Increased mortality in community-tested cases of SARS-CoV-2 lineage B.1.1.7 SARS-CoV-2 lineage B.1.1.7, a variant first detected in the United Kingdom in September 20201, has spread to multiple countries worldwide. Several studies have established that B.1.1.7 is more transmissible than preexisting variants, but have not identified whether it leads to any change in disease severity2. We analyse a dataset linking 2,245,263 positive SARS-CoV-2 community tests and 17,452 COVID-19 deaths in England from 1 September 2020 to 14 February 2021. For 1,146,534 (51%) of these tests, the presence or absence of B.1.1.7 can be identified because of mutations in this lineage preventing PCR amplification of the spike gene target (S gene target failure, SGTF1). Based on 4,945 deaths with known SGTF status, we estimate that the hazard of death associated with SGTF is 55% (95% CI 39-72%) higher after adjustment for age, sex, ethnicity, deprivation, care home residence, local authority of residence and test date. This corresponds to the absolute risk of death for a 55-69-year-old male increasing from 0.6% to 0.9% (95% CI 0.8-1.0%) within 28 days after a positive test in the community. Correcting for misclassification of SGTF and missingness in SGTF status, we estimate a 61% (42-82%) higher hazard of death associated with B.1.1.7. Our analysis suggests that B.1.1.7 is not only more transmissible than preexisting SARS-CoV-2 variants, but may also cause more severe illness.
A Time Series Analysis and Predictive Modeling of COVID-19 Impacts in the African American Community BackgroundSometimes in 2019, there was an outbreak of coronavirus pandemic. Data shows that the virus has infected millions of people and claimed thousands of lives. Vaccination and other non-pharmacological interventions have brought a relief; however, COVID-19 left some indelible marks. This work focuses on a time series analysis and prediction of COVID-19 fatality rates in the Black community. Decision makers will find the work useful in building a robust architecture for a resilient pandemic preparedness and responsiveness against the next pandemic. Method: Our analysis of COVID-19 cases and deaths spans March 2020 to December 2020. Assuming there was no vaccine and other factors remained the same, we hypothesized that COVID-19 disproportionality would have continued. To test our hypothesis, COVID-19 forecasting cases and deaths models were built for the total population as well as the Black population. Holt and Holt-Winters exponential smoothing forecast methodologies were used for the forecast modeling. Forecasting accuracy was based on Mean Absolute Percentage Error (MAPE). Furthermore, we designed, developed, and evaluated a fatality rate predictive model for a Black county. Considering the number of ethnic groups in the USA, a Black county was defined as any county in the USA that at least 45% of its population are Blacks. Five learning algorithms were trained and evaluated. Dataset was a merger of datasets obtained from John Hopkins COVID-19 repository, US Census Bureau and US Center for Disease Control and Prevention.

Results and ConclusionTime series analysis shows that there exists a strong evidence of COVID-19 disproportionate impacts in the states investigated. Using 9 different criteria for performance comparison, our predictive modeling showed that decision tree model has a slight edge over other models. Our experiment suggests that Blacks and senior citizens with pre-existing condition living in Georgia State are the most vulnerable to COVID-19.
Impact of COVID 19 on the quality of life (QoL) of patients living with Sickle Cell Disorder (SCD) in Lagos Nigeria The study aimed to assess the impact of the COVID-19 pandemic on Quality of Life (QoL) in persons living with Sickle Cell Disorder (SCD) in Lagos, Nigeria and to determine how they coped during the pandemic, particularly during the period of total lockdown with the additional "SHIELDING" measures to which they had to adhere. Data was collected using a standardized protocol PedsQL, Sickle Cell Disease Module version.3.0 designed for youth within the ages of (13-18) years, (19-35) years and their parents/Guardian if underage. The survey captured data on patients pain impact, hurts, management, treatments, communication with their caregivers and their Guardians perception. The survey was performed online, or Face-to-Face/telephone interview if online was not possible. Contacts of patients and parents were obtained from the database of Sickle Cell Foundation Nigeria. A total of 105 (80 patients and 25 parents) participants responded to the survey. The age distribution of respondents was highest at 56 % in the age bracket of 13 - 18 years old. Pain crisis were very common amongst patients. The survey revealed that the type of treatment or care received at these times determined whether or not the patients visited the hospital when they had pain crises. In addition, as patients reports an increase in ill-treatment they experienced in the hands of health care givers, so did the fear of accessing treatment during the COVID pandemic. It was observed that the frequency of pain crises experienced by SCD patients was proportional to the patients quality of life (the higher the frequency of pains, the worse the QoL). As a follow-up, a more detailed study would be required, as this study was limited in the capturing of the demographics, sex and number of participants; Considering the number of persons living with SCD that visit the Sickle Cell Foundation Nigeria, (about 3,000 patients), the number of responses in this study was low (105). It is believed that a higher number of responses would have given more information about the Sickle Cell burden and the QoL of persons living with SCD in Lagos during the COVID-19 pandemic. Lagos was the epicentre of the COVID-19 pandemic in Nigeria. Development of machine learning models for the prediction of complications after colonic, colorectal and small intestine anastomosis in psychiatric and non-psychiatric patient collectives (PSTUDY) Psychiatric and psychosomatic diseases are an increasingly cumbersome burden for the medical system. Indeed, hospital costs associated with mental health conditions have been constantly on the rise in recent years. Moreover, psychiatric conditions are likely to have a negative effect on the treatment of other medical conditions and surgical outcomes, in addition to their direct effects on the overall quality of life. Our study aims to investigate the impact of preoperative Risk factor, psychiatric and psychosomatic diseases on the outcomes of colorectal surgery and length of hospital stay via predictive modeling techniques.

MethodPatient data will be collected from several participating national and international surgical centers The machine learning models will be calculated and coded, but also published according to the TRIPOD guidelines (transparent reporting of a multivariable prediction model for individual prognosis or diagnosis).

ResultIt is conceivable to arrive at generalizable models predicting the abovementioned endpoints through large amounts of data from several centers. The models will be subsequently deployed as a free-to-use web-based prediction tool using the Shiny environment [47]. The cost for the hosting server and digital infrastructure will be covered by Dr. Anas Taha. The sponsor will store the data for ten years. 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. Rapid initiation of nasal saline irrigation to reduce severity in high-risk COVID+ outpatients: a randomized clinical trial compared to a national dataset observational arm ImportanceSARS-CoV-2 enters the nasopharynx to replicate; nasal irrigation soon after diagnosis could reduce viral load and inhibit furin cleavage necessary for cell entry, thereby reducing morbidity and mortality.

ObjectiveTo determine whether initiating nasal irrigation after COVID-19 diagnosis reduces hospitalizations and death in high-risk outpatients, and whether irrigant composition impacts severity.

DesignUnblinded randomized clinical trial of two nasal irrigation protocols in older outpatients PCR positive for SARS-CoV-2, with an observational arm using laboratory-confirmed cases in the CDC COVID-19 Case Surveillance dataset.

SettingSingle-lab community testing facility associated with the emergency department (ED) in Augusta, GA.

ParticipantsA consecutive sample of high-risk adults were enrolled within 24 hours of a positive COVID-19 test between September 24 and December 21 of 2020. Patients aged 55 and older were remotely consented. Among 826 screened, 321 of 694 eligible patients were unable to be reached, 294 refused participation, and 79 participants were enrolled.

InterventionsParticipants were randomly assigned adding 2.5 mL povidone-iodine 10% or 2.5 mL sodium bicarbonate to 240 mL of isotonic nasal irrigation twice daily for 14 days.

Main Outcomes and MeasuresThe primary outcome was hospitalization or death from COVID-19 within 28 days of enrollment by daily self-report confirmed with phone calls and hospital records, compared to the CDC Surveillance Dataset covering the same time. Secondary outcomes compared symptom resolution by irrigant additive.

ResultsSeventy-nine high-risk participants were enrolled (mean [SD] age, 64 [8] years; 36 [46%] women; 71% Non-Hispanic White), with mean BMI 30.3. Analyzed by intention-to-treat, by day 28, COVID-19 symptoms resulted in one ED visit and no hospitalizations in 42 irrigating with alkalinization, one hospitalization of 37 in the povidone-iodine group, (1.27%) and no deaths. Of nearly three million CDC cases, 9.47% were known to be hospitalized, with an additional 1.5% mortality in those without hospitalization data. The total risk of hospitalization or death (11%) was 8.57 times that of enrolled patients (SE=2.74; P=.006). 62 completed daily surveys (78%), averaging 1.8 irrigations/day. Eleven had irrigation complaints, and four discontinued. There were no significant differences by additive.

ConclusionSARS-CoV-2+ participants initiating nasal irrigation were over 8 times less likely to be hospitalized than the national rate.

Trial RegistrationClinicalTrial.gov Identifier: NCT04559035

Author ApprovalAll authors have filled out ICMJE and approved submission.

Conflict of Interest StatementMaterials were provided by Neilmed Inc. and Rhinosystems Inc. The study was supported by funding from the Bernard and Anne Gray Donor Advised Fund Community Foundation for Greater Atlanta, Neilmed Inc., and Rhinosystems. No authors have conflict of interest.

Key PointsO_ST_ABSQuestionC_ST_ABSAfter testing positive for COVID-19, will rapidly initiating nasal irrigation reduce the risk of morbidity and mortality compared to a national dataset?

FindingsA consecutive sample of 79 high-risk adults (mean age 64, BMI 30.3) were randomized to initiate one of two nasal irrigation protocols within 24 hours of a positive COVID-19 test. Compared to a CDC COVID-19 National Dataset observational arm, 1.27% of participants initiating twice daily nasal irrigation were hospitalized or died, compared to 11%, a significant difference.

MeaningIn high-risk outpatients testing positive for SARS-CoV-2 who initiated nasal irrigation rapidly after diagnosis, risk of hospitalization or death was eight times lower than national rates reported by the CDC. The Acute Treatment of Migraine with Low-Dose Naltrexone and 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. In Vivo Cortical Microstructure: A Proxy for Tauopathy and Cognitive impairment in the Elderly with and without MCI/Dementia Aggregation of hyperphosphorylated tau protein is currently one of the most reliable indicators of Alzheimers pathology and cognitive impairment in older adults. However, it would be useful to have a non-invasive, accessible proxy measure that does not rely on Positron Emission Tomography (PET). We used data from multi-shell diffusion-weighted imaging (DWI) to assess indices from the Neurite Orientation Dispersion and Density Imaging (NODDI) model to determine possible proxies for tau and relationship with cognitive impairment. After controlling for age, sex, and the time difference between the scan acquisitions (DWI vs. PET), we used multiple factor analysis (MFA) to assess the fit between NODDI indices (orientation dispersion [ODI], neurite density [NDI], and free-water [fISO]), cortical thickness, and tau binding (via PET). We used data from 80 participants from the ADNI-3 sample who had a multi-shell DWI and an [18F]AV-1451 (tau) PET scan. Of these 80, 49 individuals were considered cognitively normal older adults (age ~74 years), 26 individuals had a diagnosis of mild cognitive impairment (age ~75 years), and five individuals had Alzheimers dementia (age ~78 years). fISO and tau shared a large amount of spatial overlap, and both strongly correlated with the first MFA dimension. Macrostructural features (such as cortical thickness and subcortical volume) introduced in a follow-up analysis were less related to this first MFA dimension than fISO and eight percent less than tau. Subsequent mediation analyses demonstrated that fISO mediated the relationship between cortical thickness and tau, explaining all of the variance. Microstructural features derived from advanced DWI acquisitions such as fISO may be useful proxies for tau. Cortical fISO, rather than cortical thickness, may represent the impact of tau on the brain (and, by extension, cognition). Problems with Evidence Assessment in COVID-19 Health Policy Impact Evaluation (PEACHPIE): A systematic review of study design and evidence strength IntroductionAssessing the impact of COVID-19 policy is critical for informing future policies. However, there are concerns about the overall strength of COVID-19 impact evaluation studies given the circumstances for evaluation and concerns about the publication environment. This study systematically reviewed the strength of evidence in the published COVID-19 policy impact evaluation literature.

MethodsWe included studies that were primarily designed to estimate the quantitative impact of one or more implemented COVID-19 policies on direct SARS-CoV-2 and COVID-19 outcomes. After searching PubMed for peer-reviewed articles published on November 26, 2020 or earlier and screening, all studies were reviewed by three reviewers first independently and then to consensus. The review tool was based on previously developed and released review guidance for COVID-19 policy impact evaluation, assessing what impact evaluation method was used, graphical display of outcomes data, functional form for the outcomes, timing between policy and impact, concurrent changes to the outcomes, and an overall rating.

ResultsAfter 102 articles were identified as potentially meeting inclusion criteria, we identified 36 published articles that evaluated the quantitative impact of COVID-19 policies on direct COVID-19 outcomes. The majority (n=23/36) of studies in our sample examined the impact of stay-at-home requirements. Nine studies were set aside because the study design was considered inappropriate for COVID-19 policy impact evaluation (n=8 pre/post; n=1 cross-section), and 27 articles were given a full consensus assessment. 20/27 met criteria for graphical display of data, 5/27 for functional form, 19/27 for timing between policy implementation and impact, and only 3/27 for concurrent changes to the outcomes. Only 1/27 studies passed all of the above checks, and 4/27 were rated as overall appropriate. Including the 9 studies set aside, reviewers found that only four of the 36 identified published and peer-reviewed health policy impact evaluation studies passed a set of key design checks for identifying the causal impact of policies on COVID-19 outcomes.

DiscussionThe reviewed literature directly evaluating the impact of COVID-19 policies largely failed to meet key design criteria for inference of sufficient rigor to be actionable by policy-makers. This was largely driven by the circumstances under which policies were passed making it difficult to attribute changes in COVID-19 outcomes to particular policies. More reliable evidence review is needed to both identify and produce policy-actionable evidence, alongside the recognition that actionable evidence is often unlikely to be feasible. 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. Cell graph neural networks enable the digital staging of tumor microenvironment and precise prediction of patient survival in gastric cancer Gastric cancer is one of the deadliest cancers worldwide. Accurate prognosis is essential for effective clinical assessment and treatment. Spatial patterns in the tumor microenvironment (TME) are conceptually indicative of the staging and progression of gastric cancer patients. Using spatial patterns of the TME by integrating and transforming the multiplexed immunohistochemistry (mIHC) images as Cell-Graphs, we propose a novel graph neural network-based approach, termed Cell-Graph Signature or CGSignature, powered by artificial intelligence, for digital staging of TME and precise prediction of patient survival in gastric cancer. In this study, patient survival prediction is formulated as either a binary (short-term and long-term) or ternary (short-term, medium-term, and long-term) classification task. Extensive benchmarking experiments demonstrate that the CGSignature achieves outstanding model performance, with Area Under the Receiver-Operating Characteristic curve (AUROC) of 0.960{+/-}0.01, and 0.771{+/-}0.024 to 0.904{+/-}0.012 for the binary- and ternary-classification, respectively. Moreover, Kaplan-Meier survival analysis indicates that the  digital-grade cancer staging produced by CGSignature provides a remarkable capability in discriminating both binary and ternary classes with statistical significance (p-value < 0.0001), significantly outperforming the AJCC 8th edition Tumor-Node-Metastasis staging system. Using Cell-Graphs extracted from mIHC images, CGSignature improves the assessment of the link between the TME spatial patterns and patient prognosis. Our study suggests the feasibility and benefits of such artificial intelligence-powered digital staging system in diagnostic pathology and precision oncology. 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. 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. Distilling a High Precision Drug Adverse Effect Benchmark Using Wikipedia's Wisdom of the Crowd BackgroundLarge datasets of relational medical data, such as the adverse effects of drugs or vaccines, typically attain their large size, by relying on automatic, or semi-automatic, methods for generation. This often comes with a compromise on the precision of the generated data, which can be at least partially alleviated by having experts curate the data.

AimSince having experts review a large dataset can be costly and time consuming, here we suggest using Wikipedia for this task - that is, augment the automatic generation step by an automatic curation step based on the expert knowledge accumulated in Wikipedia.

MethodsTo curate a dataset of adverse drug effects (ADEs), we suggest retrieving the Wikipedia page associated with the drug, and checking whether the ADE appears in the sections describing adverse effects. Drug indications, typically described in the opening paragraph of the page, are similarly filtered out.

ResultsWe use the method to curate two large adverse drug effect datasets and show that the obtained datasets have a much higher precision relative to their originating ones.

ConclusionsAlgorithms which aim to infer drug-ADE relations, should at the very least be able to identify the "clear cut" cases. The high-precision benchmark constructed herein may therefore be a valuable resource for the evaluation of such algorithms. Using controlled interrupted time series to estimate the population-level effects of Ontario's recently implemented overdose prevention sites and consumption and treatment services BackgroundOntario recently implemented overdose prevention sites and consumption and treatment services (OPS/CTS) to stem the harms of the opioid epidemic. We tested whether operating any site improved local opioid-related health service use and mortality rates.

MethodsWe used monthly counts of all opioid-related emergency department (ED) visits, hospitalizations, and deaths between January 2014 and December 2020 for our outcomes. For each public health unit (PHU) that implemented any OPS/CTS, we created a synthetic control as a weighted combination of unexposed PHU. We estimated the population-level effects of operating any site using controlled interrupted time series with segmented regression and adjusted for time varying confounders (i.e. OPS/CTS capacity, naloxone kits distributed, and persons receiving opioid agonist treatment per 100,000 population). We repeated the analysis using a multiple baseline approach to estimate province-wide effects.

ResultsBetween 2017 and 2020, nine out of 34 PHU implemented at least one OPS/CTS. ED visit (RR=0.96, 95%CI: 0.92 - 0.99) and hospitalization (RR=0.95, 95%CI: 0.92 - 0.98) trends declined faster among treated units. Improvements in local ED visit rate trends were observed for the majority of treated units. Hospitalization rates declined faster for London (RR=0.97, 95%CI: 0.95 - 0.99) and Niagara (RR=0.95, 95%CI: 0.92 - 0.98); while mortality rates declined faster for Hamilton (RR=0.93, 95%CI: 0.90 - 0.96), Niagara (RR=0.97, 95%CI: 0.94 - 0.99) and Guelph (RR=0.94, 95%CI: 0.88 - 1.00).

ConclusionAlthough OPS/CTS are not sufficient to stem the harms of the opioid overdose epidemic on their own, they play a critical role in local harm reduction strategies. Observational study of changes in utilization and outcomes in non-invasive ventilation in COVID-19 RationaleThe role of non-invasive ventilation (NIV) in severe COVID-19 remains a matter of debate.

ObjectivesTo determine the utilization and outcome of NIV in COVID-19 in an unbiased cohort.

MethodsObservational study of confirmed COVID-19 cases of claims data of the Local Health Care Funds comparing patients with non-invasive and invasive mechanical ventilation (IMV) between spring versus autumn period 2020.

Measurements and Main ResultsNationwide cohort of 7490 cases (median/IQR age 70/60-79 years, 66% male) 3851 (51%) patients primarily received IMV without NIV, 1614 (22%) patients received NIV without subsequent intubation, and 1247 (17%) patients had NIV failure (NIV-F), defined by subsequent endotracheal intubation. The proportion of patients who received invasive MV decreased from 74% to 39% during the second period. Accordingly, the proportion of patients with NIV exclusively increased from 10% to 28%, and those failing NIV increased from 9% to 21%. Median length of hospital stay decreased from 26 to 22 days, and duration of MV decreased from 11.6 to 7.6 days. The NIV failure rate decreased from 49% to 42%. Overall mortality remained unchanged (51% versus 53%). Mortality was 39% with NIV-only, 52% with IMV and 66% with NIV-F with mortality rates steadily increasing from 58% in early NIV-F (day 1) to 75% in late NIV-F (>4 days).

ConclusionUtilization of NIV rapidly increased during the autumn period, which was associated with a reduced duration of MV, but not with overall mortality. High NIV-F rates are associated with increased mortality, particularly in late NIV-F.

FundingInstitutional support and physical resources were provided by the University Witten/Herdecke and Kliniken der Stadt Koln and the Federal Association of the Local Health Care Funds.

At a Glance CommentaryO_ST_ABSScientific Knowledge on the SubjectC_ST_ABSCurrent management of ventilatory support in COVID-19 patients with respiratory failure is heterogeneous. Despite increasing use of non-invasive ventilation (NIV), defining intubation criteria still remains a matter of uncertainty and discussion, especially with regard to the balance between the NIV benefits and the risk of NIV failure. In addition, robust data concerning the influence of the duration and failure of NIV on intubation and mortality rates are still missing, although the time span between initiation of NIV and subsequent intubation in case of respiratory failure progression is suggested to influence patient outcome.

What This Study Adds to the FieldThis is the first large observational study describing differences of ventilatory strategies between the spring and autumn period of the SARS-CoV-2 pandemic in Germany and provides the in-hospital mortality rate of 7,490 patients who received mechanical ventilation. The increased utilization of NIV from 10% (first period) to 29% (second period) was associated with overall reduced durations of mechanical ventilation and length of hospital stay, but overall mortality remained comparably high and reached 51%, 53% respectively. Patients succeeding with NIV had lower mortality rates than those getting intubated without preceding NIV attempts, but those failing NIV had higher mortality rates, respectively, and this became even more predominant in late NIV failure. The present observational study shows the increasing role of NIV in the concert of ICU medicine related to COVID-19, but also clearly addresses its risks in addition to its benefits, both impacting on mortality. Evaluating a first fully automated interview grounded in Multiple Mini Interview (MMI) methodology: results from a feasibility study ObjectivesGlobal, Covid-driven restrictions around face-to-face interviews for healthcare student selection have forced admissions staff to rapidly adopt adapted online systems before supporting evidence is available. We have developed, what we believe is, the first fully automated interview grounded in Multiple Mini-Interview (MMI) methodology. This study aimed to explore test re-test reliability, acceptability and usability of the system.

Design, setting and participantsmixed-methods feasibility study in Physician Associate (PA) programmes from two UK and one US university during 2019 - 2020.

Primary, secondary outcomesFeasibility measures (test retest reliability acceptability and usability) were assessed using intra-class correlation (ICC), descriptive statistics, thematic and content analysis.

MethodsVolunteers took (T1), then repeated (T2), the automated MMI, with a seven-day interval (+/- 2) then completed an evaluation questionnaire. Admissions staff participated in focus group discussions.

ResultsSixty-two students and seven admission staff participated; 34 students and four staff from UK and 28 students and three staff from US universities.

Good-excellent test-retest reliability was observed with T1 and T2 ICC between 0.62-0.81 (p<0.001) when assessed by individual total scores (range 80.6-119), station total scores 0.6-0.91, p<0.005, individual site (all ICC[&ge;] 0.76 p<0.001) and mean test retest across sites 0.82 p<0.001 (95% CI 0.7-0.9).

Admissions staff reported potential to reduce resource costs and bias through a more objective screening tool for pre-selection or to replace some MMI stations in a  hybrid model. Maintaining human interaction through  touch points was considered essential.

Users positively evaluated the system, stating it was intuitive with an accessible interface. Concepts chosen for dynamic probing needed to be appropriately tailored.

ConclusionThese preliminary findings suggest that the system is reliable, generating consistent scores for candidates and is acceptable to end-users provided human touchpoints are maintained. Thus, there is evidence for the potential of such an automated system to augment healthcare student selection processes. An ergonomic assessment tool for evaluating the effect of back exoskeletons on injury risk Low back disorders (LBDs) are a leading injury in the workplace. Back exoskeletons (exos) are wearable assist devices that complement traditional ergonomic controls and reduce LBD risks by alleviating musculoskeletal overexertion. However, there are currently no ergonomic assessment tools to evaluate risk for workers wearing back exos. Exo-LiFFT, an extension of the Lifting Fatigue Failure Tool, is introduced as a means to unify the etiology of LBDs with the biomechanical function of exos. We present multiple examples demonstrating how Exo-LiFFT can assess or predict the effect of exos on LBD risk without costly, time-consuming electromyography studies. For instance, using simulated and real-world material handling data we show an exo providing a 30 Nm lumbar moment is projected to reduce cumulative back damage by [~]70% and LBD risk by [~]20%. Exo-LiFFT provides a practical, efficient ergonomic assessment tool to assist safety professionals exploring back exos as part of a comprehensive occupational health program.

HIGHLIGHTSO_LIBack exos are wearable assist devices that complement ergonomic controls for reducing low back disorder (LBD) risks
C_LIO_LIHowever, no ergonomic assessment tools exist to evaluate LBD risks for workers wearing back exos
C_LIO_LIWe introduce Exo-LiFFT, an ergonomic assessment tool adapted from the Lifting Fatigue Failure Tool
C_LIO_LIExo-LiFFT is a practical tool that unifies the etiology of LBDs and biomechanical function of exos
C_LIO_LIExo-LiFFT can be used to assess or predict the effect of exos on LBD risk without EMG testing
C_LI What We Learned from COVID-19: From endotheliitis to treatment ObjectiveCOVID-19 may yield a variety of clinical pictures, differing from pneumonitis to Acute Respiratory Distress Syndrome (ARDS) along with vascular damage in the lung tissue, named as endotheliitis. To date, no specific treatment strategy was approved by any authority for the prevention or treatment of COVID-19 in terms of endotheliitis-related comorbidities. Here, we present our experience of COVID-19 by evaluating 11,190 COVID-19 patients with the manifestations of endotheliitis in skin, lung, and brain tissues according to the different phases of COVID-19.

MethodsAfter a retrospective examination, patients were divided into three groups according to their repercussions of vascular distress, which were represented by radiological, histopathological, and clinical findings. (Group A: no or mild pulmonary involvement, Group B: moderate pulmonary involvement with clinical risk of deterioration, Group C: severe pulmonary involvement and respiratory failure). We presented the characteristics and disease course of seven representative and complicated cases which represents the different phases of the disease, and discussed the treatment strategies in each group. The current pathophysiological mechanisms responsible from SARS-CoV-2 infection, COVID-19 related respiratory failure and current treatment strategies were reviewed and discussed in detail.

ResultsAmong 11.190 patients, 9294 patients met the criteria for Group A, and 1376 patients were presented to our clinics with Group B characteristics. Among these patients, 1896 individuals(Group B and Group C) were hospitalized. While 1220 inpatients were hospitalized within the first 10 days after the diagnosis, 676 of them were worsened and hospitalized 10 days after their diagnosis. Among hospitalized patients, 520 of them did not respond to group A and B treatments and developed hypoxemic respiratory failure (Group C) and 146 individuals needed ventilator support and were followed in the intensive care unit, and 43 (2.2%) patients died.

ConclusionDistinctive manifestations in each COVID-19 patient, including non-respiratory conditions in the acute phase and the emerging risk of long-lasting complications, suggest that COVID-19 has an endotheliitis-centred thrombo-inflammatory pathophysiology. Endotheliitis can also explain the mechanism behind the respiratory failure in COVID-19, and the difference of COVID-19 related ARDS from ARDS seen in other critical conditions. In addition, use of early corticosteroid in patients with early symptoms and early tocilizumab in ICU helps to reduce mortality and progression of the disease. Endotheliitis-based pathophysiological mechanisms are known to be momentarily changing and difficut to manage due to their risk of sudden aggrevation. Hence, daily evaluation of clinical, laboratory and radiological findings of patients and deciding appropriate pathophysiological treatment would help to reduce the mortality rate of COVID-19. GWAS of Retinal Vessel Tortuosity Identifies 173 Novel Loci Revealing Genes and Pathways Associated with Vascular Pathomechanics and Cardiometabolic Diseases BackgroundFundus images allow for non-invasive assessment of the retinal vasculature whose features provide important information on health. Blood vessel tortuosity is a morphological feature associated with many diseases including hypertension.

MethodsWe analyzed 116 639 fundus images of suitable quality from 63 662 participants from three cohorts, namely the UK Biobank (n = 62 751), SKIPOGH (n = 397), and OphtalmoLaus (n = 512). We used a fully automated image processing pipeline to annotate vessels and a deep learning algorithm to determine the vessel type, characterizing these subjects in terms of their median retinal vessel tortuosity specific to arteries and to veins. Tortuosity was measured by the distance factor (the length of a vessel segment over its chord length), as well as measures that integrate over vessel curvature. Using these measures as traits, we performed the largest genome-wide association study (GWAS) of vessel tortuosity to date. We assessed gene set enrichment using the novel high-precision statistical method PascalX.

ResultsHigher tortuosity was significantly associated with higher incidence of angina, myocardial infarction, stroke, deep vein thrombosis, and hypertension. We identified 175 significantly associated genetic loci in the UK Biobank; 173 of these were novel and 4 replicated in our second, much smaller, meta-cohort. We estimated heritability at [~]25% using linkage disequilibrium score regression. Vessel type specific GWAS revealed 114 loci for arteries and 63 for veins. Genes with significant association signals included COL4A2, ACTN4, LGALS4, LGALS7, LGALS7B, TNS1, MAP4K1, EIF3K, CAPN12, ECH1, and SYNPO2. These tortuosity genes were overexpressed in arteries and heart muscle and linked to pathways related to the structural properties of the vasculature. We demonstrated that tortuosity loci served pleiotropic functions as cardiometabolic disease variants and risk factors. Concordantly, Mendelian randomization revealed causal effects between tortuosity, BMI and LDL.

ConclusionsSeveral alleles associated with retinal vessel tortuosity point to a common genetic architecture of this trait with cardiovascular diseases and metabolic syndrome. Our results shed new light on the genetics of vascular diseases and their pathomechanisms and highlight how GWASs and heritability can be used to improve phenotype extraction from high-dimensional data, such as images.

Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIWe automatically estimated arterial and venous tortuosity in over 100k retinal fundus images using image analysis and deep learning.
C_LIO_LIGWAS revealed 173 novel loci.
C_LIO_LIMendelian randomization showed that increased venous tortuosity reduces BMI whereas elevated LDL levels reduce the tortuosity of both arteries and veins.
C_LIO_LIMeasuring tortuosity in terms of the distance factor, which is sensitive to total vessel elongation, had higher heritability and more associated loci than other tortuosity measures that are sensitive to local vessel bending.
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What are the clinical implications?O_LITortuosity genes were overexpressed in the aorta, tibial artery, coronary artery, and in two heart tissues.
C_LIO_LIHigher tortuosity was associated with higher incidence of angina, myocardial infarction, stroke, deep vein thrombosis and hypertension.
C_LIO_LIWe demonstrated a shared genetic architecture between retinal tortuosity and certain diseases related to the vasculature, and the associations included several cardiometabolic disease variants and risk factors. Further research is needed to investigate the potential of the retinal vessel tortuosity as a clinically relevant biomarker for cardiovascular disease and metabolic syndrome.
C_LIO_LIEnriched pathways include a well-known therapeutic target for ocular diseases (VEGFA-VEGFR2) affecting tissue remodeling. We highlight several transcription factors as interesting targets for further experimentation.
C_LI 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
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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
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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 The energy balance theory: an unsatisfactory model of body composition fluctuations Differential weight and fat losses under isocaloric diets of distinct macronutrient composition are well-documented findings in obesity research.1-6 Such data are considered a result of inadequate methodology as it disagree with the energy balance theory.7 A recent mathematical analysis of this paradigm has found, however, serious analytical contradictions in its foundations.8 As an alternative, a mass balance model was proposed to explain the aforesaid body composition alterations. Here, we expand on this observation by contrasting both models. We show that mass balance explains a wide range of fending experiments including those concurring with the energy balance principle. The latter, however, is less flexible and results in poor forecasts in settings consistent with mass balance. The energy balance theory is thus an unsatisfactory model of body composition changes. Consequently, by shifting to a mass balance paradigm of obesity a much deeper understanding of this disease may follow in the near future. Strain-resolved analysis in a randomized trial of antibiotic pretreatment and maintenance dose delivery mode with fecal microbiota transplant for ulcerative colitis Fecal microbiota transplant is a promising therapy for ulcerative colitis. Parameters maximizing effectiveness and tolerability are not yet clear, and it is not known how import the transmission of donor microbes to patients is. Here (clinicaltrails.gov: NCT03006809) we have tested the effects of antibiotic pretreatment and compared two modes of maintenance dose delivery, capsules versus enema, in a randomized, pilot, open-label, 2x2 factorial design with 22 patients analyzed with mild to moderate UC. Clinically, the treatment was well-tolerated with favorable safety profile. Of patients who received antibiotic pretreatment, 6 of 11 experienced remission after six weeks of treatment, versus 2 of 11 non-pretreated patients (odds ratio: 1.69, 95% confidence interval: -0.25 to 3.62). No significant differences were found between maintenance dosing via capsules versus enema. In exploratory analyses, microbiome turnover at both the species and strain levels was extensive and significantly more pronounced in the pretreated patients. Associations were also revealed between taxonomic turnover and changes in the composition of primary and secondary bile acids. Together these findings suggest that antibiotic pretreatment contributes to microbiome engraftment and possibly clinical effectiveness, and validate longitudinal strain tracking as a powerful way to monitor the dynamics and impact of microbiota transfer. Lower Risk of Multisystem Inflammatory Syndrome in Children (MIS-C) with the Delta and Omicron variants of SARS-CoV-2 Paediatric Inflammatory Multisystem Syndrome (PIMS-TS, also known as MIS-C) typically occurs 2-6 weeks after exposure to SARS-CoV-2. Early estimates suggested a risk of PIMS-TS of 1 in 3-4000 infected children. Whether this risk is sustained with new SARS-CoV-2 variants remains unknown.

We utilised prospective data from the NHS South Thames Paediatric Network (STPN), which manages all cases of PIMS-TS amongst 1.5 million children in South-East England, to assess trends over time. We compared PIMS-TS cases with two independent SARS-CoV-2 infection datasets. We used publicly available UK Health Security Agency case numbers weighted to child population distributions according to area population estimates from the Office for National Statistics (ONS). To avoid bias due to evolving testing behaviour, we also compared PIMS-TS cases to community infection rates, obtained from the ONS COVID-19 Infection Survey, which randomly selects individuals for fortnightly PCR tests. All three datasets were normalised to the peak of the Alpha wave, and plotted against time. PIMS-TS cases were plotted 40 days prior to hospitalisation, corresponding to the best fit of rising SARS-CoV-2 infection and PIMS-TS cases during the Alpha wave.

Compared with the Alpha wave, we found fewer cases of PIMS-TS relative to SARS-CoV-2 infections during both initial and subsequent Delta waves. This relative reduction continued into the Omicron wave.

Re-infection rates with the Alpha or Delta variants and vaccination rates were very low during the Delta wave. As a result, lower PIMS-TS rate relative to SARS-CoV-2 infections during the Delta wave is unlikely to be explained by population level immunity from prior infection or vaccination. It is most likely due to viral mutations in key antigenic epitopes responsible for triggering the hyperinflammatory response observed with PIMS-TS. Effects of Glucagon-like Peptide-1 Receptor Agonists on Cardiovascular and Renal Outcomes: A Meta-analysis and Meta-regression Analysis AimsCardiovascular and renal effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been inconsistent in cardiovascular outcome trials, and factors associated with the efficacy of GLP-1RAs remain to be clarified. Here, we evaluate the cardiovascular and renal outcomes with GLP-1RAs and associations between these outcomes and HbA1c or weight reduction.

Materials and MethodsWe searched PubMed/MEDLINE, EMBASE, and CENTRAL for randomized, placebo-controlled trials of GLP1-RAs reporting major adverse cardiovascular events (MACE; a composite of cardiovascular mortality, stroke, and myocardial infarction) as the primary outcome. We conducted a meta-regression analysis of primary and secondary outcomes with HbA1c or weight reduction following a meta-analysis with a random-effects model for these outcomes.

ResultsWe extracted data of 60,800 individuals from eight eligible studies (ELIXA, LEADER, SUSTAIN-6, EXSCEL, HARMONY, PIONEER 6, REWIND, and AMPLITUDE-O). GLP-1RAs reduced MACE (hazard ratio [HR] 0.86; 95% CI: 0.80-0.93; P < 0.001) and secondary outcomes including the composite renal outcome (0.80; 0.73-0.87; P < 0.001). In meta-regression analysis, every 1% reduction in HbA1c was associated with 26% and 35% decreases in the logarithm of HR of MACE (P = 0.044; R2 = 0.65) and the composite renal outcome (P = 0.040; R2 = 0.85), respectively. On the contrary, weight reduction was not associated with any outcome, including MACE (P = 0.390).

ConclusionsThe reduction in HbA1c, but not body weight, is associated with cardiovascular and renal outcomes. The magnitude of HbA1c reduction can be a surrogate for cardiovascular and renal benefits of treatment with GLP-1RAs.