Cas13d Is a Compact RNA-Targeting Type VI CRISPR Effector Positively Modulated by a WYL-Domain-Containing Accessory Protein.

Bacterial class 2 CRISPR-Cas systems utilize a single RNA-guided protein effector to mitigate viral infection. We aggregated genomic data from multiple sources and constructed an expanded database of predicted class 2 CRISPR-Cas systems. A search for novel RNA-targeting systems identified subtype VI-D, encoding dual HEPN domain-containing Cas13d effectors and putative WYL-domain-containing accessory proteins (WYL1 and WYL-b1 through WYL-b5). The median size of Cas13d proteins is 190 to 300 aa smaller than that of Cas13a-Cas13c. Despite their small size, Cas13d orthologs from Eubacterium siraeum (Es) and Ruminococcus sp. (Rsp) are active in both CRISPR RNA processing and targeting, as well as collateral RNA cleavage, with no target-flanking sequence requirements. The RspWYL1 protein stimulates RNA cleavage by both EsCas13d and RspCas13d, demonstrating a common regulatory mechanism for divergent Cas13d orthologs. The small size, minimal targeting constraints, and modular regulation of Cas13d effectors further expands the CRISPR toolkit for RNA manipulation and detection.

Tailored vs. General COVID-19 prevention for adults with mental disabilities residing in group homes: a randomized controlled effectiveness-implementation trial.

BACKGROUND: People with serious mental illness (SMI) and people with intellectual disabilities/developmental disabilities (ID/DD) are at higher risk for COVID-19 and more severe outcomes. We compare a tailored versus general best practice COVID-19 prevention program in group homes (GHs) for people with SMI or ID/DD in Massachusetts (MA). METHODS: A hybrid effectiveness-implementation cluster randomized control trial compared a four-component implementation strategy (Tailored Best Practices: TBP) to dissemination of standard prevention guidelines (General Best-Practices: GBP) in GHs across six MA behavioral health agencies. GBP consisted of standard best practices for preventing COVID-19. TBP included GBP plus four components including: (1) trusted-messenger peer testimonials on benefits of vaccination; (2) motivational interviewing; (3) interactive education on preventive practices; and (4) fidelity feedback dashboards for GHs. Primary implementation outcomes were full COVID-19 vaccination rates (baseline: 1/1/2021-3/31/2021) and fidelity scores (baseline: 5/1/21-7/30/21), at 3-month intervals to 15-month follow-up until October 2022. The primary effectiveness outcome was COVID-19 infection (baseline: 1/1/2021-3/31/2021), measured every 3 months to 15-month follow-up. Cumulative incidence of vaccinations were estimated using Kaplan-Meier curves. Cox frailty models evaluate differences in vaccination uptake and secondary outcomes. Linear mixed models (LMMs) and Poisson generalized linear mixed models (GLMMs) were used to evaluate differences in fidelity scores and incidence of COVID-19 infections. RESULTS: GHs (n=415) were randomized to TBP (n=208) and GBP (n=207) including 3,836 residents (1,041 ID/DD; 2,795 SMI) and 5,538 staff. No differences were found in fidelity scores or COVID-19 incidence rates between TBP and GBP, however TBP had greater acceptability, appropriateness, and feasibility. No overall differences in vaccination rates were found between TBP and GBP. However, among unvaccinated group home residents with mental disabilities, non-White residents achieved full vaccination status at double the rate for TBP (28.6%) compared to GBP (14.4%) at 15 months. Additionally, the impact of TBP on vaccine uptake was over two-times greater for non-White residents compared to non-Hispanic White residents (ratio of HR for TBP between non-White and non-Hispanic White: 2.28, p = 0.03). CONCLUSION: Tailored COVID-19 prevention strategies are beneficial as a feasible and acceptable implementation strategy with the potential to reduce disparities in vaccine acceptance among the subgroup of non-White individuals with mental disabilities. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04726371, 27/01/2021. https://clinicaltrials.gov/study/NCT04726371 .

Brain MRI microbleeds and risk of intracranial hemorrhage in atrial fibrillation patients: A Swedish case-control study.

OBJECTIVES: Our goal was to quantify the independent association of brain microbleeds with future intracranial hemorrhage (ICrH). Microbleed findings on brain magnetic resonance imaging (MRI) may identify distinctive risk factors for ICrH which could inform the anticoagulant therapy decision for atrial fibrillation (AF) patients. Our study design includes patients with MRIs for numerous reasons, not limited to evaluation of stroke. MATERIALS AND METHODS: The source population was all patients with AF from a nationwide Swedish health care register. Case patients had an ICrH between 2006 and 2013 and ≥1 brain MRI for an unrelated condition before the ICrH. Each case was matched to four controls who had a brain MRI without a subsequent ICrH. The MRIs were re-reviewed by neuroradiologists. Associations between MRI findings and subsequent ICrH were assessed using logistic regression, adjusting for comorbidities and antithrombotic medications. RESULTS: A total of 78 cases and 312 matched controls were identified; 29 cases and 79 controls had MRI sequences suitable for analysis of microbleeds. Patients with ≥10 microbleeds had a markedly increased risk of ICrH (adjusted odds ratio 14.56; 95 % confidence interval: 2.86-74.16, p < 0.001). All patients with ≥10 microbleeds had microbleeds in the lobar region and ≥10 lobar microbleeds was associated with intracerebral hemorrhages, univariable OR 8.54 (2.01-36.33), p = 0.004. CONCLUSIONS: Leveraging a nationwide database with brain imaging obtained prior to ICrH, we identified a strong association between ≥10 microbleeds on brain MRI and subsequent ICrH among AF patients. Lobar brain regions were involved whenever there were ≥10 microbleeds. Brain MRIs may help optimize the anticoagulation decision in selected AF patients.

COVID-19-Related Outcomes Among Group Home Residents with Serious Mental Illness in Massachusetts in the First Year of the Pandemic.

This study examined COVID-19 infection and hospitalizations among people with serious mental illness who resided in residential care group homes in Massachusetts during the first year of the COVID-19 pandemic. The authors analyzed data on 2261 group home residents and COVID-19 data from the Massachusetts Department of Public Health. Outcomes included positive COVID-19 tests and COVID-19 hospitalizations March 1, 2020-June 30, 2020 (wave 1) and July 1, 2020-March 31, 2021 (wave 2). Associations between hazard of outcomes and resident and group home characteristics were estimated using multi-level Cox frailty models including home- and city-level frailties. Between March 2020 and March 2021, 182 (8%) residents tested positive for COVID-19, and 51 (2%) had a COVID-19 hospitalization. Compared with the Massachusetts population, group home residents had age-adjusted rate ratios of 3.0 (4.86 vs. 1.60 per 100) for COVID infection and 13.5 (1.99 vs. 0.15 per 100) for COVID hospitalizations during wave 1; during wave 2, the rate ratios were 0.5 (4.55 vs. 8.48 per 100) and 1.7 (0.69 vs. 0.40 per 100). In Cox models, residents in homes with more beds, higher staff-to-resident ratios, recent infections among staff and other residents, and in cities with high community transmission risk had greater hazard of COVID-19 infection. Policies and interventions that target group home-specific risks are needed to mitigate adverse communicable disease outcomes in this population.Clinical Trial Registration Number This study provides baseline (i.e., pre-randomization) data from a clinical trial study NCT04726371.

Impact of age, race, and family history on COVID-19-related changes in breast cancer screening among the Boston mammography cohort study.

PURPOSE: We studied women enrolled in the Boston Mammography Cohort Study to investigate whether subgroups defined by age, race, or family history of breast cancer experienced differences in the incidence of screening or diagnostic imaging rates during the COVID-19 lockdown and had slower rebound in the incidence of these rates during reopening. METHODS: We compared the incidence of monthly breast cancer screening and diagnostic imaging rates over during the pre-COVID-19 (January 2019-February 2020), lockdown (March-May 2020), and reopening periods (June-December 2020), and tested for differences in the monthly incidence within the same period by age (< 50 vs ≥ 50), race (White vs non-White), and first-degree family history of breast cancer (yes vs no). RESULTS: Overall, we observed a decline in breast cancer screening and diagnostic imaging rates over the three time periods (pre-COVID-19, lockdown, and reopening). The monthly incidence of breast cancer screening rates for women age ≥ 50 was 5% higher (p = 0.005) in the pre-COVID-19 period (January 2019-February 2020) but was 19% lower in the reopening phase (June-December 2020) than that of women aged < 50 (p < 0.001). White participants had 36% higher monthly incidence of breast cancer diagnostic imaging rates than non-White participants (p = 0.018). CONCLUSION: The rebound in screening was lower in women age ≥ 50 and lower in non-White women for diagnostic imaging. Careful attention must be paid as the COVID-19 recovery continues to ensure equitable resumption of care.

Tobacco carcinogen 4-[methyl(nitroso)amino]-1-(3-pyridinyl)-1-butanone (NNK) drives metabolic rewiring and epigenetic reprograming in A/J mice lung cancer model and prevention with diallyl sulphide (DAS).

Early detection of biomarkers in lung cancer is one of the best preventive strategies. Although many attempts have been made to understand the early events of lung carcinogenesis including cigarette smoking (CS) induced lung carcinogenesis, the integrative metabolomics and next-generation sequencing approaches are lacking. In this study, we treated the female A/J mice with CS carcinogen 4-[methyl(nitroso)amino]-1-(3-pyridinyl)-1-butanone (NNK) and naturally occurring organosulphur compound, diallyl sulphide (DAS) for 2 and 4 weeks after NNK injection and examined the metabolomic and DNA CpG methylomic and RNA transcriptomic profiles in the lung tissues. NNK drives metabolic changes including mitochondrial tricarboxylic acid (TCA) metabolites and pathways including Nicotine and its derivatives like nicotinamide and nicotinic acid. RNA-seq analysis and Reactome pathway analysis demonstrated metabolism pathways including Phase I and II drug metabolizing enzymes, mitochondrial oxidation and signaling kinase activation pathways modulated in a sequential manner. DNA CpG methyl-seq analyses showed differential global methylation patterns of lung tissues from week 2 versus week 4 in A/J mice including Adenylate Cyclase 6 (ADCY6), Ras-related C3 botulinum toxin substrate 3 (Rac3). Oral DAS treatment partially reversed some of the mitochondrial metabolic pathways, global methylation and transcriptomic changes during this early lung carcinogenesis stage. In summary, our result provides insights into CS carcinogen NNK's effects on driving alterations of metabolomics, epigenomics and transcriptomics and the chemopreventive effect of DAS in early stages of sequential lung carcinogenesis in A/J mouse model.

Risk of Infections With Ustekinumab and Tofacitinib Compared to Tumor Necrosis Factor α Antagonists in Inflammatory Bowel Diseases.

BACKGROUND & AIMS: The comparative safety of therapies is important to inform relative positioning within the therapeutic algorithm. Tumor necrosis factor α antagonists (anti-TNF) are associated with an increased risk of infections. Whether there is a similar increase with ustekinumab (UST) or tofacitinib has not been established. METHODS: We identified patients with Crohn's disease or ulcerative colitis from a national commercial health insurance plan in the United States between 2008 and 2019. Infectious outcomes were ascertained for patients newly initiating anti-TNF, UST, or tofacitinib therapy. Cox proportional hazards models were fit in propensity score-weighted cohorts to compare rates between patients treated with UST or tofacitinib and anti-TNF therapy. RESULTS: Our study included 19,096, 2420, and 305 patients with inflammatory bowel disease initiating anti-TNF, UST, and tofacitinib therapy, respectively. Over follow-up on-treatment, 7% and 44% of anti-TNF patients had infection-related hospitalizations and developed infections, respectively, compared with 4% and 32% of UST patients and 6% and 41% of tofacitinib patients. In the weighted Cox analysis, UST was associated with a significantly lower risk of infection (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.86-0.99) compared with anti-TNF therapy. There was a trend towards a reduction in infection-related hospitalizations (HR, 0.84; 95% CI, 0.66-1.03). The risk of infections (HR, 0.97; 95% CI, 0.75-1.24) or infection-related hospitalizations (HR, 0.59; 95% CI, 0.27-1.05) were similar between patients on tofacitinib and anti-TNF. CONCLUSIONS: UST is associated with reduced risk of infections compared to anti-TNF biologics in inflammatory bowel disease, whereas no difference was observed between tofacitinib and anti-TNF therapy.

Comorbidity Influences the Comparative Safety of Biologic Therapy in Older Adults With Inflammatory Bowel Diseases.

INTRODUCTION: There are limited data on comparative risk of infections with various biologic agents in older adults with inflammatory bowel diseases (IBDs). We aimed to assess the comparative safety of biologic agents in older IBD patients with varying comorbidity burden. METHODS: We used data from a large, national commercial insurance plan in the United States to identify patients 60 years and older with IBD who newly initiated tumor necrosis factor-α antagonists (anti-TNF), vedolizumab, or ustekinumab. Comorbidity was defined using the Charlson Comorbidity Index (CCI). Our primary outcome was infection-related hospitalizations. Cox proportional hazards models were fitted in propensity score-weighted cohorts to compare the risk of infections between the different therapeutic classes. RESULTS: The anti-TNF, vedolizumab, and ustekinumab cohorts included 2,369, 972, and 352 patients, respectively, with a mean age of 67 years. The overall rate of infection-related hospitalizations was similar to that of anti-TNF agents for patients initiating vedolizumab (hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.84-1.04) and ustekinumab (0.92, 95% CI 0.74-1.16). Among patients with a CCI of >1, both ustekinumab (HR: 0.66, 95% CI: 0.46-0.91, p-interaction <0.01) and vedolizumab (HR: 0.78, 95% CI: 0.65-0.94, p-interaction: 0.02) were associated with a significantly lower rate of infection-related hospitalizations compared with anti-TNFs. No difference was found among patients with a CCI of ≤1. DISCUSSION: Among adults 60 years and older with IBD initiating biologic therapy, both vedolizumab and ustekinumab were associated with lower rates of infection-related hospitalizations than anti-TNF therapy for those with high comorbidity burden.

Variation in the receipt of human papilloma virus co-testing for cervical screening: Individual, provider, facility and healthcare system characteristics.

Since 2012, cervical cancer screening guidelines allow for choice of screening test for women age 30-65 years (i.e., Pap every 3 years or Pap with human papillomavirus co-testing every 5 years). Intended to give patients and providers options, this flexibility reflects a trend in the growing complexity of screening guidelines. Our objective was to characterize variation in cervical screening at the individual, provider, clinic/facility, and healthcare system levels. The analysis included 296,924 individuals receiving screening from 3626 providers at 136 clinics/facilities in three healthcare systems, 2010 to 2017. Main outcome was receipt of co-testing vs. Pap alone. Co-testing was more common in one healthcare system before the 2012 guidelines (adjusted odds ratio (AOR) of co-testing at the other systems relative to this system 0.00 and 0.50) but was increasingly implemented over time in a second with declining uptake in the third (2017: AORs shifted to 7.32 and 0.01). Despite system-level differences, there was greater heterogeneity in receipt of co-testing associated with providers than clinics/facilities. In the three healthcare systems, providers in the highest quartile of co-testing use had an 8.35, 8.81, and 25.05-times greater odds of providing a co-test to women with the same characteristics relative to the lowest quartile. Similarly, clinics/ facilities in the highest quartile of co-testing use had a 4.20, 3.14, and 6.56-times greater odds of providing a co-test relative to the lowest quartile. Variation in screening test use is associated with health system, provider, and clinic/facility levels even after accounting for patient characteristics.

Increased relative proportions of advanced melanoma among veterans: A comparative analysis with the Surveillance, Epidemiology, and End Results registry.

BACKGROUND: The Surveillance, Epidemiology, and End Results (SEER) program reflects a third of the population of the United States. However, SEER may not be generalizable to the veteran population. Because veterans comprise a high-risk population, this discrepancy may limit our understanding of the epidemiology of melanoma in such high-risk populations. OBJECTIVES: To assess differences in demographics, tumor characteristics, and melanoma-specific survival (MSS) in veterans compared to the general population. METHODS: Data were collected from the Veterans Affairs Cancer Registry (VACR) and SEER (18 registries) from 2009 to 2017. RESULTS: We identified 15,334 veterans and 166,265 SEER patients with melanoma. Veterans were more likely to present with regional or distant disease (17.5% vs 13.0% in SEER). In VACR relative to SEER, the 5-year MSS was lower across all ages, except those diagnosed at ≥80 years. From 2009 to 2017, MSS by stage was lower across all stages in VACR. However, for stage IV melanomas diagnosed in 2015 to 2017 compared to 2011-2014, 2-year MSS increased from 37.8% to 51.5% in VACR versus 36.4% to 44.8% in SEER. LIMITATIONS: Unique veteran demographics and missing data inherent to VACR. CONCLUSION: Compared to SEER, veterans with melanoma were diagnosed at later stages; however, both exhibited recent improvement in stage IV MSS.

Comparative Risk of Thrombotic and Cardiovascular Events with Tofacitinib and Anti-TNF Agents in Patients with Inflammatory Bowel Diseases.

BACKGROUND: Tofacitinib and inflammatory bowel disease (IBD) have been associated with increased risks for thromboembolic and cardiovascular events, but drug attributable risk is unknown. METHODS: We conducted a retrospective cohort study in a US claims database. We identified patients with IBD by International Classification of Disease (ICD) codes, stipulated 180 days of continuous enrollment prior to tofacitinib or anti-tumor necrosis factor (TNF) initiation to determine new users. Primary outcomes were ICD codes for venous thromboembolism (VTE) and cardiovascular (CV) events. We constructed propensity score (PS)-weighted Cox proportional hazard models to estimate hazard ratios (HRs) and time-to-event outcomes comparing tofacitinib and anti-TNF. We conducted a subgroup analysis of patients ≥ 50 years. RESULTS: We identified 305 patients with IBD initiating tofacitinib and compared them with 19,096 initiating anti-TNFs. After weighting, balance was achieved across all demographic covariates. VTE occurred in 5% of patients treated with tofacitinib and 4% of anti-TNF users; in a PS-weighted cohort, tofacitinib did not confer a significantly elevated VTE risk compared with anti-TNF therapy (HR: 1.72, 95% CI: 0.74-3.01). A major CV event (MACE) occurred in 2% of tofacitinib users and 1% of anti-TNF users; tofacitinib also did not confer a significantly elevated risk for MACE (HR: 2.50, 95% CI: 0.37-6.18). Those with a Charlson comorbidity index ≥ 2 had greater risks for thromboembolic and cardiovascular events. Similar findings were noted in patients ≥ 50 years. CONCLUSIONS: In this large, active comparator, study, we demonstrate that tofacitinib was not associated with a higher risk of adverse thrombotic events compared with anti-TNFs in patients with IBD.

Safety and Efficacy of Tumor Necrosis Factor Antagonists in Older Patients With Ulcerative Colitis: Patient-Level Pooled Analysis of Data From Randomized Trials.

BACKGROUND & AIMS: Treatment of older patients (more than 60 years) with ulcerative colitis (UC) can be a challenge, because they might be more vulnerable to adverse events (AEs). We determined the effects of age on the safety and efficacy of anti-tumor necrosis factor (TNF) therapy in a pooled analysis of data from randomized trials. METHODS: We obtained individual patient-level data from 4 trials of anti-TNF therapy for patients with UC from the Yale Open Data Access Project. Participants were assigned to groups of older age (60 years or older) and younger age (younger than 60 years). The primary outcome was difference in serious AEs (SAEs), defined as death, life-threatening event, hospitalization, and/or significant disability. Secondary outcomes were severe infections, non-severe infections, neoplasms, and achievement of clinical remission, defined by trial investigators as Mayo score ≤ 2 with no sub-score >1 at the end of induction or maintenance therapy. A random effects logistic regression model was fitted to estimate the effect of anti-TNF therapy on safety and efficacy by age, adjusting for confounders and trial-level effects. RESULTS: The study cohort included 2257 patients (231 60 years or older). Higher proportions of older patients receiving anti-TNF therapy had SAEs (20%) and hospitalizations (14.4%), compared with younger patients (10.2% had SAEs and 5.2% were hospitalized); there were no significant differences between groups in proportions with severe or non-severe infections. Compared with placebo, there was no significant difference in safety risks associated with anti-TNF therapy (SAEs reduced by 5.4% in older patients vs reduction of 2.4% in younger patients; hospitalizations reduced by 6.7% in older patients vs reduction of 2.5% in younger patients; severe infections reduced by 3.1% vs increase of 0.7% in younger patients). There was no significant difference in between older vs younger patients in efficacy of anti-TNF therapy in inducing remission (odds risk ratio, 1.05, 95% CI, 0.33-3.39) or in maintaining remission (odds risk ratio, 0.49; 95% CI, 0.18-1.33). CONCLUSIONS: In a pooled analysis of data from randomized trials, we found that older patients with UC have an increased baseline increased risk of SAEs, but no increase in risk can be attributed to anti-TNF therapy in older vs younger patients.

PTEN deletion drives aberrations of DNA methylome and transcriptome in different stages of prostate cancer.

Phosphatase and tensin homolog located on chromosome 10 (PTEN) is a tumor suppressor gene and one of the most frequently mutated/deleted genes in human prostate cancer (PCa). However, how PTEN deletion would impact the epigenome and transcriptome alterations remain unknown. This hypothesis was tested in a prostate-specific PTEN-/- (KO) mouse prostatic adenocarcinoma model through DNA methyl-Seq and RNA-Seq analyses. Examination of cancer genomic datasets revealed that PTEN is expressed at lower levels in PTEN-deleted tumor samples than in normal solid tissue samples. Methylome and transcriptome profiling identified several inflammatory responses and immune response signaling pathways, including NF-kB signaling, IL-6 signaling, LPS/IL-1-mediated inhibition of RXR Function, PI3K in B lymphocytes, iCOS-iCOSL in T helper cells, and the role of NFAT in regulating the immune response, were affected by PTEN deletion. Importantly, a small subset of genes that showed DNA hypermethylation or hypomethylation was correlated with decreased or increased gene expression including CXCL1. quantitative polymerase chain reaction analyses of representative genes validated the RNA-Seq results. Histopathological examinations showed that the severity of prostatic intraepithelial neoplasia and inflammation development gradually increased as PTEN null mice aged. Collectively, these findings suggest that loss of PTEN drives global changes in DNA CpG methylation and transcriptomic gene expression and highly associated with several inflammatory and immune molecular pathways during PCa development. These biomarkers could be valuable molecular targets for cancer drug discovery and development against PCa.

Robust and efficient semi-supervised estimation of average treatment effects with application to electronic health records data.

We consider the problem of estimating the average treatment effect (ATE) in a semi-supervised learning setting, where a very small proportion of the entire set of observations are labeled with the true outcome but features predictive of the outcome are available among all observations. This problem arises, for example, when estimating treatment effects in electronic health records (EHR) data because gold-standard outcomes are often not directly observable from the records but are observed for a limited number of patients through small-scale manual chart review. We develop an imputation-based approach for estimating the ATE that is robust to misspecification of the imputation model. This effectively allows information from the predictive features to be safely leveraged to improve efficiency in estimating the ATE. The estimator is additionally doubly-robust in that it is consistent under correct specification of either an initial propensity score model or a baseline outcome model. It is also locally semiparametric efficient under an ideal semi-supervised model where the distribution of the unlabeled data is known. Simulations exhibit the efficiency and robustness of the proposed method compared to existing approaches in finite samples. We illustrate the method by comparing rates of treatment response to two biologic agents for treatment inflammatory bowel disease using EHR data from Partners' Healthcare.

The trajectory of racial/ethnic disparities in the use of cancer screening before and during the COVID-19 pandemic: A large U.S. academic center analysis.

Cancer screening rates declined sharply early in the COVID-19 pandemic. The impact of the pandemic may have exacerbated existing disparities in cancer screening due to the disproportionate burden of illness and job loss among racial/ ethnic minorities, and potentially, uneven resumption of care between different racial/ ethnic groups. Using electronic health record data from Mass General Brigham (MGB), we assessed changes in rates of breast, cervical, colorectal and lung cancer screening before and during the pandemic. Among patients who received primary care in an MGB-affiliated primary care practice, cancer screening rates were calculated as the number of individuals who received a screening test for each cancer type over the number of individuals due for each test, during each month between April 2019-November 2020. We conducted an interrupted time-series analysis to test for changes in screening rates by race/ethnicity before and during the pandemic. Prior to the pandemic, relative to White individuals, Asian women were less likely to receive breast cancer screening (p < 0.001), and Latinx and Black individuals were less likely to screen for lung cancer (p < 0.001 and p = 0.02). Our results did not show significant improvement or worsening of racial/ethnic disparities for any cancer screening type as screening resumed. However, as of November 2020 rates of screening for breast cancer were lower than pre-pandemic levels for Latinx individuals, and lung cancer screening rates were higher than baseline for Latinx, Black or White individuals. Further monitoring of disparities in cancer screening is warranted as the pandemic evolves.

The Effectiveness of Intraosseous Basivertebral Nerve Radiofrequency Neurotomy for the Treatment of Chronic Low Back Pain in Patients with Modic Changes: A Systematic Review.

OBJECTIVE: Determine the effectiveness of intraosseous basivertebral nerve radiofrequency neurotomy for the treatment of chronic low back pain with type 1 or 2 Modic changes. DESIGN: Systematic review. POPULATION: Persons aged ≥18 years with chronic low back pain with type 1 or 2 Modic changes. INTERVENTION: Intraosseous basivertebral nerve radiofrequency neurotomy. COMPARISON: Sham, placebo procedure, active standard care treatment, or none. OUTCOMES: The primary outcome of interest was the proportion of individuals with ≥50% pain reduction. Secondary outcomes included ≥10-point improvement in function as measured by Oswestry Disability Index as well as ≥2-point reduction in pain score on the Visual Analog Scale or Numeric Rating Scale, and decreased use of pain medication. METHODS: Three reviewers independently assessed publications before May 15, 2020, in MEDLINE and Embase and the quality of evidence was evaluated using the Grades of Recommendation, Assessment, Development, and Evaluation framework. RESULTS: Of the 725 publications screened, seven publications with 321 participants were ultimately included. The reported 3-month success rate for ≥50% pain reduction ranged from 45% to 63%. Rates of functional improvement (≥10-point Oswestry Disability Index improvement threshold) ranged from 75% to 93%. For comparison to sham treatment, the relative risk of treatment success defined by ≥50% pain reduction and ≥10-point Oswestry Disability Index improvement was 1.25 (95% confidence interval [CI]: .88-1.77) and 1.38 (95% CI: 1.10-1.73), respectively. For comparison to continued standard care treatment the relative risk of treatment success defined by ≥50% pain reduction and ≥10-point Oswestry Disability Index improvement was 4.16 (95% CI: 2.12-8.14) and 2.32 (95% CI: 1.52-3.55), respectively. CONCLUSIONS: There is moderate-quality evidence that suggests this procedure is effective in reducing pain and disability in patients with chronic low back pain who are selected based on type 1 or 2 Modic changes, among other inclusion and exclusion criteria used in the published literature to date. Success of the procedure appears to be dependent on effective targeting of the BVN. Non-industry funded high-quality, large prospective studies are needed to confirm these findings.

Are racial/ethnic minorities recently diagnosed with diabetes less likely than white individuals to receive guideline-directed diabetes preventive care?

BACKGROUND: Diabetes mellitus has reached epidemic proportions in the United States. As the prevalence of diabetes continues to rise, the burden of disease is divided unevenly among different populations. Racial/ethnic disparities in diabetes care are pervasive, including the provision of care for prevention of complications. Prevention efforts should be focused on the time that immediately follows a diagnosis of diabetes. The aim of this study was to assess racial/ethnic differences in the receipt of guideline-directed diabetes care for complication prevention by individuals recently diagnosed with diabetes. METHODS: We used repeated cross-sections of individuals recently diagnosed with diabetes (within the past 5 years) from the National Health Interview Survey from 2011 to 2017. Multivariate regression was used to estimate the associations between race/ethnicity (non-Hispanic White, non-Hispanic Black and Hispanic) and guideline-directed process measures for prevention of diabetes complications (visits to an eye and foot specialist, and blood pressure and cholesterol checks by a health professional - each in the prior year). We assessed effect modification of these associations by socioeconomic status (SES). RESULTS: In a sample of 7,341 participants, Hispanics had lower rates of having any insurance coverage (75.9 %) than Non-Hispanic Whites (93.2 %) and Blacks (88.1 %; p<0.001). After adjustment for demographics, total comorbidities, SES, and health insurance status, Hispanics were less likely to have an eye exam in the prior year (OR 0.80; (95 % CI 0.65-0.99); p=0.04) and a blood pressure check (OR 0.42; (95 % CI 0.28-0.65); p<0.001) compared to Non-Hispanic Whites. There was no significant effect modification of race/ethnicity by SES. CONCLUSIONS: Hispanics recently diagnosed with diabetes were less likely to receive some indicators of guideline-directed care for the prevention of complications. Lack of insurance and SES may partially explain those differences. Future work should consider policy change and providers' behaviors linked to racial/ethnic disparities in diabetes care.

How Should Native Crotalid Envenomation Be Managed in the Emergency Department?

BACKGROUND: Pit vipers, also known as crotalids, are a group of snakes including rattlesnakes, copperheads, and cottonmouths (water moccasins). Crotalids have a broad geographic distribution across the United States, and bites from these snakes can carry significant morbidity. Their envenomations are characterized by local tissue effects, hematologic effects, and systemic effects. Envenomations are generally treated with 1 of 2 antivenoms available in the United States. OBJECTIVE: We developed a series of clinical questions to assist and guide the emergency physician in the acute management of a patient envenomated by a crotalid. METHODS: We conducted a PubMed literature review from January 1970 to May 2020 in English for articles with the keywords "bite" and "crotalidae." RESULTS: Our literature search resulted in 177 articles. A total of 33 articles met criteria for rigorous review and citation in the development of these consensus guidelines. CONCLUSIONS: Patients should be initially evaluated, stabilized, and assessed for local effects, hematologic effects, and systemic toxicity suggestive of envenomation. Antivenom should be given if toxic effects are present. Surgical intervention including debridement and fasciotomy should be avoided. Prophylactic antibiotics are not necessary.

A proof-of-concept application of a novel scoring approach for personalized medicine in multiple sclerosis.

BACKGROUND: Stratified medicine methodologies based on subgroup analyses are often insufficiently powered. More powerful personalized medicine approaches are based on continuous scores. OBJECTIVE: We deployed a patient-specific continuous score predicting treatment response in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Data from two independent randomized controlled trials (RCTs) were used to build and validate an individual treatment response (ITR) score, regressing annualized relapse rates (ARRs) on a set of baseline predictors. RESULTS: The ITR score for the combined treatment groups versus placebo detected differential clinical response in both RCTs. High responders in one RCT had a cross-validated ARR ratio of 0.29 (95% confidence interval (CI) = 0.13-0.55) versus 0.62 (95% CI = 0.47-0.83) for all other responders (heterogeneity p = 0.038) and were validated in the other RCT, with the corresponding ARR ratios of 0.31 (95% CI = 0.18-0.56) and 0.61 (95% CI = 0.47-0.79; heterogeneity p = 0.036). The strongest treatment effect modifiers were the Short Form-36 Physical Component Summary, age, Visual Function Test 2.5%, prior MS treatment and Expanded Disability Status Scale. CONCLUSION: Our modelling strategy detects and validates an ITR score and opens up avenues for building treatment response calculators that are also applicable in routine clinical practice.

Estimating average treatment effects with a double-index propensity score.

We consider estimating average treatment effects (ATE) of a binary treatment in observational data when data-driven variable selection is needed to select relevant covariates from a moderately large number of available covariates X . To leverage covariates among X predictive of the outcome for efficiency gain while using regularization to fit a parametric propensity score (PS) model, we consider a dimension reduction of X based on fitting both working PS and outcome models using adaptive LASSO. A novel PS estimator, the Double-index Propensity Score (DiPS), is proposed, in which the treatment status is smoothed over the linear predictors for X from both the initial working models. The ATE is estimated by using the DiPS in a normalized inverse probability weighting estimator, which is found to maintain double robustness and also local semiparametric efficiency with a fixed number of covariates p. Under misspecification of working models, the smoothing step leads to gains in efficiency and robustness over traditional doubly robust estimators. These results are extended to the case where p diverges with sample size and working models are sparse. Simulations show the benefits of the approach in finite samples. We illustrate the method by estimating the ATE of statins on colorectal cancer risk in an electronic medical record study and the effect of smoking on C-reactive protein in the Framingham Offspring Study.