of medical devices that they will use.
C_LI Decoding hand and wrist movement intention from chronic stroke survivors with hemiparesis using a user-friendly, wearable EMG-based neural interface Prosthetics and orthotics have been recognized for decades as a potential means to restore hand function and independence to individuals living with impairment due to stroke. However, 75% of stroke survivors, caregivers, and health care professionals (HCP) believe current practices are insufficient, specifically calling out the upper extremity as an area where innovation is needed to develop highly usable prosthetics/orthotics for the stroke population. A promising method for controlling upper limb technologies is to infer movement intent non-invasively from surface electromyography (EMG) activity. While this approach has garnered significant attention in the literature, existing technologies are often limited to research settings and struggle to meet stated user needs. To address these limitations, we have developed the NeuroLife(R) EMG System, which consists of a wearable forearm sleeve with 150 embedded electrodes and associated hardware and software to record and decode surface EMG. Here, we demonstrate accurate decoding of 12 functional hand, wrist, and forearm movements, including multiple types of grasps from participants with varying levels of chronic impairment from stroke, with an overall accuracy of 77.1{+/-}5.6%. Importantly, we demonstrate the ability to decode a subset of 3 fundamental movements in individuals with severe hand impairment at 85.4{+/-}6.4% accuracy, highlighting the potential as a control mechanism for assistive technologies. Feedback from stroke survivors who tested the system indicates that the sleeves design meets various user needs, including being comfortable, portable, and lightweight. The sleeve is in a form factor such that it can be used at home without an expert technician and can be worn for multiple hours without discomfort. Taken together, the NeuroLife EMG System represents a platform technology to record and decode high-definition EMG for the eventual real-time control of assistive devices in a form factor designed to meet user needs. Cohort profile: Actionable Register of Geneva Out- and inpatients with SARS-CoV-2 (ARGOS) PurposeThe Actionable Register of Geneva Out- and inpatients with SARS-CoV-2 (ARGOS) is an ongoing prospective cohort created by the Geneva Directorate of Health (GDH). It consists of an operational database compiling all SARS-CoV-2 test results conducted in the Geneva area since late February 2020. This article aims at presenting this comprehensive cohort, in light of some of the varying public health measures in Geneva, Switzerland, since March 2020.

ParticipantsAs of June 1st, 2021, the database included 356868 patients, among which 65475 had at least one positive test result for SARS-CoV-2. Among all positive patients, 37.6% were contacted only once, 10.6 % had one follow-up call, 8.5% had two, and 27.7% had 3 or more follow-up calls. Participation rate among positive patients is 94%. Data collection is ongoing.

Findings to dateARGOS data illustrates the magnitude of COVID-19 pandemic in Geneva, Switzerland, and details a variety of population factors and outcomes. The content of the cohort includes demographic data, comorbidities and risk factors for poor clinical outcome, self-reported COVID-19 symptoms, environmental and socio-economic factors, prospective and retrospective contact tracing data, travel quarantine data, and deaths. The registry has already been used in several publications focusing on symptoms and long COVID, infection fatality rate, and re-infection.

Future plansThe data of this large real-world registry provides a valuable resource for various types of research, such as clinical research, epidemiological research or policy assessment as it illustrates the impact of public health policies and overall disease burden of COVID-19.

STRENGTHS AND LIMITATIONS OF THIS STUDYO_LIARGOS main strength consists of its large number of cases, representative of all diagnosed cases on a regional level with the primary aim of assessing all cases.
C_LIO_LIARGOS involves every individual who performed a SARS-CoV-2 test (PCR or antigenic) and is not limited to hospitalized patients, thus providing a valuable resource to assess the overall disease burden of COVID-19 in a geographically defined population.
C_LIO_LITo mitigate confounding effects and improve data analysis and interpretation, we present the data according to four policy periods.
C_LIO_LIThis cohort is multicentric as it includes all tests performed in Genevas hospitals (both public and private), private practices and medical centers.
C_LIO_LIDue to operational needs, symptoms and comorbidities are self-reported, which may lead to measurement error or misclassification.
C_LI Correcting the Reproduction Number for Time-Varying Tests: a Proposal and an Application to COVID-19 in France We provide a novel way to correct the effective reproduction number for the time-varying amount of tests, using the acceleration index as a simple measure of viral spread dynamics (Baunez et al., 2021). Not doing so results in the reproduction number being a biased estimate of viral acceleration and we provide a formal decomposition of the resulting bias, involving the useful notions of test and infectivity intensities. When applied to French data for the COVID-19 pandemic (May 13 - November 19, 2020), our decomposition shows that the reproduction number, when considered alone, consistently underestimates the resurgence of the pandemic since the summer of 2020, compared to the acceleration index which accounts for the time-varying volume of tests. Because the acceleration index aggregates all relevant information and captures in real time the sizable time variation featured by viral circulation, it is a more parsimonious indicator to track the dynamics of an infectious disease outbreak in real time, compared to the equivalent alternative which would be to complement the reproduction number with the test and infectivity intensities. Macular vascular complexity analysis of diabetes mellitus by swept-source optical coherence tomographic angiography PurposeTo evaluate the associations of retinal vascular complexity features, including fractal dimension (FD) and blood vessel tortuosity (BVT), with the severity of diabetic retinopathy (DR) by using noninvasive optical coherence tomographic angiography (OCTA).

MethodsThis prospective cross-sectional study recruited ocular-treatment-naive patients with type 2 diabetes mellitus (DM) registered in the community of Guangzhou, China. OCTA was used to obtain the measurements of FD and BVT in the superficial capillary plexus (SCP) and the deep capillary plexus (DCP). Univariate and multivariate linear regression was used to analyse the correlation of FD and BVT in different layers with DR severity.

ResultsA total of 1282 patients with DM (1282 eyes), with a mean age of 64.2{+/-}7.8 years, were included. FD in the DCP decreased and BVT in the DCP increased in DR patients compared to non-DR patients, even after adjusting for confounding factors (P< 0.05). Trend analysis showed a significant decrease in the FD values as the DR progressed, while the BVT progressively increased with worsening DR severity (P< 0.01). The FD in DCP had a statistically significant positive correlation with FD in SCP and a negative correlation with BVT in SCP and BVT in DCP in all of the participants, including the non-DR group, moderate DR group and severe DR group (P< 0.01).

ConclusionFD and BVT determined using OCTA might be useful parameters for objectively distinguishing DR from non-DR and indicating DR progression. Factors affecting first return to work following arthroscopic rotator cuff repair: A retrospective observational study in an occupational medicine clinic and single-surgeon practice BackgroundReturn to work (RTW) following arthroscopic rotator cuff repair (aRCR) within New South Wales (NSW), Australia, under compensable schemes has not been reported.

AimsDetermine factors affecting RTW status and time in patients treated with aRCR under state-based compensation schemes, compared to those outside such schemes.

MethodsPatients undergoing aRCR by one surgeon with minimum 1-year follow-up were grouped into those under (CP) or outside (non-CP) workers or vehicle accident compensation schemes, matched by age and gender. RTW status and time were assessed using chi-square analysis and multivariable linear regression.

ResultsOf 1054 available patients, 90 CP patients were identified with 29 consented and matched to non-CP (N=29). A higher proportion of CP patients (17.2 vs 0%, P<0.001) never returned to work and a lower proportion resumed pre-injury duties at first RTW (3 vs 52%, P<0.01). Median time to first RTW did not differ between CP and non-CP groups (5.1 vs 4.4, P=0.86). Smoking (P=0.007) and post-injury activity level (P=0.004) were significantly associated with longer time to first RTW, whereas compensation status was not.

ConclusionsCP patients undergoing aRCR in NSW are at risk of not returning to work. For those that return, there is no significant difference compared to non-CP in time to first RTW. Particularly, patient and management factors associated with extended time to first RTW have been identified. Interventions aimed at modifiable factors such as smoking cessation and increasing preoperative activity may improve future outcomes.

What is already known about this subjectO_LIWork-related injury and disease present a significant financial burden to the Australian economy ($AUD61.8billion per annum), with shoulder conditions due to body stressing accounting for 7% of this total cost (>$AUD4.2billion)
C_LIO_LIPatients receiving compensation appear to have poorer outcomes and take longer to return to work than their non-compensated counterparts, but the degree to which this occurs is variably reported in the literature
C_LIO_LIThe effect of modifiable factors on return to work status and time remain unclear, and have not previously been reported for the Australian population under the New South Wales workers compensation scheme
C_LI

What this study addsO_LIPatients receiving arthroscopic rotator cuff repair under a compensable scheme in New South Wales are at increased risk of not returning to work compared to patients presenting outside of a compensable scheme and patients in equivalent schemes internationally
C_LIO_LIPatients reporting a longer duration of symptoms and smokers are at increased risk of extended time to first return to work
C_LI

What impact this may have on practice or policyO_LIThe study has identified smoking and pre-surgery activity levels as key targets for intervention in patients receiving arthroscopic rotator cuff repair under a workers compensation scheme in New South Wales
C_LIO_LIBy further investigating whether interventions designed to modify these factors are able to favourably affect patient outcomes, there is potential to return patients to their preoperative level of work sooner
C_LI Uncovering the gastrointestinal passage, intestinal epithelial cellular uptake and Ago2 loading of milk miRNAs in neonates using xenobiotic tracers BackgroundExclusive breastfeeding is the best source of nutrition for most infants, but it is not always possible. Enteral nutrition influences intestinal gene regulation and the susceptibility for inflammatory bowel disorders, such as necrotizing enterocolitis (NEC). In modern neonatology it is observed that lactase activity increases during intestinal maturation, but formula-fed infants exhibit lower activity levels than milk-fed infants.

ObjectiveWe interrogate the transmissibility of milk miRNAs, since human breast milk has a high miRNA content in comparison to other body fluids. Our data contribute to the controversial discussion whether milk miRNAs could influence gene regulation in term and preterm neonates and thus might vertically transmit developmental relevant signals.

DesignFollowing their cross-species profiling via miRNA deep-sequencing we utilized dietary xenobiotic taxon-specific milk miRNA as tracers in human and porcine neonates, followed by functional studies in primary human fetal intestinal epithelial cells (HIEC-6) using Ad5-mediated miRNA-gene transfer.

ResultsWe show that mammals have in common many milk miRNAs yet exhibit taxon-specific miRNA fingerprints. We traced intact bovine-specific miRNAs from formula-nutrition in human preterm stool and 9 days after the onset of enteral feeding in intestinal cells of preterm piglets. Few hours after introducing enteral feeding in preterm piglets with supplemented reporter miRNAs (cel-miR-39-5p/-3p), we observed enrichment of the xenobiotic cel-miR in blood serum and in Ago2-immunocomplexes from intestinal biopsies. In contrast, we did not observe xenobiotic miRNAs in neonatal porcine cerebrospinal fluid.

ConclusionsTaken together, our data point to a transmissibility of milk miRNA signals, which could be relevant at least for intestinal maturation. Ad5-based miRNA-gene transfer into HIEC-6 revealed putative milk miRNA targets on the protein and transcriptome levels. Results suggest that milk miRNAs could influence gene expression in intestinal epithelia of neonates under special conditions.

Graphical abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/21262525v4_ufig1.gif" ALT="Figure 1">
View larger version (80K):
org.highwire.dtl.DTLVardef@8e0435org.highwire.dtl.DTLVardef@1b6747corg.highwire.dtl.DTLVardef@1998821org.highwire.dtl.DTLVardef@b84a04_HPS_FORMAT_FIGEXP  M_FIG C_FIG It is already known that exclusive breastfeeding is the best source of nutrition for neonates.Human breast milk has a high miRNA content in comparison to other body fluids. It is controversially discussed whether they could influence gene regulation in term and preterm neonates and thus might vertically transmit developmental relevant signals. Here, we contribute important new findings: Mammals have in common a significant number of milk miRNAs yet exhibit taxon-specific fingerprints. These differences allowed us to exploit xenobiotic miRNAs as tracers in human preterm neonates, who routinely received formula-supplemented nutrition in addition to breast milk. Tracer miRNAs survived the gastrointestinal (GI) transit in human preterm neonates. In a preterm piglet model the reporter miRNA did not only survive GI transit, but accumulated in the bloodstream few hours post-feeding. Moreover, we show that, cel-mir-39-5p and cel-miR-39-3p became loaded to Ago2 in intestinal tissue samples, which is prerequisite for milk microRNAs biological relevance. Adenovirus type 5-based miRNA-gene transfer into HIEC-6 allowed us to examine predicted bovine milk miRNA targets on the protein and transcriptome levels. A Randomised Trial of a Wearable UV dosimeter for Skin Cancer Prevention BackgroundNon-melanoma skin cancer (NMSC) is the most prevalent cancer in the United States, affecting 5 million people and costing $8.1 billion per year. Despite well-defined guidelines on ultraviolet radiation (UVR) avoidance, it remains difficult for people to assess their individual exposure, as UVR is invisible and the onset of symptoms due to UVR damage are delayed.

MethodsIn a prospective, randomized-controlled trial, 97 patients with a history of actinic keratoses were enrolled from March 2018 to July 2018 and followed over 6 months. 50 patients were given a wearable device that measured UV exposure and a smartphone application that provided both real-time and cumulative UV exposure information, and 47 patients were provided with UV protection counseling by a dermatologist.

ResultsWe observed a significant decrease in the incidence rate of NMSC in the intervention group compared to the control group over 3 months (p = 0.02). We did not observe a significant decrease in the incidence rate of actinic keratoses (AK) in the intervention group compared to the control group. The observed clinical benefit was not accompanied by psychological side effects such as anxiety and depression.

ConclusionsThis study suggests that providing real-time UV exposure data using a wearable UV dosimeter is a safe and effective behavioral change strategy to prevent NMSC. (Funded by the National Cancer Institute, contract HHSN261201700005C; ClinicalTrials.gov number NCT03315286.) The Addiction Risk Factor: A Unitary Genetic Vulnerability Characterizes Substance Use Disorders and Their Associations with Common Correlates Substance use disorders commonly co-occur with one another and with other psychiatric disorders. They share common features including high impulsivity, negative affect, and lower executive function. We tested whether a common genetic factor undergirds liability to problematic alcohol use (PAU), problematic tobacco use (PTU), cannabis use disorder (CUD), and opioid use disorder (OUD) by applying genomic structural equation modelling to genome-wide association study summary statistics for individuals of European ancestry (Total N = 1,019,521; substance specific Ns range: 82,707-435,563), while adjusting for the genetics of substance use (Ns = 184,765-632,802). We also tested whether shared liability across SUDs is associated with behavioral constructs (risk taking, executive function, neuroticism; Ns = 328,339-427,037) and non-substance use psychopathology (psychotic, compulsive, and early neurodevelopmental disorders). Shared genetic liability to PAU, PTU, CUD, and OUD was characterized by a unidimensional addiction risk factor (termed The Addiction-Risk-Factor, independent of substance use. OUD and CUD demonstrated the largest loadings, while problematic tobacco use showed the lowest loading. The Addiction-Risk-Factor was associated with risk taking, neuroticism, executive function, and non-substance psychopathology, but retained specific variance before and after accounting for genetics of substance use. Thus, a common genetic factor partly explains susceptibility for alcohol, tobacco, cannabis, and opioid use disorder. The Addiction-Risk-Factor has a unique genetic architecture that is not shared with normative substance use or non-substance psychopathology, suggesting that addiction is not the linear combination of substance use and psychopathology. Structural disconnectome mapping of cognitive function in post-stroke patients Sequalae following stroke represents a significant challenge in current rehabilitation. The location and size of focal lesions are only moderately predictive of the diverse cognitive outcome after stroke. One explanation building on recent work on brain networks proposes that the cognitive consequences of focal lesions are caused by damages to anatomically distributed brain networks supporting cognition rather than specific lesion locations. To investigate the association between post-stroke structural disconnectivity and cognitive performance, we estimated individual level whole-brain disconnectivity probability maps based on lesion maps from 102 stroke patients using normative data from healthy controls. Cognitive performance was assessed in the whole sample using Montreal Cognitive Assessment, and a more comprehensive computerized test protocol was performed on a subset (n=82). Multivariate analysis using Partial Least Squares on the disconnectome maps revealed that higher disconnectivity in right insular and frontal operculum, superior temporal gyrus and putamen was associated with poorer MoCA performance, indicating that lesions in regions connected with these brain regions are more likely to cause cognitive impairment. Furthermore, our results indicated that disconnectivity within these clusters was associated with poorer performance across multiple cognitive domains. These findings demonstrate that the extent and distribution of structural disconnectivity following stroke are sensitive to cognitive deficits and may provide important clinical information predicting post stroke cognitive sequalae. Colorectal Cancer Disparities Across the Continuum of Cancer Care with a Focus on Surgery and Black Patients: A Systematic Review and Meta-Analysis ImportanceDespite increases in screening among vulnerable populations, colorectal cancer disparities persist.

ObjectiveTo direct future efforts towards high impact opportunities in addressing these disparities, we performed a systematic review and meta-analysis of the colorectal cancer disparities literature with a focus on the utilization of Surgery, the primary treatment for colorectal cancer.

Data SourcesTwo electronic databases (PubMed and SCOPUS) were searched for prospective and retrospective studies reporting on colorectal cancer disparities between 2011 and March 29, 2021.

Study SelectionStudies for the systematic review were selected if: (1) reported on disparities within colorectal, colon, or rectal cancer (2) articles were published in the English language (3) articles used only United States-sourced data.

Studies for the meta-analysis were selected if: (1) reported on at least one of three utilization of surgery outcomes: receipt of colorectal, colon, or rectal surgery, refusal of surgery, or receipt of laparoscopic versus open surgery (2) Outcomes were reported as Odds ratio according to multivariate analysis.

Data Extraction and SynthesisQuality appraisal and data extraction were performed independently by 2 reviewers using the Newcastle-Ottawa Scale for quality assessment. For the meta-analysis, pooled multivariate odds ratios for the three outcomes regarding utilization of surgery were separately calculated according to fixed or random-effects models. Reporting followed the Preferred Reporting Items for Systematic Review and Meta-analyses guidelines.

Main Outcomes and MeasuresSystematic Review: The volume of publications attributed to the following sectors of the colorectal cancer care continuum: (1) Prevention, Screening, or Diagnosis (2) Treatment (3) Survivorship (4) End-of-life Care. Meta-analysis: Receipt of Colorectal, Colon, or Rectal Surgery and Black Race, Refusal of Surgery and Black Race, or Receipt of Laparoscopic versus Open Surgery and Black Race.

ResultsThe systematic review included 1,199 relevant publications. Among them, 60% were focused on Prevention, Screening, or Diagnosis, followed by Survivorship (20%), Treatment (15%), and End-of-Life Care (1%). Within the studies reporting on treatment disparities, 46% were focused on Race/Ethnicity, followed by Socioeconomic Status (28%), Age (17%), Gender (6%), Disabilities/Comorbidities (3%), and LGBTQI+ (0%). A total of 16 studies, including 1,110,674 patients, were applied to three separate meta-analyses regarding utilization of Surgery. Patients of black race were less likely to receive colorectal, or colon, or rectal surgery (OR 0.75, 95% CI 0.67-0.83), less likely to receive laparoscopic versus open colorectal cancer surgery (OR 0.91, 95% CI 0.88-0.94), and twice as likely to refuse colon surgery (OR 2.41, 95% CI 1.91-3.06).

Conclusions and RelevanceThe majority of research, to date, related to colorectal cancer disparities is focused on prevention, screening, or diagnosis and a minimal amount is dedicated to treatment. Additionally, all of the limited publications related to colorectal cancer surgery, as a treatment modality, are observational in nature. The application of this knowledge of past efforts and current continuing adverse outcomes is required in order to shift the focus of the research community towards treatment. In particular, research addressing surgical disparities is necessary, as surgery remains the primary treatment for colorectal cancer. Prospectively validated disease-agnostic predictive medicine with augmented intelligence Despite numerous superhuman achievements in complex challenges1,2, standalone AI does not free life science from the long-term bottleneck of linearly extracting new knowledge from exponentially growing new data3, severely limiting the success rate of drug discovery4. Inspired by the state-of-the-art AI training methods, we trained a human-centric hybrid augmented intelligence5 (HAI) to learn a foundation model6 that extracts all-encompassing knowledge of human physiology and diseases. To evaluate the quality of HAIs extracted knowledge, we designed the public, prospective prediction of pivotal ongoing clinical trial outcomes at large scale (PROTOCOLS) challenge to benchmark HAIs real-world performance of predicting drug clinical efficacy without access to human data. HAI achieved a 10.5-fold improvement from the baseline with 99% confidence7 in the PROTOCOLS validation, readily increasing the average clinical success rate of investigational new drugs from 7.9%8 to 90% for almost any human diseases9,10. The validated HAI confirms that exponentially extracted knowledge alone is sufficient for accurately predicting drug clinical efficacy, effecting a total reversal of Erooms law4. HAI is also the worlds first clinically validated model of human aging that could substantially speed up the discovery of preventive medicine for all age-related diseases11. Our results demonstrate that disruptive breakthroughs necessitate the smallest team size to attain the largest HAI for optimal knowledge extraction from high-dimensional low-quality data space, thus establishing the first prospective proof of the previous discovery that small teams disrupt12. The global adoption of training HAI provides a well-beaten economic path to mass-produce scientific and technological breakthroughs via exponential knowledge extraction and better designs of data labels for training better-performing AI13. The Acute Treatment of Migraine with Low-Dose Naltrexone/Acetaminophen Combinations and Each Component: Findings of a Small, Randomized, Double-Blind, and Placebo-Controlled Clinical Trial We tested two low-dose naltrexone and acetaminophen combinations and each component in the acute treatment of migraine. The patients use a single-dose of the study medication for a moderate or severe pain intensity migraine attack. Patients were adults with migraine with or without aura experiencing 2 to 20 (average 6.4) monthly migraine days. The co-primary endpoints were pain-freedom and absence of prospectively-identified most bothersome migraine-associated symptom 2 hours after dosing. We randomized 92 patients; 72 completed the study (mean age, 43 years; 75% women). Pain-freedom at 2 hours was 10.2% higher than placebo with naltrexone 2.25 mg/acetaminophen 325 mg, 10.9% with naltrexone 3.25 mg/acetaminophen 325 mg, 17.3% with naltrexone 2.25 mg, and 31.3% with acetaminophen 325 mg. The treatment groups migraine burden at baseline was unbalanced due to randomized patients uneven study completion. The acetaminophen group had the lowest migraine burden, giving its results lower credibility.

Saliently, Low-dose naltrexone alone (n=19) had a 17.3% higher response rate for headache pain-freedom at 2 hours than placebo (n=17). The naltrexone and the placebo groups were the largest and had a balanced disease burden, implying higher credibility to the naltrexone group results. We found low-dose naltrexone and acetaminophen combination, low-dose naltrexone, and acetaminophen had higher response rates than placebo in treating headache pain. The most commonly reported adverse events were sedation, nausea, and dizziness. We postulate that naltrexones toll-like receptor (TLR4) antagonism properties prevent pro-inflammatory cytokines production in the trigeminal ganglion averting "overactive nerves" (laymans term) and migraine. Although this trial used low-dose naltrexone (defined as 1 - 5 mg/day), future phase 3 studies will test a range of naltrexone and acetaminophen combination doses. Statistical modeling for quality risk assessment of clinical trials: follow-up at the era of remote auditing BackgroundAs investigator site audits have largely been conducted remotely during the COVID-19 pandemic, remote quality monitoring has gained some momentum. To further facilitate the conduct of remote Quality Assurance (QA) activities for clinical trials, we developed new quality indicators, building on a previously published statistical modeling methodology.

MethodsWe modeled the risk of having an audit or inspection finding using historical audits and inspections data from 2011 - 2019. We used logistic regression to model finding risk for 4 clinical impact factor (CIF) categories: Safety Reporting, Data Integrity, Consent and Protecting Endpoints.

ResultsWe could identify 15 interpretable factors influencing audit finding risk of 4 out of 5 CIF categories. They can be used to realistically predict differences in risk between 25 and 43% for different sites which suffice to rank sites by audit and inspection finding risk.

ConclusionContinuous surveillance of the identified risk factors and resulting risk estimates could be used to complement remote QA strategies for clinical trials and help to manage audit targets and audit focus also in post-pandemic times. A Cross-Sectional Examination of Conflict-of-Interest Disclosures of Physician-Authors Publishing in High-Impact US Medical Journals ObjectiveTo assess the accuracy of self-reported financial conflict-of-interest (COI) disclosures in the New England Journal of Medicine (NEJM) and Journal of the American Medical Association (JAMA) within the requisite disclosure period prior to article submission.

DesignCross-sectional investigation.

Data SourcesOriginal clinical-trial research articles published in NEJM (n = 206) or JAMA (n = 188) from January 1 to December 31, 2017; self-reported COI disclosure forms submitted to NEJM or JAMA with the authors published articles; Open Payments website (from database inception; latest search: August 2019).

Main outcome measuresFinancial data reported to Open Payments from 2014 to 2016 (time period that included all subjects requisite disclosure windows) were compared to self-reported disclosure forms submitted to the journals. Payments were defined as those not associated with a research study or formal research funding. Payment types were categorized as "disclosed," "undisclosed," "indeterminate," or "unrelated."

ResultsThirty-one articles from NEJM and 31 articles from JAMA met inclusion criteria. The physician-authors (n = 118) received a combined total of $7.48 million. Of the 106 authors (89.8%) who received payments, 86 (81.1%) received undisclosed payments. The top 23 most highly compensated received $6.32 million, of which $3.00 million (47.6%) was undisclosed. Disclosure rates were the equivalent between the top 23 and the entire sample.

ConclusionsHigh payment amounts, as well as high proportions of undisclosed financial compensation, regardless of amount received, comprised potential COIs for two influential US medical journals. Further research is needed to explain why such high proportions of general payments were undisclosed and whether journals that rely on self-reported COI disclosure need to reconsider their policies. Deceased donor kidney degradomics indicates cytoskeletal proteolytic alterations impacting post-transplant function. BackgroundIn brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys that adversely impacts the quality of grafts. Here, we hypothesized that DBD kidneys may undergo proteolytic processes that renders grafts susceptible to post-transplant dysfunction.

Material & MethodsUsing mass spectrometry and immunoblotting analyses, we profiled degradation patterns of cytoskeletal proteins in deceased (n=55) and living (n=10) donor kidneys.

ResultsWe found that in DBD kidneys, key podocyte cytoskeletal proteins had been proteolytically cleaved. Generated degradation profiles were not associated to donor related demographic and clinical factors but were associated to suboptimal post-transplant function. Strikingly, -actinin -4 and Talin-1 degradation profiles were not observed in circulatory-death or living-donor kidneys. As Talin-1 is a specific proteolytic target of Calpain-1, we investigated a potential trigger of Calpain activation and Talin-1 degradation using ex-vivo precision-cut human kidney slices and in-vitro immortalised human podocytes. Notably, we found that Transforming-Growth Factor-{beta} (TGF-{beta}) activated Calpain-1 and proteolytically cleaved Talin-1 to generate distinct peptide fragments. These peptide fragments were of similar size and matched the degradation patterns observed in DBD kidneys. Talin-1 degradation was prevented in vitro by Calpain-1 inhibition.

ConclusionsHere, we provide initial evidence that DBD kidneys are susceptible to cytoskeletal protein degradation that impacts posttransplant kidney function. Subsequent studies should aim to further investigate the link between brain death and activation of proteolytic pathways exploring new therapeutic opportunities. Molecular analysis suggests oligoclonality and metastasis of endometriosis lesions across anatomically defined subtypes. Endometriosis symptoms are heterogeneous with controversy on whether it constitutes a single disease or multiple distinct types. Our previous work found recurrent somatic cancer-driver alterations in endometriosis; however, these have not been found ubiquitously. A handful of cases spread across studies also suggest mutations might be shared (clonal) between lesions of the same type. As current classification systems correlate poorly with symptoms or outcomes, somatic genomics may improve the current system. Here, we investigate heterogeneity of somatic cancer-driver mutations within patients and across endometriosis types. We examined anatomically distinct types of endometriosis (ovarian, deep infiltrating, and superficial endometriosis) in 27 individual patients all of whom had at least two types of endometriosis. Specimens were analyzed using high-sensitivity targeted sequencing with orthogonal validation from droplet digital PCR and mutation-surrogate immunohistochemistry. Results found 13/27 patients had informative somatic driver mutation in endometriosis, 9/13 had identical mutations across distinct lesions. Endometriomas tended to have a higher mutational complexity, with functionally redundant driver mutations in same gene and within the same lesions.

Our data are consistent with clonality across endometriosis lesions regardless of subtype. Further the finding of redundancy in mutations with the same gene and lesions is also consistent with endometriosis representing an oligoclonal disease with dissemination likely to consist of multiple epithelial clones travelling together. This suggests the current anatomically defined classification of endometriosis does not fully recognize the etiology of the disease. A novel classification should take into account genomic and other molecular features. These findings could further contribute to development of a more personalized endometriosis diagnosis and care. Substance Use Onset in High-Risk 9-13 Year-Olds in the ABCD Study AimA key aim of the Adolescent Brain Cognitive DevelopmentSM (ABCD) Study is to document substance use onset, patterns, and sequelae across adolescent development. However, substance use misreporting obscures accurate drug use characterization. Hair toxicology tests provide objective historical substance use data, but are rarely investigated in youth. Here, we compare objective hair toxicology results with self-reported substance use in youth.

MethodsA literature-based substance use risk algorithm identified 696 ABCD Study(R) participants for hair sample collections between baseline and 2-year follow-up (spanning ages 9-13) for laboratory analysis. Chi-square and t-tests assessed differences between participants demographics, positive and negative hair tests, risk algorithm scores, and self-reported substance use.

ResultsHair testing confirmed that 17% of at-risk 9-13 year-olds had evidence of past 3-month use of one (n=99), two (n=17), three (n=3), or four (n=2) drug classes. After considering prescribed medication use, 11% had a positive test incongruent with self- or parent-report. No participant with a positive result self-reported substance use consistent with their toxicology results. Participants with positive tests under-reported use (p<.001), reported less sipping of alcohol (p<.001), and scored higher on the risk algorithm (p<.001) than those with negative hair toxicology.

ConclusionsAn alarming 11% of tested samples in at-risk 9-13 year-olds were positive for at least one unreported substance, suggesting underreporting in this population when participating in a national healthy development study. The degree of underreporting cannot yet be calculated, as at-risk samples were prioritized for assays. Expanded toxicology testing is key to characterize substance use in youth.