Pathogenic mechanisms and etiologic aspects of Mycobacterium avium subspecies paratuberculosis as an infectious cause of cutaneous melanoma.

Infectious etiologies have previously been proposed as causes of both melanoma and non-melanoma skin cancer. This exploratory overview explains and presents the evidence for the hypothesis that a microorganism excreted in infected ruminant animal feces, Mycobacterium avium subspecies paratuberculosis (MAP), is the cause of some cases of cutaneous melanoma (CM). Occupational, residential, and recreational contact with MAP-contaminated feces, soil, sand, and natural bodies of water may confer a higher rate of CM. Included in our hypothesis are possible reasons for the differing rates and locations of CM in persons with white versus nonwhite skin, why CM develops underneath nails and in vulvar skin, why canine melanoma is an excellent model for human melanoma, and why the Bacille Calmette-Guérin (BCG) vaccine has demonstrated efficacy in the prevention and treatment of CM. The pathogenic mechanisms and etiologic aspects of MAP, as a transmittable agent underlying CM risk, are carefully deliberated in this paper. Imbalances in gut and skin bacteria, genetic risk factors, and vaccine prevention/therapy are also discussed, while acknowledging that the evidence for a causal association between MAP exposure and CM remains circumstantial.

The Inverse Log-Rank Test: A Versatile Procedure for Late Separating Survival Curves.

Often in the planning phase of a clinical trial, a researcher will need to choose between a standard versus weighted log-rank test (LRT) for investigating right-censored survival data. While a standard LRT is optimal for analyzing evenly distributed but distinct survival events (proportional hazards), an appropriately weighted LRT test may be better suited for handling non-proportional, delayed treatment effects. The "a priori" misspecification of this alternative may result in a substantial loss of power when determining the effectiveness of an experimental drug. In this paper, the standard unweighted and inverse log-rank tests (iLRTs) are compared with the multiple weight, default Max-Combo procedure for analyzing differential late survival outcomes. Unlike combination LRTs that depend on the arbitrary selection of weights, the iLRT by definition is a single weight test and does not require implicit multiplicity correction. Empirically, both weighted methods have reasonable flexibility for assessing continuous survival curve differences from the onset of a study. However, the iLRT may be preferable for accommodating delayed separating survival curves, especially when one arm finishes first. Using standard large-sample methods, the power and sample size for the iLRT are easily estimated without resorting to complex and timely simulations.

A Centralized EHR-Based Model for the Recruitment of Rural and Lower Socioeconomic Participants in Pragmatic Trials: A Secondary Analysis of the Diuretic Comparison Project.

Importance: Participant diversity is important for reducing study bias and increasing generalizability of comparative effectiveness research. Objective: Demonstrate the operational efficiency of a centralized electronic health record (EHR)-based model for recruiting difficult-to-reach participants in a pragmatic trial. Design, Setting, and Participants: This comparative effectiveness study was a secondary analysis of Diuretic Comparison Project, a randomized clinical trial conducted between 2016 and 2022 (mean [SD] follow-up, 2.4 [1.4] years) comparing 2 commonly prescribed antihypertensives, which used an EHR-based recruitment model. Electronic study workflows, in tandem with routine clinical practice, were adapted by 72 Veteran Affairs (VA) primary care networks. Data were analyzed from August to December 2022. Main Outcomes and Measures: Measures reflecting recruitment capacity (monthly rate), operational efficiency (median time for completion of electronic procedures), and geographic reach (percentage of patients recruited from rural areas) were examined. Results: A total of 13 523 patients with hypertension (mean [SD] age, 72 [5.4] years; 13 092 male [96.8%]) were recruited from 537 outpatient clinics. Approximately 205 patients were randomized per month and a median of 35 days (Q1-Q3, 23-80 days) was needed to complete electronic recruitment. The annual income was below the national median for 69% of the cohort. Patients from all 50 states, Puerto Rico, and the District of Columbia were included and 45% resided in rural areas. Conclusions and Relevance: In this secondary analysis of a multicenter pragmatic trial, a centralized EHR-based recruitment model was associated with improved participation from underrepresented groups. These participants often are difficult to reach, with their exclusion potentially biasing trial results; eliminating in-person study visits and local site involvement can minimize barriers for the recruitment of patients from rural and lower socioeconomic areas. Trial Registration: The Diuretic Comparison Project (DCP) was registered on ClinicalTrials.gov Identifier: NCT02185417.

The evidence for Mycobacterium avium subspecies paratuberculosis (MAP) as a cause of nonsolar uveal melanoma: a narrative review.

Background and Objective: Animal microorganisms have been proposed as a cause of human cancers associated with farming, agricultural occupation or residence, and related downstream exposures. Several studies have described uveal melanoma (UvM) as a farming-associated cancer. A possible suspect is the animal microorganism Mycobacterium avium subspecies paratuberculosis (MAP), the causative agent of paratuberculosis in dairy cows. This microbe is transmitted to humans through various means, including contact with animal faeces, contaminated dust and soil, organic fertilizers, and as workers in slaughterhouses/animal processing facilities. The objective of the current manuscript was to examine the putative association between Mycobacterium avium sub-species paratuberculosis and non-solar UvM. Methods: Online data sources (PubMed, Scopus, Cochrane Library, and Google) published in English between 1980 to present were searched for key words pertaining to MAP exposure, farming-related occupations and activities, and locations with or in the vicinity of dairy cattle. Key Content and Findings: While higher than expected rates of eye cancer have been suggested among dairy farmers, with MAP being ubiquitous in their environment, the involvement of MAP in the aetiology of non-solar UvMs (which account for ~97% of UvM cases) remains uncertain. Conclusions: Alternative explanations exist and future cause-and-effect research is needed to answer this hypothesis. A precautionary approach to exposure continues to be a prudent strategy.

Self-management program and Black women with hypertension: Randomized controlled trial substudy.

The prevalence of hypertension (HTN) among Black women in the United States has increased over the past 10 years with a decline in levels of HTN awareness, treatment, and control. Higher death rates occur in Black women from HTN-related diseases when compared with women of other racial/ethnic groups. Although interventions aimed at self-care/self-management are vital to adults becoming the cornerstone of their own health and well-being, there is a paucity of research in Black women. This randomized controlled pilot trial substudy examined the influence of a Chronic Disease Self-Management Program (CDSMP) with tailored coaching versus the CDSMP alone on blood pressure (BP), weight, and scores on self-care questionnaires and medication adherence for Black women with HTN over 9 months. Eighty-three women who had completed the CDSMP were randomly assigned to coaching or no coaching. Median age was 54 years and the time since the HTN diagnosis was 9 years. Significant differences were noted in self-care maintenance and management over time with better self-care in the treatment group. Though not significant, both groups denoted a trend toward better medication adherence. Almost 60% of the participants in both groups showed improvements in their systolic and/or diastolic BP. However, there was no significant difference between the study groups' BP and weight variables. The CDSMP was effective in decreasing BP and improving medication adherence. Further research is needed to evaluate effective coaching strategies that motivate Black women with HTN toward self-care management.

Association Between Blood Donor Demographics and Post-injury Multiple Organ Failure after Polytrauma.

OBJECTIVE: To test the hypothesis that blood donor demographics are associated with transfused polytrauma patients' post-injury multiple organ failure (MOF) status. SUMMARY OF BACKGROUND DATA: Traumatic shock and MOF are preventable causes of death and post-traumatic hemorrhage is a frequent indication for transfusion. The role of blood donor demographics on transfusion recipients is not well known. METHODS: A log-linear analysis accounting for the correlated structure of the data based on our prospective MOF database was utilized. Tests for trend and interaction were computed using a likelihood ratio procedure. RESULTS: A total of 229 critically injured transfused trauma patients were included, with 68% of them being males and a mean age of 45 years. On average 10 units of blood components were transfused per patient. A total of 4379 units of blood components were donated by donors aged 46 years on average, 74% of whom were males. Blood components used were red blood cells (47%), cryoprecipitate (29%), fresh frozen plasma (24%), and platelets (less than 1%). Donor-recipient sex mismatched red blood cells transfusions were more likely to be associated with MOF ( P = 0.0012); fresh frozen plasma and cryoprecipitate recipients were more likely to experience MOF when transfused with a male (vs female) component ( P = 0.0014 and <0.0001, respectively). Donor age was not significantly associated with MOF for all blood components. CONCLUSIONS: Blood components donor sex, but not age, may be an important factor associated with post-injury MOF. Further validation of our findings will help guide future risk mitigation strategies specific to blood donor demographics.

Use of coaching and technology to improve blood pressure control in Black women with hypertension: Pilot randomized controlled trial study.

Hypertension is the main cause of cardiovascular disease, especially in women. Black women (58%) are affected by higher rates of hypertension than other racial/ethnic groups contributing to increased cardio-metabolic disorders. To decrease blood pressure (BP) in this population, a pilot randomized controlled trial was conducted to examine the effects of Interactive Technology Enhanced Coaching (ITEC) versus Interactive Technology (IT) alone in achieving BP control, adherence to antihypertensive medication, and adherence to lifestyle modifications among Black women diagnosed with and receiving medication for their hypertension. Participants completed a 6-week Chronic Disease Self-Management Program (CDSMP), and 83 participants were randomly assigned to ITEC versus IT. Participants were trained to use three wireless tools and five apps that were synchronized to smartphones to monitor BP, weight, physical activity (steps), diet (caloric and sodium intake), and medication adherence. Fitbit Plus, a cloud-based collaborative care platform was used to collect, track, and store data. Using a mixed-effects repeated measures model, the main effect of group means indicated no significant difference between the treatment and referent groups on study variables. The main effect of time indicated significant differences between repeated measures for systolic BP (p < .0001), weight (p < .0001), and steps (p = .018). An interaction effect revealed differences over time and was significant for study measures except diastolic BP. An important goal of this preliminary analysis is to help Black women prioritize self-care management in their everyday environment. Future research is warranted in a geographically broader population of hypertensive Black women.

Factors influencing surgical choice and anxiety in patients with pulmonary nodules smaller than 8 mm.

Background: The detection of pulmonary nodules significantly impacts the lives and mental health of patients. Although the 2020 National Comprehensive Cancer Network (NCCN) guidelines recommend scheduled surveillance for nodules ≤8 mm, patients often opt to have their nodules surgically removed. Methods: A cross-sectional questionnaire was administered to patients with small pulmonary nodules who presented to a local grade 3 hospital with small pulmonary nodules and decided to receive surgery versus prescribed monitoring. The questionnaire included four aspects: (I) patient characteristics; (II) nodule-specific knowledge; (III) doctor-patient communication; and (IV) nodular-specific distress. Nodular-specific distress was measured by the Impact of Event Scale-Revised (IES-R). Results: A total of 234 (69%) patients responded to the survey and were included in the final analysis. Poor performance in activities of daily living (ADLs), the presence of solid nodules, multifocal disease, and a family history of lung cancer were significantly associated with reported anxiety. Most notably, facilitating patient choice for surgery was the computed tomography (CT) scan results, with reference to lung nodule size and number of nodules, where concerns related to lung nodule, cancer risk, and fear of surgery or death had a significant psychological impact on patients. Conclusions: In this cohort of patients who elected to have their small pulmonary nodules surgically removed, we identified key factors underlying their anxiety toward guideline recommended surveillance. Our findings will be useful for clinicians when discussing treatment options with their patients.

Association Between Social Determinants of Health and Glycemic Control Among African American People with Type 2 diabetes: The Jackson Heart Study.

BACKGROUND: Social determinants of health have a significant impact on health outcomes. However, the complexity and interaction of multiple factors influencing glycemic control remain understudied. PURPOSE: This study examined associations of socioeconomic position (income, education, and occupation), environmental (physical activity facilities, neighborhood social cohesion, neighborhood problem, and violence), behavioral (physical activity, nutrition, and smoking), and psychological factors (depressive symptoms, stress, and discrimination) with glycemic control (hemoglobin A1c [A1c]) using the World Health Organization Social Determinants of Health framework in African American adults with type 2 diabetes. METHODS: A secondary data analysis was conducted using a longitudinal cohort of 1,240 African American adults with type 2 diabetes who participated in the community-based Jackson Heart Study. Socioeconomic position, environmental, behavioral, and psychological factors were measured using validated instruments in the Jackson Heart Study. Longitudinal structural equation modeling was used with glycemic control (A1c) collected over time (Exams 1-3) as the study outcome. RESULTS: Our study presents the complex interplay of socioeconomic determinants of health and glycemic control over time. Higher socioeconomic position (higher income, higher level of education, and professional occupation) was directly associated with improvement in glycemic control over time. An association of socioeconomic position on glycemic control mediated through health behavior factors was also observed. CONCLUSIONS: In this analysis, socioeconomic position components were determinants of glycemic control in African American adults with type 2 diabetes. Future studies aimed at reducing health disparities and achieving equality of outcomes in this population will benefit from embedding socioeconomic position components into their design.

Dermatological Autoimmune Considerations of Immune Checkpoint Therapy.

The most common immune-related adverse events (irAEs) involve the skin, and several serve as predictors of response to immune checkpoint inhibitor (ICI) therapy, especially in melanoma. Patients with pre-existing skin autoimmune diseases (ADs) have been excluded from ICI studies for safety concerns, yet recent research has shown that dermatological ADs can be managed without discontinuing ICI therapy. Patients with ADs respond as well or better to ICIs and can be included as candidates in clinical trials. Frequently taken during ICI therapy, steroids impair immunotherapy efficacy in certain anatomical sites of tumors but not others, including the brain. ICI efficacy can be enhanced by radiotherapy without increasing adverse events, as neoadjuvant radiotherapy is thought to sensitize tumors to ICIs. This perspective highlights clinical autoimmune considerations of ICI therapy in melanoma and discusses important areas for future exploration.

On the Frontiers of Breast Cancer Diagnosis and Treatment: Current and Future Directions in a Rapidly Changing Field.

Breast cancer (BCa) represents a medically heterogeneous group of malignancies, with differing biological and genetic makeups [...].

Breast Cancer Disparities in Asian Women: The Need for Disaggregated Research.

Asian (AZN) women are a heterogeneous group, comprising a wide array of cultural beliefs, languages, and healthcare needs. Yet, studies of breast cancer (BCa) risks and outcomes predominately consider AZNs in aggregate, assuming that the distinct ethnicities have similar disease profiles and homogeneous responses to treatment. This stereotypical portrayal of AZNs as a homogenous group tends to mask disparities. For example, healthcare-seeking behaviors and attitudes of medical providers toward AZN BCa patients frequently differ within this group and from other races. Misconceptions may arise that significantly influence the prevention, detection, treatment, and post-therapeutic care of AZN women. In addition to low BCa screening rates among AZN women, disparities also exist in various stages of BCa treatment-omission of radiation after breast-conserving surgery, less access to hypofractionation, underutilization of hormonal therapy, and higher-cost treatment owing to high HER2+ incidence. In this perspective, we highlight the need for disaggregated research of BCa among AZN women and advocate for comprehensive, culturally sensitive strategies to address health disparities in this priority population. Improving BCa literacy and awareness, access to care, and equitable recruitment into clinical trials are a few amelioratory goals to consider in the future.

Medications Associated with Lower Mortality in a SARS-CoV-2 Positive Cohort of 26,508 Veterans.

BACKGROUND: Many severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) positive patients take commonly prescribed medications with properties which may affect mortality. OBJECTIVE: Assess if common medications postulated to affect clinical outcomes are associated with mortality in SARS-CoV-2 positive patients in the Veterans Health Administration (VHA). DESIGN: Observational national cohort analysis. PARTICIPANTS: Consecutive 26,508 SARS-CoV-2 positive Veterans (7% of 399,290 tested from March 1 to September 10, 2020) constitute the study cohort. MAIN MEASURES: The primary outcome was 30-day mortality from the first positive SARS-CoV-2 test date. In patients receiving medications or drug pairs within 2 weeks post-SARS-CoV-2 positive test, 30-day mortality was estimated as relative risk (RR) on the log-binomial scale or using multinomial models with and without adjusting for covariates. KEY RESULTS: The 26,508 SARS-CoV-2 positive patients were predominantly male (89%) and White (59%), and 82% were overweight/obese. Medications associated with decreased 30-day mortality risk included the following: metformin (aRR, 0.33; 95% CI, 0.25-0.43), colchicine, angiotensin-converting-enzyme inhibitors (ACEi), angiotensin II receptor blockers, statins, vitamin D, antihistamines, alpha-blockers, anti-androgens, and nonsteroidal anti-inflammatory drugs (aRR, 0.69; 95% CI, 0.61-0.78). The effect of co-prescribed medications on 30-day mortality risk revealed the lowest risk for combined statins and metformin (aRR, 0.21; 95% CI, 0.15-0.31), followed by ACEi and statins (aRR, 0.25; 95% CI, 0.18-0.35), ACEi and metformin (aRR, 0.26; 95% CI, 0.17-0.40), antihistamines and NSAIDs (aRR, 0.41; 95% CI, 0.32-0.52), and in men, combined alpha-blockers and anti-androgens (aRR, 0.51; 95% CI, 0.42-0.64). CONCLUSIONS: In this large national cohort, treatment of SARS-CoV-2 positive patients with individual or co-prescribed metformin and statins, ACEi and statins (or metformin) and other medications was associated with a markedly decreased 30-day mortality and can likely be continued safely. Clinical trials may assess their therapeutic benefit.

Systematic analysis of ferroptosis-related long non-coding RNA predicting prognosis in patients with lung squamous cell carcinoma.

Background: Ferroptosis is a novel iron-dependent cell death, and an increasing number of studies have shown that long non-coding RNA (lncRNAs) are involved in the ferroptosis process. However, studies on ferroptosis-related lncRNAs in lung squamous cell carcinoma (LUSC) are limited. In addition, the prognostic role of ferroptosis-related lncRNAs and their relationship with the immune microenvironment and methylation of LUSC is unclear. This study aimed to investigate the potential prognostic value of ferroptosis-related lncRNAs and their involved biological functions in LUSC. Methods: The Cancer Genome Atlas (TCGA) database and the FerrDb website were used to obtain ferroptosis-related genes for LUSC. The "limma" R package and Pearson analysis were used to find ferroptosis-related lncRNAs. The biological functions of the characterized lncRNAs were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). We evaluated the prognostic power of this model using Kaplan-Meier analysis, receiver operating characteristic (ROC), and decision curve analysis (DCA). Univariate and multifactor Cox (proportional-hazards) risk model and a nomogram were produced using risk models and clinicopathological parameters for further verification. In addition, the relationship between characterized lncRNAs and tumor immune infiltration and methylation was also discussed. Results: We identified 29 characterized lncRNAs to produce prognostic risk models. Kaplan-Meier analysis revealed the high-risk group was associated with poor prognosis in LUSC (P<0.001), and ROC (AUC =0.658) and DCA suggested that risk models could predict prognosis. Univariate and multifactorial Cox as well as nomogram further validated the prognostic model (P<0.001). Gene set enrichment analysis (GSEA) showed that the high-risk group was associated with pro-tumor pathways and high-frequency mutations in TP53 were present in both groups. Single sample gene set enrichment analysis (ssGSEA) showed significant differences in immune cell infiltration subtypes and corresponding functions between the two groups. Some immune checkpoint and methylation-related genes were significantly different between the two groups (P<0.05). Conclusions: We investigated the potential mechanisms of LUSC development from the perspective of ferroptosis-related lncRNAs, providing new insights into LUSC research, and identified 29 lncRNAs as biomarkers to predict the prognosis of LUSC patients.

Longitudinal assessment of colonoscopy adverse events in the prospective Cooperative Studies Program no. 380 colorectal cancer screening and surveillance cohort.

BACKGROUND AND AIMS: Data are limited regarding colonoscopy risk during long-term, programmatic colorectal cancer screening and follow-up. We aimed to describe adverse events during follow-up in a colonoscopy screening program after the baseline examination and examine factors associated with increased risk. METHODS: Cooperative Studies Program no. 380 includes 3121 asymptomatic veterans aged 50 to 75 years who underwent screening colonoscopy between 1994 and 1997. Periprocedure adverse events requiring significant intervention were defined as major events (other events were minor) and were tracked during follow-up for at least 10 years. Multivariable odds ratios (ORs) were calculated for factors associated with risk of follow-up adverse events. RESULTS: Of 3727 follow-up examinations in 1983 participants, adverse events occurred in 105 examinations (2.8%) in 93 individuals, including 22 major and 87 minor events (examinations may have had >1 event). Incidence of major events (per 1000 examinations) remained relatively stable over time, with 6.1 events at examination 2, 4.8 at examination 3, and 7.2 at examination 4. Examinations with major events included 1 perforation, 3 GI bleeds requiring intervention, and 17 cardiopulmonary events. History of prior colonoscopic adverse events was associated with increased risk of events (major or minor) during follow-up (OR, 2.7; 95% confidence interval, 1.6-4.6). CONCLUSIONS: Long-term programmatic screening and surveillance was safe, as major events were rare during follow-up. However, serious cardiopulmonary events were the most common major events. These results highlight the need for detailed assessments of comorbid conditions during routine clinical practice, which could help inform individual decisions regarding the utility of ongoing colonoscopy follow-up.

A Phenome-Wide Association Study of genes associated with COVID-19 severity reveals shared genetics with complex diseases in the Million Veteran Program.

The study aims to determine the shared genetic architecture between COVID-19 severity with existing medical conditions using electronic health record (EHR) data. We conducted a Phenome-Wide Association Study (PheWAS) of genetic variants associated with critical illness (n = 35) or hospitalization (n = 42) due to severe COVID-19 using genome-wide association summary data from the Host Genetics Initiative. PheWAS analysis was performed using genotype-phenotype data from the Veterans Affairs Million Veteran Program (MVP). Phenotypes were defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods. Among 658,582 Veterans, variants associated with severe COVID-19 were tested for association across 1,559 phenotypes. Variants at the ABO locus (rs495828, rs505922) associated with the largest number of phenotypes (nrs495828 = 53 and nrs505922 = 59); strongest association with venous embolism, odds ratio (ORrs495828 1.33 (p = 1.32 x 10-199), and thrombosis ORrs505922 1.33, p = 2.2 x10-265. Among 67 respiratory conditions tested, 11 had significant associations including MUC5B locus (rs35705950) with increased risk of idiopathic fibrosing alveolitis OR 2.83, p = 4.12 × 10-191; CRHR1 (rs61667602) associated with reduced risk of pulmonary fibrosis, OR 0.84, p = 2.26× 10-12. The TYK2 locus (rs11085727) associated with reduced risk for autoimmune conditions, e.g., psoriasis OR 0.88, p = 6.48 x10-23, lupus OR 0.84, p = 3.97 x 10-06. PheWAS stratified by ancestry demonstrated differences in genotype-phenotype associations. LMNA (rs581342) associated with neutropenia OR 1.29 p = 4.1 x 10-13 among Veterans of African and Hispanic ancestry but not European. Overall, we observed a shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes. Differing associations between genotype-phenotype across ancestries may inform heterogenous outcomes observed with COVID-19. Divergent associations between risk for severe COVID-19 with autoimmune inflammatory conditions both respiratory and non-respiratory highlights the shared pathways and fine balance of immune host response and autoimmunity and caution required when considering treatment targets.