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.
C_LI

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
Best practices for multi-ancestry, meta-analytic transcriptome-wide association studies: lessons from the Global Biobank Meta-analysis Initiative SUMMARYThe Global Biobank Meta-analysis Initiative (GBMI), through its genetic and demographic diversity, provides a valuable opportunity to study population-wide and ancestry-specific genetic associations. However, with multiple ascertainment strategies and multi-ethnic study populations across biobanks, the GBMI provides a distinct set of challenges in implementing statistical genetics methods. Transcriptome-wide association studies (TWAS) are a popular tool to boost detection power for and provide biological context to genetic associations by integrating single nucleotide polymorphism to trait (SNP-trait) associations from genome-wide association studies (GWAS) with SNP-based predictive models of gene expression. TWAS presents unique challenges beyond GWAS, especially in a multi-biobank and meta-analytic setting like the GBMI. In this work, we present the GBMI TWAS pipeline, outlining practical considerations for ancestry and tissue specificity and meta-analytic strategies, as well as open challenges at every step of the framework. Our work provides a strong foundation for adding tissue-specific gene expression context to biobank-linked genetic association studies, allowing for ancestry-aware discovery to accelerate genomic medicine.
How Informative Were Early SARS-CoV-2 Treatment and Prevention Trials? A longitudinal cohort analysis of trials registered on clinicaltrials.gov BackgroundEarly in the SARS-CoV-2 pandemic, commentators warned that some COVID trials were inadequately conceived, designed and reported. Here, we retrospectively assess the prevalence of informative COVID trials launched in the first 6 months of the pandemic.

MethodsWe created a cohort of SARS-CoV-2 treatment and prevention efficacy trials that were initiated from 2020-01-01 to 2020-06-30 using ClinicalTrials.gov registration records. We evaluated trials on 3 criteria of informativeness: potential redundancy, design quality and feasibility of patient-participant recruitment. The study protocol was prospectively registered with the Open Science Framework (https://osf.io/fp726/).

ResultsWe included 500 trials in our cohort, 58% of which were Phase 2 and 84.8% were directed towards the treatment of SARS-CoV-2. Close to one third of trials met all three criteria and were deemed informative (29.0% (95% Confidence Interval 23.7 - 36.9)). The proportion of potentially redundant trials in our cohort was 4.1%. Over half of the trials in our cohort (56.2%) did not meet our criteria for high quality trial design. The proportion of trials with infeasible patient-participant recruitment was 22.6%.

ConclusionsLess than one third of COVID-19 trials registered on ClinicalTrials.gov during the first six months met all three criteria for informativeness. Shortcomings in trial design, recruitment feasibility and redundancy reflect longstanding weaknesses in the clinical research enterprise that were likely amplified by the exceptional circumstances of a pandemic. The effect of D-cycloserine on brain processing of breathlessness over pulmonary rehabilitation - an experimental medicine study BackgroundPulmonary rehabilitation is the best treatment for chronic breathlessness in COPD but there remains an unmet need to improve efficacy. Pulmonary rehabilitation has strong parallels with exposure-based cognitive behavioural therapies (CBT), both clinically and in terms of brain activity patterns. The partial NMDA-receptor agonist, D-cycloserine has shown promising results in enhancing efficacy of CBT, thus we hypothesised that it would similarly augment the effects of pulmonary rehabilitation in the brain. Positive findings would support further development in phase 3 clinical trials.

Methods72 participants with mild-to-moderate COPD were recruited to a double-blind pre-registered (ID: NCT01985750) experimental medicine study running parallel to a pulmonary rehabilitation course. Participants were randomised to 250mg D-cycloserine or placebo, administered immediately prior to the first four sessions of pulmonary rehabilitation. Primary outcome measures were differences between D-cycloserine and placebo in brain activity in the anterior insula, posterior insula, anterior cingulate cortices, amygdala and hippocampus following completion of pulmonary rehabilitation. Secondary outcomes included the same measures at an intermediate time point and voxel-wise difference across wider brain regions.

ResultsNo difference between D-cycloserine and placebo groups was observed across the primary or secondary outcome measures. Questionnaire and measures of respiratory function showed no group difference.

ConclusionsThis is the first study testing brain-active drugs in pulmonary rehabilitation. Rigorous trial methodology and validated surrogate end-points maximised statistical power. Although increasing evidence supports therapeutic modulation of NMDA pathways to treat symptoms, we conclude that a phase 3 clinical trial of D-cycloserine would not be worthwhile.

Key MessagesO_ST_ABSWhat is the key question?C_ST_ABSDoes the partial NMDA-receptor agonist, D-cycloserine, augment the effects of pulmonary rehabilitation on breathlessness related brain activity?

What is the bottom line?Rigorous trial methodology and validated surrogate end-points revealed no effect of D-cycloserine on breathlessness related brain activity across pulmonary rehabilitation.

Why read on?This study highlights both the value of functional magnetic resonance imaging in "de-risking" expensive clinical trials and provides detailed investigation of brain-targeted points for pharmacological treatments of breathlessness. A protocol for a multicentre observational study across an integrated care system to understand the effect of living with frailty on access to video consultations Risks for digital exclusion include older age, disability, and deprivation. No literature exists examining frailty as an additional possible risk factor. Many studies have shown frailty to be a more accurate predictor of adverse outcome in healthcare than age alone. Understanding risk factors for digital exclusion may help healthcare services appropriately tailor interventions. The Healthier Together integrated care system (HTICS) in Bristol is developing video consultations for clinics. The aim of this prospective observational cross-sectional study is to identify whether living with frailty is a risk factor of digital exclusion from video consultation. Data will be collected using a structured survey including patients from three sites across the Heal secondary care services at North Bristol Trust, and then two subsequent sites will be included across HTICS. Data will be collected on known risk factors for digital exclusion, frailty using the Clinical Frailty Scale, and will cover four domains for digital exclusion as defined by NHS Digital: access, skill, motivation, and confidence. Data will be presented with descriptive statistics. The association between frailty and outcomes will be analysed with a multivariable logistic regression.

Key Study Contacts

O_TBL View this table:
org.highwire.dtl.DTLVardef@134f5d7org.highwire.dtl.DTLVardef@1f8149forg.highwire.dtl.DTLVardef@11dbf0org.highwire.dtl.DTLVardef@7e854borg.highwire.dtl.DTLVardef@61272f_HPS_FORMAT_FIGEXP  M_TBL C_TBL Study Summary

O_TBL View this table:
org.highwire.dtl.DTLVardef@53a9f0org.highwire.dtl.DTLVardef@b9e76dorg.highwire.dtl.DTLVardef@108bd12org.highwire.dtl.DTLVardef@b500ddorg.highwire.dtl.DTLVardef@14be1d8_HPS_FORMAT_FIGEXP  M_TBL C_TBL Funding and Support in Kind

O_TBL View this table:
org.highwire.dtl.DTLVardef@d86811org.highwire.dtl.DTLVardef@1985973org.highwire.dtl.DTLVardef@118ca5corg.highwire.dtl.DTLVardef@8d7839org.highwire.dtl.DTLVardef@1cff6e1_HPS_FORMAT_FIGEXP  M_TBL C_TBL Role of Study Sponsor and FunderThe pilot at North Bristol Trust (NBT) is overseen by Neuromusculoskeletal (NMSK) Division governance. NBT NMSK Division takes responsibility for ensuring that the design of the study meets appropriate standards and that arrangements are in place to ensure appropriate conduct and reporting. Governance oversight for Hospital at Home was registered with NBT NMSK, and for primary care with Horfield Health Centre.

Roles and Responsibilities

Study Flow Chart

O_TBL View this table:
org.highwire.dtl.DTLVardef@594232org.highwire.dtl.DTLVardef@904b3org.highwire.dtl.DTLVardef@138af7org.highwire.dtl.DTLVardef@10898a3org.highwire.dtl.DTLVardef@15d2719_HPS_FORMAT_FIGEXP  M_TBL C_TBL Pulsed electromagnetic fields may be effective for the management of primary osteoporosis: a systematic review and meta-analysis ObjectiveTo investigate the effectiveness of pulsed electromagnetic fields (PEMFs) for the management of primary osteoporosis in older adults.

DesignSystematic review and meta-analysis.

Data SourcesMEDLINE, EMBASE, Web of Science, CENTRAL and CCTR, Physiotherapy Evidence Database, CNKI, VIP, Wan Fang, ClinicalTrials.gov and Current controlled trials from the inception dates to April 30, 2021.

Eligibility criteria for study selectionRandomised controlled trials or quasi-randomised trials examining the effects of PEMFs compared to placebo or sham or other agents for the management of primary osteoporosis (including those with previous fractures).

Data extraction and synthesisTwo independent reviewers extracted data. Primary outcomes were bone mass and number of incident fractures. Secondary outcomes were functional assessments, quality of life, and adverse events. Risk of bias was assessed with the Cochrane Collaborations tool and certainty of evidence with the grading of recommendations assessment, development and evaluation (GRADE) framework. A random effects model was used to calculate mean differences and 95% confidence intervals.

ResultsEight trials including 396 participants met the inclusion criteria. Low certainty evidence showed that PEMFs was non-inferior to conventional pharmacological agents in preventing the decline of Bone Mineral Density (BMD) at the lumbar (MD 0.01; CI -0.04 to 0.06) and femur neck (MD 0.01; CI -0.02 to 0.04), and improving balance function measured by Berg Balance Scale (BBS) (MD 0.01; CI -0.09 to 0.11) and Timed Up and Go test (MD -0.04; CI -0.80 to 0.72), directly after intervention. The similar effects were observed in BMD and BBS at 12- and 24-weeks follow-up from baseline with moderate certainty evidence. Very low certainty evidence showed that PEMFs (versus exercise) had small but significant effect on BMD at the femur neck (MD 0.10; CI 0.01 to 0.20), and no effect on BMD at the lumbar (MD 0.15; CI -0.04 to 0.35).

ConclusionPEMFs had positive effects non-inferior to first-line treatment on BMD and balance function in older adults with primary osteoporosis, but with low to very low certainty evidence and short-term follow-ups. There is a need for high-quality randomised controlled trials evaluating PEMFs for the management of primary osteoporosis.

RegistrationPROSPERO CRD42018099518. Survival and outcomes of tocilizumab use in severe and critically ill COVID-19 patients not responding to steroids BackgroundMortality and morbidity are highest in severe and critically ill patients with COVID -19 pneumonia. Recently corticosteroids have shown a definite mortality benefit in these patients. In this study we used interleukin -6 inhibitor, tocilizumab in patients who failed to show any clinical improvement after initial treatment with steroids.

Patients and methodsThis is a retrospective observational study conducted at a tertiary care referral hospital in India. Severe and critical COVID 19 patients, who got admitted to intensive care unit and subsequently received tocilizumab were included. Patients who worsened clinically or had no change in oxygen requirement even after 24hrs of receiving Intravenous methylprednisolone at a dose of 1-2mg/kg/day received a maximum total dose of 800mg of intravenous tocilizumab. The day 28 all cause mortality and progression to mechanical ventilation were the primary outcome measures. Clinical improvement and oxygen requirements after tocilizumab administration along with trends in inflammatory markers were secondary outcome. Secondary infections rates and other drug related side effects were also noted.

ResultsA total of 51 patients who did not show clinical improvement even after 24 hours of intravenous steroids and received tocilizumab were included. In these patients, there was a significant decrease in oxygen requirement by day 3 and clinical improvement by day 7 of tocilizumab administration. Among the inflammatory markers, we observed elevated median baseline values of CRP (114.2 mg/L), IL-6 (55.4 pg/ml) and Neutrophil to Lymphocyte Ratio (12.4). Out of these only CRP showed a significant decrease after the drug administration. 13 (26.5%) of the 49 patients who were on non-invasive or conventional oxygen support progressed to mechanical ventilation. The day 28 all-cause mortality rate was 10/51(19.6%). 10(19.6%) of the 51 patients had life threatening infections, 5/51 had thrombocytopenia, 3/51 had pneumo-mediastenum/pneumothorax, 1 patient had colonic perforation and 1 patient had transaminitis following tocilizumab administration.

ConclusionEarly and timely administration of tocilizumab only in selected severe and critical covid patients not responding to initial steroids appears to increase the survival. Further randomized controlled trials are required to confirm this finding. 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. Efficacy and Safety of FLOT regimen vs DCF, FOLFOX, and ECF regimens as Perioperative Chemotherapy Treatments for Resectable Gastric Cancer Patients PurposeThis study aimed to compare the efficacy and toxicity of perioperative chemotherapy regimens including ECF, DCF, FOLFOX, and FLOT to identify the most effective chemotherapy regimen with less toxicity.

MethodThis retrospective cohort study(2014-2021) was based on 152 eligible resectable gastric cancer patients who had received one of the perioperative chemotherapy regimens including ECF, DCF, FOLFOX, or FLOT, and followed for at least two years. The primary endpoint of this study was Overall Survival (OS), Progression-Free Survival (PFS), Overall Response Rate (ORR), and R0 resection. We also considered toxicity according to CTCAE (v.4.0) criteria as a secondary endpoint.

ResultsOf included patients, 32(21%), 51(33.7%), 37(24.3%), and 32(21%) had received ECF, DCF, FOLFOX and FLOT, respectively. After the median 30 months follow-up, overall survival was higher with the FLOT regimen in comparison with other regimens (hazard ratio [HR] = 0. 276). The median OS of the FLOT regimen was 39 months. Besides, the median OS was 28, 25, and 21 months for DCF, FOLOFX, and ECF regimens, respectively. Moreover, a median PFS of 24, 18, 17, and 14 months was observed for FLOT, DCF, FOLFOX, and ECF regimens, respectively (Log-rank <0.001). FLOT regimen showed 84. 4% ORR, was notably higher than other groups (p-value<0. 01).

ConclusionsFor resectable gastric cancer patients, the perioperative FLOT regimen led to a significant improvement in patients OS and PFS in comparison with ECF, DCF, and FOLFOX regimens. As such, the FLOT regimen could be considered the optimal option for managing resectable gastric cancer patients. The Ophthalmic Surgical Backlog caused by the COVID-19 Pandemic: A population-based and microsimulation modelling study BackgroundJurisdictions worldwide ramped down ophthalmic surgeries to mitigate the effects of coronavirus disease 2019 (COVID-19), creating a global surgical backlog. We sought to predict the long-term impact of COVID-19 on ophthalmology surgical care delivery.

MethodsThis is a population-based and a microsimulation modelling study. Provincial administrative data from January 2019 to May 2021 was used to estimate the backlog size and wait-times following the COVID-19 pandemic. For the post-pandemic recovery phase, we estimated the resources required to clear the backlog of patients accumulated on the waitlist during the pandemic.

ResultsA total of 56,923 patients were on the waitlist in the province of Ontario awaiting non-emergency ophthalmic surgery as of March 15, 2020. The number of non-emergency surgeries performed in the province decreased by 45-98% from March to May 2020, and 48-80% from April to May 2021 compared to the same months in 2019. By 2 years and 3 years, the overall estimated number of patients awaiting surgery grew by 129% and 150%, respectively. The estimated mean wait-time for patients for all subspecialty surgeries increased to 282 (SD 91) in March 2023 compared to 94 days (SD 97) in 2019. The provincial monthly additional resources required to clear the backlog by March 2023 was estimated to be a 34% escalation from the pre-pandemic volumes (4,626 additional surgeries).

InterpretationThe magnitude of the ophthalmic surgical backlog from COVID-19 has important implications for the recovery phase. The estimates from this microsimulation modelling can be adapted to other jurisdictions to assist with recovery planning for vision saving surgeries. Subpopulation-specific Machine Learning Prognosis for Underrepresented Patients with Double Prioritized Bias Correction Many clinical datasets are intrinsically imbalanced, dominated by overwhelming majority groups. Off-the-shelf machine learning models that optimize the prognosis of majority patient types (e.g., healthy class) may cause substantial errors on the minority prediction class (e.g., disease class) and demographic subgroups (e.g., Black or young patients). For example, our work found that missed death cases are 3.14 times higher than missed survival cases in a mortality prediction model. In the typical one-machine-learning-model-fits-all paradigm, racial and age disparities are likely to exist, but unreported. What makes it worse is the deceptive nature of widely used whole-population metrics, such as AUC-ROC. We show that some metrics fail to reflect serious prediction deficiencies. To mitigate representational biases, we design a double prioritized (DP) bias correction technique. Our method trains customized models for specific ethnicity or age groups, a substantial departure from the one-model-predicts-all convention. We report our findings on four prognosis tasks over two imbalanced clinical datasets. DP reduces relative disparities among race and age groups, 5.6% to 86.8% better than the 8 existing sampling solutions being compared, in terms of the minority class' recall. Simple risk scores to predict hospitalization or death in outpatients with COVID-19 including the Omicron variant ImportanceOutpatient physicians need guidance to support their clinical decisions regarding management of patients with COVID-19, in particular whether to hospitalize a patient and if managed as an outpatient, how closely to follow them.

ObjectiveTo develop and prospectively validate a clinical prediction rule to predict the likelihood of hospitalization for outpatients with COVID-19 that does not require laboratory testing or imaging.

DesignDerivation and temporal validation of a clinical prediction rule, and prospective validation of two externally derived clinical prediction rules.

SettingPrimary and Express care clinics in a Pennsylvania health system.

ParticipantsPatients 12 years and older presenting to outpatient clinics who had a positive polymerase chain reaction test for COVID-19.

Main outcomes and measuresClassification accuracy (percentage in each risk group hospitalized) and area under the receiver operating characteristic curve (AUC).

ResultsOverall, 7.4% of outpatients in the early derivation cohort (5843 patients presenting before 3/1/21) and 5.5% in the late validation cohort (3806 patients presenting 3/1/21 or later) were ultimately hospitalized. We developed and temporally validated three risk scores that all included age, dyspnea, and the presence of comorbidities, adding respiratory rate for the second score and oxygen saturation for the third. All had very good overall accuracy (AUC 0.77 to 0.78) and classified over half of patients in the validation cohort as very low risk with a 1.7% or lower likelihood of hospitalization. Two externally derived risk scores identified more low risk patients, but with a higher overall risk of hospitalization (2.8%).

Conclusions and relevanceSimple risk scores applicable to outpatient and telehealth settings can identify patients with very low (1.6% to 1.7%), low (5.2% to 5.9%), moderate (14.7% to 15.6%), and high risk (32.0% to 34.2%) of hospitalization. The Lehigh Outpatient COVID Hospitalization (LOCH) risk score is available online as a free app: https://ebell-projects.shinyapps.io/LehighRiskScore/. Synergetic measures to contain highly transmissible variants of SARS-CoV-2 BackgroundThe public and scientific discourse on how to mitigate the COVID-19 pandemic is often focused on the impact of individual protective measures, in particular on vaccination. In view of changing virus variants and conditions, however, it seems not clear if vaccination or any other protective measure alone may suffice to contain the transmission of SARS-CoV-2.

MethodsHere, we investigate the effectiveness and synergies of vaccination and non-pharmaceutical interventions like masking, distancing & ventilation, testing & isolation, and contact reduction as a function of compliance in the population. Our new analysis accounts for the practical compliance in the population and for both droplet transmission and aerosol transmission.

FindingsFor realistic conditions, we find that it would be difficult to contain highly contagious SARS-CoV-2 variants by any individual measure. Instead, we show how multiple synergetic measures have to be combined to reduce the effective reproduction number (Re) below unity for different basic reproduction numbers ranging from the SARS-CoV-2 ancestral strain up to measles-like values (R0 = 3 to 18). For R0 = 5 as reported for the Delta variant and [~]70% vaccination rate, the synergies of masking and distancing & ventilation with compliances around 30% appear sufficient to keep Re < 1. In combination with 2-3 tests per week, this would work also at lower vaccination rates, e.g., in schools.

InterpretationIf the Omicron variant were to reach R0 = 8, it could still be contained with the synergetic measures outlined above. In case of measles-like transmissibilities (R0 = 12 to 18), higher compliances and testing rates or additional measures like general contact reductions would be required. The presented findings and approach can be used to design and communicate efficient strategies for mitigating the COVID-19 pandemic.

FundingMax Planck Society.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSStudies on how to mitigate the COVID-19 pandemic are often focused on the impact of individual protective measures, in particular on vaccination. The effectiveness of non-pharmaceutical interventions (NPIs) like masking or distancing & ventilation are often under debate due to a lack of understanding of different transmission pathways (droplet versus aerosol transmission) and protective measures, in particular for the efficacy of masking and contrasting randomized trial results under different conditions (virus-limited vs. virus-rich) and at different levels of practical compliance. Thus, in view of more contagious variants such as Delta or Omicron, it is not clear if vaccination or any other protective measure alone may suffice to contain the transmission of SARS-CoV-2.

Added value of this studyOur analysis explicitly accounts for both droplet and aerosol transmission as well as for practical compliance in the population, which is the main reason for divergent results on the effectiveness of the same NPIs in different regions. This was not fully considered before and may have led to misunderstandings and misinformation about the actual effects of preventive measures. For realistic conditions, we find that it would be difficult to contain highly contagious SARS-CoV-2 variants by any individual measure. Instead, we show that combining multiple synergetic measures with realistic compliances can reduce Re below unity without lockdown.

Implications of all the available evidenceOur findings and the presented scientific approach can be used to design and communicate efficient strategies for mitigating the COVID-19 pandemic for specific environments like schools as well as on a population level. A novel echo-parameter supersedes the Society of Thoracic Surgeons risk score in predicting post transcatheter aortic valve replacement mortality ObjectiveTo accurately predict post-TAVR mortality, we proposed a family of new echo-parameters (augmented blood pressure) derived from blood pressure and aortic valve gradient measurements and examined them in this study.

Patients and MethodsPatients in the Mayo Clinic National Cardiovascular Diseases Registry-TAVR database who underwent TAVR between January 1, 2012, and June 30, 2017, were identified to retrieve baseline demographics, echocardiographic and mortality data. Augmented blood pressure parameters and valvulo-arterial impedance were evaluated by univariate and multivariate Cox regression. Receiver operating characteristic curve analysis was used to assess the model performance against the Society of Thoracic Surgeons (STS) risk score.

ResultsThe final cohort contained 974 patients with a mean age of 81.4{+/-}8.3 years old, and 56.6% were male. The mean STS risk score was 8.2{+/-}5.2. The median follow-up duration was 354 days, and the one-year all-cause mortality rate was 14.2%. Both univariate and multivariate Cox regression showed that augmented systolic blood pressure and augmented mean arterial pressure (AugMAP) parameters were independent predictors for 1-year post-TAVR mortality (all p<0.0001). A univariate model of AugMAP1 supersedes the STS score model in predicting 1-year post-TAVR mortality (area under curve: 0.700 vs. 0.587, p=0.0051).

ConclusionAugmented mean arterial pressure provides a simple but effective approach for clinicians to quickly estimate the clinical outcome of TAVR patients. It can be incorporated in the assessment of TAVR candidacy. Clinical impact of the rapid molecular detection of RSV and influenza A and B viruses in the emergency department IntroductionUsing respiratory viruses rapid diagnostic tests in the emergency room (ER) could allow a better and faster clinical management. Point-of-care PCR instruments provide now results in less than 30 minutes. The objective of this study was to assess the impact of the use of the cobas(R) Influenza A/B & RSV Assay for use on Roches cobas(R) Liat(R) instrument on the clinical management of ER patients.

MethodsPatients (adults and children) requiring admission or suffering from an underlying condition at risk of respiratory complication were prospectively recruited in the ER of four hospitals in the Brussels region. Physicians intentions regarding admission, isolation, antibiotic and antiviral use were collected before and after performing a cobas(R) Influenza A/B & RSV molecular test. Additionally, a comparison of the analytical performance of this test against antigen rapid tests and viral culture was performed as well as a time-to-result evaluation.

ResultsPCR yielded twice more positive results than antigen rapid diagnostic tests. It allowed a decrease in the overall need for isolation and treatment by limiting the isolation of negative patients and the antibiotic use for positive patients. Meanwhile, antiviral treatments better targeted patients with a positive influenza PCR.

ConclusionThe use of a rapid influenza and RSV molecular test improves the clinical management of patients admitted to the ER by providing a fast and reliable result. Their additional cost compared to antigen tests should be balanced with the benefit of their analytical performance, leading to efficient reductions in the need of isolation and antibiotic use. Reports of myocarditis and pericarditis following mRNA COVID-19 vaccines: A systematic review of spontaneously reported data from the UK, Europe, and the US and of the literature ObjectivesTo bring together spontaneously reported data from around the world to estimate the reporting rate in different countries and better understand the risk factors for myocarditis and pericarditis following exposure to COVID-19 mRNA vaccines.

DesignSystematic review of the literature and systematic review of spontaneously reported data from the United Kingdom (UK), United States (US), and European Union/European Economic Area (EU/EEA).

Data sourcesSpontaneously reported data for COVID-19 Vaccine Pfizer/BioNTech (Comirnaty) and COVID-19 Vaccine Moderna (Spikevax) were obtained using outputs from the UKs Yellow Card scheme (covering the period 09/12/2020 - 20/10/2021), the Vaccine Adverse Event Reporting System (VAERS; US; covering the period 23/08/2021 - 21/10/2021), and EudraVigilance (EU/EEA; covering the period 21/12/2020 - 21/10/2021). Systematic searches of PubMed and Embase literature databases were performed with a datalock point of 11 October 2021.

Eligibility criteriaAll publicly available spontaneous reporting data from the three regions of interest were included. Data on events labelled "Myocarditis" and "Pericarditis" were included. No restrictions on age or gender were applied. For the systematic literature review, all pharmacoepidemiological studies of observational design investigating myocarditis and pericarditis following mRNA COVID-19 vaccines identified by our search were included. No restrictions on language or date were applied. Pre-print manuscripts were included if no peer-reviewed version was available. Studies of non-observational design, case reports, and case series were excluded. Study quality was assessed using relevant Critical Appraisal Skills Programme (CASP) tools. All studies were considered of sufficient quality for inclusion.

Data extraction and synthesisOne researcher extracted data from spontaneous reporting systems and published pharmacoepidemiological studies. Spontaneously reported events of myocarditis and pericarditis were presented for each individual data source, and stratified by vaccine, age, sex, and dose where this information was available. Vaccination data were obtained to the same date, and reporting rates were calculated for the events of myocarditis and pericarditis for each population of interest. For published pharmacoepidemiological studies, the study design, participant characteristics, and study results were tabulated.

ResultsOverall, there were 435 reports of myocarditis and 327 reports of pericarditis reported to the UKs Yellow Card scheme up to 20 October 2021. To 21 October 2021, in the US, 1936 reports of myocarditis and 1271 reports of pericarditis had been submitted to VAERS; there had been 2924 reports of myocarditis and 1855 reports of pericarditis submitted to EudraVigilance to the same date. Most reports (73.3%) had been submitted following Comirnaty (Pfizer/BioNTech). Males represented 74.9% of reports of myocarditis and 56.9% of pericarditis overall (for US and EU/EEA populations only), and the majority of reports concerned vaccinees ages under 40 years. Reports were more frequent following the second dose of mRNA COVID-19 vaccine. Reporting rates of myocarditis and pericarditis were consistent between the data sources. Seven pharmacoepidemiological studies were included; results of these studies were largely consistent with results of our spontaneous report analyses.

ConclusionsThis study provides evidence that younger vaccinees more frequently report myocarditis and pericarditis following mRNA COVID-19 vaccines compared with older vaccinees. These events had mild clinical course followed by full recovery in most cases. Results from published literature supported the results of our analyses.

Strengths and Limitations of the StudyO_LIThis is the first study to bring together spontaneously reported data from the United Kingdom, United States, and Europe on myocarditis and pericarditis following mRNA COVID-19 vaccines.
C_LIO_LIResults from this study provide evidence on the frequency of reported events of myocarditis and pericarditis following mRNA vaccines in different age groups, and by sex and vaccine dose. Analyses of spontaneous reports were consolidated with results of published literature, identified by systematic review.
C_LIO_LIResults may have been influenced by biases including different vaccination policies in each region examined, and publicity on events of myocarditis and pericarditis following mRNA vaccines.
C_LIO_LIThe study relied on outputs from spontaneous reporting systems in which the level of detail differed between the systems examined; furthermore, it is not possible to estimate incidence rates using spontaneous reports due to the lack of data on the exposed population, and there is no unvaccinated comparison group.
C_LIO_LIThere is an urgent need for further pharmacoepidemiological studies to be conducted to provide more accurate estimates of the frequency, clinical course, long term outcome, effects of treatment and impact on quality of life, to address many of the limitations of spontaneous reporting.
C_LI The kidney releases a non-polymerizing form of Uromodulin in the urine and circulation that retains the external hydrophobic patch domain Uromodulin (Tamm-Horsfall protein, THP) is a glycoprotein uniquely produced in the kidney. It is released by cells of the thick ascending limbs (TAL) apically in the urine, and basolaterally in the renal interstitium and systemic circulation. Processing of mature urinary THP, which polymerizes into supra-molecular filaments, requires cleavage of an external hydrophobic patch (EHP) at the C terminus. However, THP in the circulation is not polymerized, and it remains unclear if non-aggregated forms of THP exist natively in the urine. We propose that an alternative processing path, which retains the EHP domain, can lead to a non-polymerizing form of THP. We generated an antibody that specifically recognizes THP with retained EHP (THP+EHP) and established its presence in the urine in a non-polymerized native state. Proteomic characterization of urinary THP+EHP revealed its C-terminus to end at F617. In the human kidney, THP+EHP was not only detected in TAL cells, but also diffusely in the renal parenchyma. Using immunoprecipitation followed by proteomic sequencing and immunoblotting, we then demonstrated that serum THP has also retained EHP. In a small cohort of patients at risk for acute kidney injury (AKI), admission urinary THP+EHP was significantly lower in patients who subsequently developed AKI during hospitalization. Our findings uncover novel insights into uromodulin biology by establishing the presence of an alternative path for cellular processing, which could explain the release of non-polymerizing THP in the circulation. Larger studies are needed to establish the utility of urinary THP+EHP as a sensitive biomarker of kidney health and susceptibility to injury. Acute-stress induced change in salience network coupling prospectively predicts post-trauma symptom-development. Substantial individual differences exist in how acute stress affects large-scale neurocognitive networks, including Salience (SN), Default Mode (DMN) and Central Executive Networks (CEN). Changes in the connectivity strength of these network upon acute stress may predict vulnerability to long-term stress effects, which can only be tested in prospective longitudinal studies. Using such longitudinal design, we investigated whether the magnitude of acute-stress induced functional connectivity changes (delta-FC) predicts the development of posttraumatic stress disorder (PTSD) symptoms in a relatively resilient group of young police students that are known to be at high risk for trauma-exposure.

Using resting-state fMRI, we measured acute-stress induced delta-FC in 190 police recruits before (baseline) and after trauma exposure during repeated emergency aid services (16-month follow-up). Delta-FC was then linked to the changes in perceived stress levels (PSS) and post-traumatic stress symptoms (PCL and CAPS).

Weakened connectivity between the SN and DMN core regions upon acute stress induction at baseline predicted longitudinal increases in perceived stress level but not of post-traumatic stress symptoms, whereas increased coupling between the overall SN and anterior cerebellum was observed in participants with higher clinician-rated PTSD symptoms, particularly intrusion levels. All effects remained significant when controlling for trauma exposure-levels and cortisol stress-reactivity. Neither hormonal nor subjective measures exerted similar predictive or acquired effects.

The reconfiguration of large-scale neural networks upon acute stress induction is relevant for assessing and detecting risk and resilience factors for PTSD. This study highlights the SN connectivity-changes as a potential marker for trauma-related symptom-development, which is sensitive even in a relatively resilient sample. The Preventive Treatment of Migraine with Low-Dose Naltrexone/Acetaminophen Combination: Findings of a Small, Randomized, Double-Blind, and Placebo-Controlled Clinical Trial with an Open-Label Extension for None-Responders We tested a low-dose naltrexone and acetaminophen combination for episodic migraine prevention. We randomly assigned patients to naltrexone and acetaminophen combination (n=6) or placebo (n=6) for a 12-week double-blind treatment. Non-responders continued into open-label treatment with naltrexone and acetaminophen combination (n=5) for additional 12 weeks. Patients were adults who experienced 5 to 17 (average 9.7) migraine days at baseline. The primary endpoint was the mean change in the monthly migraine days during the last 4 weeks of the double-blind treatment period. The key secondary endpoint was the mean change in the monthly migraine days from the 4-week double-blind follow-up (2nd baseline) to the last 4 weeks of the open-label treatment period.

The magnitude of the treatment effect for the naltrexone and acetaminophen combination observed in the double-blind period was 2.2 fewer monthly migraine days than placebo (p=0.43). Four out of 6 (66.7%) naltrexone and acetaminophen-treated patients experienced 75% reduction in migraine days compared to 1 out of 6 (16.7%) placebo-treated patients (p=0.09).

In the open-label phase, treatment with the naltrexone and acetaminophen combination (n=5) led to 8.2 fewer mean monthly migraine days (from 11.8 to 3.6), representing 69.5% improvement (p=0.03), and 100% of the patients experienced a 50% reduction in monthly migraine days. Adverse events were mild to moderate and transient, included dry mouth, fatigue, sedation, nausea, and feeling jittery.

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), in future phase 3 studies we will test a range of naltrexone and acetaminophen combination doses. 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 Survey of Contaminated Percutaneous Injuries in Anesthesia Practitioners BackgroundAnesthesia practitioners are at inherent risk for percutaneous injuries by blood-contaminated needles and sharp objects. These exposures may result in transmission of HIV and hepatitis viruses. Data about this occupational hazard from contaminated needles and sharp devices is limited and decades old. We conducted a web-based survey to assess the occurrence, reporting, characteristics, and outcome of contaminated percutaneous injuries (CPI) in anesthesia residents, fellows, and attendings.

MethodsAfter institutional research board approval, an email was sent to 217 anesthesia practitioners requesting their participation in an online survey about contaminated percutaneous injuries. Responses were collected from February through March 2020. Results are reported as absolute numbers and proportions with 95% confidence interval (CI).

ResultsThe overall survey response rate was 51% (110/217). 59% (65/110) (95% CI, 50-68) of participants reported having one or more contaminated percutaneous injury during their years of anesthesia practice (42% (21/50) of residents, 50% (4/8) of fellows, 77% (40/52) of anesthesia attendings). Prevalence of injuries related to attendings years of anesthesia practice was 69% (95% CI, 44-94) for 5-10 years, 62.5% (95% CI, 29-96) for 10-15 years, and 79% (95% CI, 63- 95) for greater than 15 years of practice.

35% (95% CI, 26-44) of participants reported having one or more CPI within the last 5 years (40% of residents, 50% of fellows, 29% of attendings). Occurrence of CPI within the last 5 years based on attending anesthesiologist years of practice was 57% for less than 5 years, 37.5% for 10-15 years, and 20% for 15-20 years of practice. 75% (95% CI, 65-85) reported the incident at the time of injury. 59% (95% CI, 48-70) of injuries were due to hollow bore needles. 50% (95% CI, 39-61) of total injuries were high risk. 26% of injured anesthesia practitioners received post-exposure prophylaxis and there were zero seroconversions.

ConclusionMost anesthesiologists will sustain a contaminated percutaneous injury during their careers. Incidence of these injuries decreases with years of practice. Occurrence of these injuries is high among anesthesia residents, with the majority reporting their injuries. Half of the injuries are high risk with a quarter requiring postexposure prophylaxis. More education and interventions are needed to reduce percutaneous injuries and improve reporting. Unexposed populations and potential COVID-19 burden in European countries as of 21st November 2021 We estimate the potential remaining COVID-19 burden in 19 European countries by estimating the proportion of each countrys population that has acquired immunity to severe disease through infection or vaccination. Our results suggest that many European countries could still face a substantial burden of hospitalisations and deaths, particularly those with lower vaccination coverage, less historical transmission, and/or older populations. Continued non-pharmaceutical interventions and efforts to achieve high vaccination coverage are required in these countries to limit severe COVID-19 outcomes. CD19+IgD+CD27- naive B Cells as predictors of humoral response to COVID 19 mRNA vaccination in immunocompromised patients Immunocompromised patients are considered high-risk and prioritized for vaccination against COVID-19. We aimed to analyze B-cell subsets in these patients to identify potential predictors of humoral vaccination response. Patients (n=120) suffering from hematologic malignancies or other causes of immunodeficiency and healthy controls (n=79) received a full vaccination series with an mRNA vaccine. B-cell subsets were analyzed prior to vaccination. Two independent anti-SARS-CoV-2 immunoassays targeting the receptor-binding domain (RBD) or trimeric S protein (TSP) were performed three to four weeks after the second vaccination. Seroconversion occurred in 100% of healthy controls, in contrast to 67% (RBD) and 82% (TSP) of immunocompromised patients, while only 32% (RBD) and 22% (TSP) achieved antibody levels comparable to those of healthy controls. The number of circulating CD19+IgD+CD27- naive B cells was strongly associated with antibody levels ({rho}=0.761, P<0.001) and the only independent predictor for achieving antibody levels comparable to healthy controls (OR 1.07 per 10-{micro}l increase, 95%CI 1.02-1.12, P=0.009). Receiver operating characteristic analysis identified a cut-off at [&ge;]61 naive B cells per {micro}l to discriminate between patients with and without an optimal antibody response. Consequently, measuring naive B cells in immunocompromised hematologic patients could be useful in predicting their humoral vaccination response. The effects of modifiable maternal pregnancy risk factors on molar-incisor hypomineralisation: A negative control study ObjectivesO_LITo explore the associations between modifiable maternal pregnancy exposures: pre-pregnancy body mass index (BMI), pregnancy smoking and alcohol consumption with offspring molar-incisor hypomineralisation (MIH).
C_LIO_LITo explore for the presence of residual confounding using negative control analyses.
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MethodsThis study used data from Avon Longitudinal Study of Parents and Children (ALSPAC), a UK prospective birth cohort. We defined offspring MIH using prospectively collected questionnaire data. We used logistic regression to explore confounder adjusted associations between maternal pre-pregnancy BMI and smoking and alcohol consumption during pregnancy with MIH. We included negative control exposure (paternal BMI, smoking and alcohol around the time of pregnancy) and outcome (offspring dental trauma) analyses to explore for the presence of residual confounding.

Results5536 mother/offspring pairs were included (297 MIH cases [5.4%]). We found a positive association between maternal mean BMI and offspring MIH (OR per 1-kg/m2 difference in maternal BMI: 1.04, 95% CI: 1.00, 1.08). In subsequent analyses, we found evidence that this effect was non-linear and being driven by women in the highest BMI quintiles. In negative control analyses, we found no evidence of association between paternal BMI and offspring MIH (OR: 0.94, 95% CI: 0.89, 1.00) and maternal BMI and offspring dental trauma (OR: 0.99, 95% CI: 0.96, 1.02). There was no clear evidence of an association for maternal pregnancy smoking (OR: 0.76, 95%CI: 0.46, 1.22) and alcohol consumption (OR: 0.79, 95% CI: 0.56, 1.21) with offspring MIH with results imprecisely estimated.

ConclusionIn summary we found evidence of a possible intrauterine effect of high maternal pre-pregnancy BMI on offspring MIH. We did not find robust evidence for an intrauterine effect of maternal pregnancy smoking or alcohol consumption on offspring MIH. Our findings provide further support for women of reproductive age to maintain a healthy weight. Future studies are warranted to explore possible mechanisms on how the pregnancy environment may relate to offspring MIH. Colorectal Cancer Disparities Across the Continuum of Cancer Care: 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. Effects of the second emergency status declaration for the COVID-19 outbreak in Japan BackgroundBefore Olympic and Paralympic Games in Tokyo, whether an audience shall be allowed or not has been a subject of concern in Japan as of early June, 2021. Object: We evaluated effects of professional baseball games with audiences as an example of the large sports events, on COVID-19 infectiousness.

MethodWe regressed the effective reproduction number R(t) on a dummy variable for professional baseball games with audiences as along with temperature, humidity, mobility, and countermeasures. We examined two study periods: those including and excluding before initiation of the games in 2020.

ResultsEstimation results indicate that the period with audiences exhibited significantly lower infectiousness than when audiences were excluded before initiation of the games with audience attendance. However, audiences were found to have a negative but insignificant effect when compared to the period before initiation of the attended games.

Discussion and ConclusionThis study found no clear evidence indicating that big sports events with audiences raise the COVID-19 infectiousness.