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ObjectivesTo develop cross-validated prediction models for severe outcomes in COVID-19 using blood biomarker and demographic data; Demonstrate best practices for clinical data curation and statistical modelling decisions, with an emphasis on Bayesian methods. DesignRetrospective observational cohort study. SettingMulticentre across National Health Service (NHS) trusts in Southwest region, England, UK. ParticipantsHospitalised adult patients with a positive SARS-CoV 2 by PCR during the first wave (March - October 2020). 843 COVID-19 patients (mean age 71, 45% female, 32% died or needed ICU stay) split into training (n=590) and validation groups (n=253) along with observations on demographics, co-infections, and 30 laboratory blood biomarkers. Primary outcome measuresICU admission or death within 28-days of admission to hospital for COVID-19 or a positive PCR result if already admitted. ResultsPredictive regression models were fit to predict primary outcomes using demographic data and initial results from biomarker tests collected within 3 days of admission or testing positive if already admitted. Using all variables, a standard logistic regression yielded an internal validation median AUC of 0.7 (95% Interval [0.64,0.81]), and an external validation AUC of 0.67 [0.61, 0.71], a Bayesian logistic regression using a horseshoe prior yielded an internal validation median AUC of 0.78 [0.71, 0.85], and an external validation median AUC of 0.70 [0.68, 0.71]. Variable selection performed using Bayesian predictive projection determined a four variable model using Age, Urea, Prothrombin time and Neutrophil-Lymphocyte ratio, with a median AUC of 0.74 [0.67, 0.82], and external validation AUC of 0.70 [0.69, 0.71]. ConclusionsOur study reiterates the predictive value of previously identified biomarkers for COVID-19 severity assessment. Given the small data set, the full and reduced models have decent performance, but would require improved external validation for clinical application. The study highlights a variety of challenges present in complex medical data sets while maintaining best statistical practices with an emphasis on showcasing recent Bayesian methods.

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IntroductionSepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin-6 (IL-6). Genetic variants in IL6R known to downregulate IL-6 signalling are associated with improved COVID-19 outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RA). We hypothesised that blockade of IL6R could also improve outcomes in sepsis. MethodsWe performed a Mendelian randomisation analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis, sepsis severity, other infections, and COVID-19. We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP in a similar analysis. ResultsIn the UK Biobank cohort (N=485,825, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of sepsis (OR=0.80; 95% CI 0.66-0.96, per unit of natural log transformed CRP decrease). The size of this effect increased with severity, with larger effects on 28-day sepsis mortality (OR=0.74; 95% CI 0.38-0.70); critical care admission with sepsis (OR=0.48, 95% CI 0.30-0.78) and critical care death with sepsis (OR=0.37, 95% CI 0.14 - 0.98) Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 - 0.97) and for sepsis survival in critical care (OR=0.22; 95% CI 0.04- 1.31) in the GainS and GenOSept consortium. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR=0.69, 95% 0.57 - 0.84) in the COVID-19 HGI, which was of similar magnitude to that seen in sepsis. Sensitivity analyses did not alter our primary results. ConclusionsIL6R blockade is causally associated with reduced incidence of sepsis, sepsis related critical care admission, and sepsis related mortality. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. This data suggests a randomised trial of IL-6 receptor antagonists in sepsis should be considered.

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For human head magnetic resonance imaging at 10.5 tesla (T), we built an 8-channel transceiver dipole antenna array and evaluated the influence of coaxial feed cables. The influence of coaxial feed cables was evaluated in simulation and compared against a physically constructed array in terms of transmit magnetic field (B1+) and specific absorption rate (SAR) efficiency. A substantial drop (23.1% in simulation and 20.7% in experiment) in B1+ efficiency was observed with a tight coaxial feed cable setup. For the investigation of the feed location, the center-fed dipole antenna array was compared to two 8-channel end-fed arrays: monopole and sleeve antenna arrays. The simulation results with a phantom indicate that these arrays achieved ~24% higher SAR efficiency compared to the dipole antenna array. For a human head model, we observed 30.8% lower SAR efficiency with the 8-channel monopole antenna array compared to the phantom. Importantly, our simulation with the human model indicates that the sleeve antenna arrays can achieve 23.8% and 21% higher SAR efficiency compared to the dipole and monopole antenna arrays, respectively. Finally, we obtained high-resolution human cadaver images at 10.5 T with the 8-channel sleeve antenna array.

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OBJECTIVE: This study investigated the policies of cardiac and cardiovascular system journals concerning clinical trial registration and guideline adoption to understand how frequently journals use these mechanisms to improve transparency, trial reporting and overall study quality. METHODS: We selected the top 20 (by impact factor) journals cited in the subcategory 'Cardiac and Cardiovascular Systems' of the Expanded Science Citation Index of the 2014 Journal Citation Reports to extract journal policies concerning the 17 guidelines we identified. In addition, trial and systematic review registration adherence statements were extracted. 300 randomised controlled trials published in 2016 in the top 20 journals were searched for clinical trial registry numbers and CONSORT diagrams. RESULTS: Of the 19 cardiac and cardiovascular system journals included in our analysis, eight journals (42%) did not require or recommend trial or review registration. Seven (37%) did not recommend or require a single guideline within their instructions to authors. Consolidated Standards for Reporting Trials guidelines (10/19, 53%) were recommended or required most often. Of the trials surveyed, 122/285 (42.8%) published a CONSORT diagram in their manuscript, while 236/292 (80.8%) published a trial registry number. DISCUSSION: Cardiac and cardiovascular system journals infrequently require, recommend or enforce the use of reporting guidelines. Furthermore, too few require or enforce the use of clinical trial registration. Cardiology journal editors should consider guideline adoption due to their potential to limit bias and increase transparency.

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BACKGROUND: Little is known about how accountable care organizations (ACOs) participate with rural health providers. This pilot study examines ACO participation with rural health clinics (RHCs). METHODS: Telephone interviews with 8 ACO administrators were conducted to determine the early implementation experiences of these organizations, and their participation with rural health providers, such as RHCs, using qualitative content analysis, ACO characteristics, and emerging themes from the ACO executive responses was identified. RESULTS: Three predominant themes emerged: 1) ACOs are growing in size and number and have various organizational structures; 2) there is an expanding emphasis on preventive primary care and chronic disease management for patients; and 3) there is a need for improved information technology integration with clinical services and financial systems. CONCLUSION: Of 8 participants, 7 reported that their ACO was planning to expand into rural areas and partner with rural providers.

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