Association of Frailty with Healthcare Utilization for Patients over One Year Following Surgical Evaluation.

OBJECTIVE: Characterize the distribution of healthcare utilization associated with pre-operative frailty in the year following evaluation by a surgeon. SUMMARY BACKGROUND DATA: Frailty is associated with increased morbidity, mortality, and costs for surgical patients. However, the total financial burden for frail patients beyond the index surgery and inpatient stay remains unknown. METHODS: Prospective cohort assembled from February 2016 to December 2020 within a multi-hospital integrated healthcare delivery and finance system (IDFS), from patients evaluated with the Risk Analysis Index (RAI) of frailty. Inclusion criteria: age greater than 18, valid RAI, membership in the IDFS Health Plan. Data were stratified by frailty and surgical status. RESULTS: The mean (SD) age was 54.7 (16.1) and 58.2% female of the cohort (n=86,572). For all patients with reimbursement for surgery (n=53,856), frail and very frail patients incurred respective increases of 8% ( P =0.027) and 29% ( P <0.001) on utilization relative to the normal group. Robust patients saw a 52% ( P <0.001) decrease. This pattern was more pronounced in the cohort without surgery (n=32,716). The increase over normal utilization for frail and very frail patients increased to 23% ( P =0.004) and 68% ( P <0.001), respectively. Utilization among robust patients decreased 62% ( P <0.001). Increases among the frail were primarily due to increased inpatient medical and post-acute care services (all P <0.001). CONCLUSIONS: Patient frailty is associated with increased total healthcare utilization, primarily via increased inpatient medical and post-acute care following surgery. Quantifying these frailty-related financial burdens may inform clinical decision making as well as the design of value-based reimbursement strategies.

A Surgical Desirability of Outcome Ranking (DOOR) Reveals Complex Relationships Between Race/Ethnicity, Insurance Type, and Neighborhood Deprivation.

OBJECTIVE: Develop an ordinal Desirability of Outcome Ranking (DOOR) for surgical outcomes to examine complex associations of Social Determinants of Health. BACKGROUND: Studies focused on single or binary composite outcomes may not detect health disparities. METHODS: Three health care system cohort study using NSQIP (2013-2019) linked with EHR and risk-adjusted for frailty, preoperative acute serious conditions (PASC), case status and operative stress assessing associations of multilevel Social Determinants of Health of race/ethnicity, insurance type (Private 13,957; Medicare 15,198; Medicaid 2835; Uninsured 2963) and Area Deprivation Index (ADI) on DOOR and the binary Textbook Outcomes (TO). RESULTS: Patients living in highly deprived neighborhoods (ADI>85) had higher odds of PASC [adjusted odds ratio (aOR)=1.13, CI=1.02-1.25, P <0.001] and urgent/emergent cases (aOR=1.23, CI=1.16-1.31, P <0.001). Increased odds of higher/less desirable DOOR scores were associated with patients identifying as Black versus White and on Medicare, Medicaid or Uninsured versus Private insurance. Patients with ADI>85 had lower odds of TO (aOR=0.91, CI=0.85-0.97, P =0.006) until adjusting for insurance. In contrast, patients with ADI>85 had increased odds of higher DOOR (aOR=1.07, CI=1.01-1.14, P <0.021) after adjusting for insurance but similar odds after adjusting for PASC and urgent/emergent cases. CONCLUSIONS: DOOR revealed complex interactions between race/ethnicity, insurance type and neighborhood deprivation. ADI>85 was associated with higher odds of worse DOOR outcomes while TO failed to capture the effect of ADI. Our results suggest that presentation acuity is a critical determinant of worse outcomes in patients in highly deprived neighborhoods and without insurance. Including risk adjustment for living in deprived neighborhoods and urgent/emergent surgeries could improve the accuracy of quality metrics.

The association between frailty and outcomes following ruptured abdominal aortic aneurysm repair.

OBJECTIVE: Endovascular aortic repair (EVAR) is a less invasive method than the more physiologically stressful open surgical repair (OSR) for patients with anatomically appropriate abdominal aortic aneurysms (AAAs). Early postoperative outcomes are associated with both patients; physiologic reserve and the physiologic stresses of the surgical intervention. Among frail patients with reduced physiologic reserve, the stress of an aortic rupture in combination with the stress of an operative repair are less well tolerated, raising the risk of complications and mortality. This study aims to evaluate the difference in association between frailty and outcomes among patients undergoing minimally invasive EVAR and the physiologically more stressful OSR for ruptured AAAs (rAAAs). METHODS: Our retrospective cohort study included adults undergoing rAAA repair in the Vascular Quality Initiative from 2010 to 2022. The validated Risk Analysis Index (RAI) (robust, ≤20; normal, 21-29; frail, 30-39; very frail, ≥40) quantified frailty. The association between the primary outcome of 1-year mortality and frailty status as well as repair type were compared using multivariable Cox models generating adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs). Interaction terms evaluated the association's moderation. RESULTS: We identified 5806 patients (age, 72 ± 9 years; 77% male; EVAR, 65%; robust, 6%; normal, 48%; frail, 36%; very, frail 10%) with a 53% observed 1-year mortality rate following rAAA repair. OSR (aHR, 1.43; 95% CI, 1.19-1.73) was associated with increased 1-year mortality when compared with EVAR. Increasing frailty status (frail aHR, 1.26; 95% CI, 1.00-1.59; very frail aHR, 1.64; 95% CI, 1.26-2.13) was associated with increased 1-year mortality, which was moderated by repair type (P-interaction < .05). OSR was associated with increased 1-year mortality in normal (aHR, 1.49; 95% CI, 1.20-1.87) and frail (aHR, 1.51; 95% CI, 1.20-1.89), but not among robust (aHR, 0.88; 95% CI, 0.59-1.32) and very frail (aHR, 1.29; 95% CI, 0.97-1.72) patients. CONCLUSIONS: Frailty and OSR were associated with increased adjusted risk of 1-year mortality following rAAA repair. Among normal and frail patients, OSR was associated with an increased adjusted risk of 1-year mortality when compared with EVAR. However, there was no difference between OSR and EVAR among robust patients who can well tolerate the stress of OSR and among very frail patients who are unable to withstand the surgical stress from rAAA regardless of repair type.

Care Fragmentation, Social Determinants of Health, and Postoperative Mortality in Older Veterans.

INTRODUCTION: Veterans Affairs Surgical Quality Improvement Program (VASQIP) benchmarking algorithms helped the Veterans Health Administration (VHA) reduce postoperative mortality. Despite calls to consider social risk factors, these algorithms do not adjust for social determinants of health (SDoH) or account for services fragmented between the VHA and the private sector. This investigation examines how the addition of SDoH change model performance and quantifies associations between SDoH and 30-d postoperative mortality. METHODS: VASQIP (2013-2019) cohort study in patients ≥65 y old with 2-30-d inpatient stays. VASQIP was linked to other VHA and Medicare/Medicaid data. 30-d postoperative mortality was examined using multivariable logistic regression models, adjusting first for clinical variables, then adding SDoH. RESULTS: In adjusted analyses of 93,644 inpatient cases (97.7% male, 79.7% non-Hispanic White), higher proportions of non-veterans affairs care (adjusted odds ratio [aOR] = 1.02, 95% CI = 1.01-1.04) and living in highly deprived areas (aOR = 1.15, 95% CI = 1.02-1.29) were associated with increased postoperative mortality. Black race (aOR = 0.77, CI = 0.68-0.88) and rurality (aOR = 0.87, CI = 0.79-0.96) were associated with lower postoperative mortality. Adding SDoH to models with only clinical variables did not improve discrimination (c = 0.836 versus c = 0.835). CONCLUSIONS: Postoperative mortality is worse among Veterans receiving more health care outside the VA and living in highly deprived neighborhoods. However, adjusting for SDoH is unlikely to improve existing mortality-benchmarking models. Reduction efforts for postoperative mortality could focus on alleviating care fragmentation and designing care pathways that consider area deprivation. The adjusted survival advantage for rural and Black Veterans may be of interest to private sector hospitals as they attempt to alleviate enduring health-care disparities.

The structure, binding and function of a Notch transcription complex involving RBPJ and the epigenetic reader protein L3MBTL3.

The Notch pathway transmits signals between neighboring cells to elicit downstream transcriptional programs. Notch is a major regulator of cell fate specification, proliferation, and apoptosis, such that aberrant signaling leads to a pleiotropy of human diseases, including developmental disorders and cancers. The pathway signals through the transcription factor CSL (RBPJ in mammals), which forms an activation complex with the intracellular domain of the Notch receptor and the coactivator Mastermind. CSL can also function as a transcriptional repressor by forming complexes with one of several different corepressor proteins, such as FHL1 or SHARP in mammals and Hairless in Drosophila. Recently, we identified L3MBTL3 as a bona fide RBPJ-binding corepressor that recruits the repressive lysine demethylase LSD1/KDM1A to Notch target genes. Here, we define the RBPJ-interacting domain of L3MBTL3 and report the 2.06 Å crystal structure of the RBPJ-L3MBTL3-DNA complex. The structure reveals that L3MBTL3 interacts with RBPJ via an unusual binding motif compared to other RBPJ binding partners, which we comprehensively analyze with a series of structure-based mutants. We also show that these disruptive mutations affect RBPJ and L3MBTL3 function in cells, providing further insights into Notch mediated transcriptional regulation.

Novel Skin Prep Technique Reduces OR Preparation Times in a Randomized Trial for Podiatric and Orthopedic Procedures.

The primary objectives of any high-volume surgery department should be patient safety, block time utilization and operating room efficiency. Reducing preparation time in the OR prior to actual surgery can improve operating room efficiency and utilization, but only if patient safety can be maintained. With this goal, this study evaluated a novel skin preparation technique using a device named ULTRAPREP™, a sterile, medical-grade plastic bag that is applied to the upper or lower extremity in the pre-operative holding area which allows for skin disinfection outside the OR (referred to as "disinfection bag"). The study compared preparation times required in the OR and antiseptic efficiency (through Colony Forming Units (CFU) counts) for traditional methods versus using the disinfection bag on a total of 115 patients undergoing podiatric or orthopedic surgeries (upper and lower extremities) in one hospital. The disinfection bag reduced skin preparation time in the OR from 16.8±3.5min to 10.9±2.7min, which was a 35.2% reduction, and was statistically significant (p<0.01). Skin antisepsis met safety standards of <15 CFUs for all cases regardless of preparation type at 48h and 72h. There was no statistical difference in CFU levels between the traditional and disinfection bag methods at 48h or 72h (p>0.11). Therefore, ULTRAPREP™ has shown the ability to decrease operating room time while keeping surgical site infection rates to a minimum. Minimizing activities in the OR optimizes use of this costly resource and brings overall savings to the surgery department.

An exploration into the relationship between insomnia and repetitive negative thinking among cancer survivors.

OBJECTIVE: Insomnia and repetitive negative thinking (RNT) are both prevalent among cancer survivors, yet little work has investigated their interrelationship. To explore the hypothesis that RNT and insomnia are related, we conducted secondary analyses on data from a pilot clinical trial of cognitive behavioral therapy for insomnia (CBT-I) for cancer survivors. METHODS: This study analyzed survey data from 40 cancer survivors with insomnia who participated in a pilot randomized trial of CBT-I. Correlations and linear regression models were used to determine associations between aspects of RNT and related constructs (fear of cancer recurrence [FCR], cancer-specific rumination, worry, and intolerance of uncertainty) and sleep (insomnia and sleep quality), while accounting for psychiatric symptoms such as anxiety and depression. Treatment-related change in RNT was examined using a series of linear mixed models. RESULTS: Evidence for an association between RNT and insomnia among cancer survivors emerged. Higher levels of FCR and cancer-related rumination were correlated with more severe insomnia symptoms and worse sleep quality. Notably, FCR levels predicted insomnia, even after controlling for anxiety and depression. Results identified potential benefits and limitations of CBT-I in addressing RNT that should be examined more thoroughly in future research. CONCLUSIONS: RNT is a potential target to consider in insomnia treatment for cancer survivors.

Trajectory Analysis of Healthcare Utilization Before and After Major Surgery.

OBJECTIVE: To characterize patterns of healthcare utilization before and after surgery and determine any association with pre-operative frailty. SUMMARY BACKGROUND DATA: Frail patients experience worse post-operative outcomes and increased costs during the surgical encounter. Evidence is comparatively lacking for longer-term effects of frailty on post-operative healthcare utilization. METHODS: Retrospective, longitudinal cohort analysis of adult patients undergoing any elective surgical procedure following pre-operative frailty assessment with the Risk Analysis Index (RAI) from 02/2016-12/2020 at a large integrated healthcare delivery and financing system. Group-based trajectory modeling of claims data estimated distinct clusters of patients with discrete utilization trajectories. Multivariable regression predicted membership in trajectories of interest using preoperative characteristics, including frailty. RESULTS: Among 29,067 surgical encounters, four distinct utilization trajectories emerged in longitudinal data from the 12 months before and after surgery. All cases exhibited a surge in utilization during the surgical month, after which most patients returned to "low" [25,473 (87.6%)], "medium" [1,403 (4.8%)], or "high" [528 (1.8%)] baseline utilization states established before surgery. The fourth trajectory identified 1,663 (5.7%) cases where surgery occasioned a transition from "low" utilization before surgery to "high" utilization afterward. RAI score alone did not effectively predict membership in this transition group, but a multivariable model with other preoperative variables was effective (c=0.859, max re-scaled R-squared 0.264). CONCLUSIONS AND RELEVANCE: Surgery occasions the transition from low to high healthcare utilization for a substantial subgroup of surgical patients. Multivariable modeling may effectively discriminate this utilization trajectory, suggesting an opportunity to tailor care processes for these patients.

Association of Frailty and the Expanded Operative Stress Score with Preoperative Acute Serious Conditions, Complications, and Mortality in Males Compared to Females: A Retrospective Observational Study.

OBJECTIVE: The aim of this study was to expand Operative Stress Score (OSS) increasing procedural coverage and assessing OSS and frailty association with Preoperative Acute Serious Conditions (PASC), complications and mortality in females versus males. SUMMARY BACKGROUND DATA: Veterans Affairs male-dominated study showed high mortality in frail veterans even after very low stress surgeries (OSS1). METHODS: Retrospective cohort using NSQIP data (2013-2019) merged with 180-day postoperative mortality from multiple hospitals to evaluate PASC, 30-day complications and 30-, 90-, and 180-day mortality. RESULTS: OSS expansion resulted in 98.2% case coverage versus 87.0% using the original. Of 82,269 patients (43.8% male), 7.9% were frail/very frail. Males had higher odds of PASC [adjusted odds ratio (aOR) = 1.31, 95% confidence interval (CI) = 1.21-1.41, P < 0.001] and severe/life-threatening Clavien-Dindo IV (CDIV) complications (aOR = 1.18, 95% CI = 1.09-1.28, P < 0.001). Although mortality rates were higher (all time-points, P < 0.001) in males versus females, mortality was similar after adjusting for frailty, OSS, and case status primarily due to increased male frailty scores. Additional adjustments for PASC and CDIV resulted in a lower odds of mortality in males (30-day, aOR = 0.81, 95% CI = 0.71-0.92, P = 0.002) that was most pronounced for males with PASC compared to females with PASC (30-day, aOR = 0.75, 95% CI = 0.56-0.99, P = 0.04). CONCLUSIONS: Similar to the male-dominated Veteran population, private sector, frail patients have high likelihood of postoperative mortality, even after low-stress surgeries. Preoperative frailty screening should be performed regardless of magnitude of the procedure. Despite males experiencing higher adjusted odds of PASC and CDIV complications, females with PASC had higher odds of mortality compared to males, suggesting differences in the aggressiveness of care provided to men and women.

Validation of the Lee-Jones theoretical model of fear of cancer recurrence among breast cancer survivors using a structural equation modeling approach.

OBJECTIVE: The Lee-Jones model posits that antecedent individual and interpersonal factors predicate the development of fear of cancer recurrence (FCR) through cognitive and emotional processing, which further to behavioral, emotional, and/or physiological responses. We analyzed data from FoRtitude, a FCR intervention grounded in the Lee-Jones FCR model, to evaluate associations between FCR antecedents, resources (e.g., breast cancer self-efficacy, BCSE) and psychological and behavioral consequences. METHODS: Women with breast cancer who completed treatment and reported clinically elevated levels of FCR were randomized into a 4-week online psychosocial intervention or contact control group. We assessed BCSE, FCR, and physical activity, anxiety and depression, or symptoms at baseline, 4 and 8 weeks. Separate structural equation models were constructed with both baseline data and change scores (baseline-8 weeks) to examine the pathways linking BCSE, FCR and: (1) physical activity; (2) anxiety and depression; and (3) symptoms (fatigue, sleep disturbance, cognitive concerns). RESULTS: At baseline, higher levels of BCSE were associated with lower levels of FCR. Higher FCR was associated with worse psychological effects and symptoms but not behavioral response. Change models revealed that an increase in BCSE was associated with a decrease in FCR at 8-week assessment, which was associated with reductions in psychological effects. A change in BCSE was also directly associated with reductions in psychological effects. CONCLUSIONS: Results support the Lee-Jones model as a foundation for FCR interventions among breast cancer survivors. Replicability among varied populations is needed to examine effects on behavioral outcomes of FCR such as health care utilization. CLINICAL TRIALS REGISTRATION: NCT03384992.

A Retrospective Cohort Study to Evaluate Adding Biomarkers to the Risk Analysis Index of Frailty.

INTRODUCTION: The Risk Analysis Index (RAI) is a frailty assessment tool associated with adverse postoperative outcomes including 180 and 365-d mortality. However, the RAI has been criticized for only containing subjective inputs rather than including more objective components such as biomarkers. METHODS: We conducted a retrospective cohort study to assess the benefit of adding common biomarkers to the RAI using the Veterans Affairs Surgical Quality Improvement Program (VASQIP) database. RAI plus body mass index (BMI), creatinine, hematocrit, and albumin were evaluated as individual and composite variables on 180-d postoperative mortality. RESULTS: Among 480,731 noncardiac cases in VASQIP from 2010 to 2014, 324,320 (67%) met our inclusion criteria. Frail patients (RAI ≥30) made up to 13.0% of the sample. RAI demonstrated strong discrimination for 180-d mortality (c = 0.839 [0.836-0.843]). Discrimination significantly improved with the addition of Hematocrit (c = 0.862 [0.859-0.865]) and albumin (c = 0.870 [0.866-0.873]), but not for body mass index (BMI) or creatinine. However, calibration plots demonstrate that the improvement was primarily at high RAI values where the model overpredicts observed mortality. CONCLUSIONS: While RAI's ability to predict the risk of 180-d postoperative mortality improves with the addition of certain biomarkers, this only observed in patients classified as very frail (RAI >49). Because very frail patients have significantly elevated observed and predicted mortality, the improved discrimination is likely of limited clinical utility for a frailty screening tool.

Sex-Related Differences in Acuity and Postoperative Complications, Mortality and Failure to Rescue.

INTRODUCTION: Yentl syndrome describing sex-related disparities has been extensively studied in medical conditions but not after surgery. This retrospective cohort study assessed the association of sex, frailty, presenting with preoperative acute serious conditions (PASC), and the expanded Operative Stress Score (OSS) with postoperative complications, mortality, and failure-to-rescue. METHODS: The National Surgical Quality Improvement Program from 2015 to 2019 evaluating 30-d complications, mortality, and failure-to-rescue. RESULTS: Of 4,860,308 cases (43% were male; mean [standard deviation] age of 56 [17] y), 6.0 and 0.8% were frail and very frail, respectively. Frailty score distribution was higher in men versus women (P < 0.001). Most cases were low-stress OSS2 (44.9%) or moderate-stress OSS3 (44.5%) surgeries. While unadjusted 30-d mortality rates were higher (P < 0.001) in males (1.1%) versus females (0.8%), males had lower odds of mortality (adjusted odds ratio (aOR) = 0.92, 95% confidence interval [CI] = 0.90-0.94, P < 0.001) after adjusting for frailty, OSS, case status, PASC, and Clavien-Dindo IV (CDIV) complications. Males have higher odds of PASC (aOR = 1.33, CI = 1.31-1.35, P < 0.001) and CDIV complications (aOR = 1.13, CI = 1.12-1.15, P < 0.001). Male-PASC (aOR = 0.76, CI = 0.72-0.80, P < 0.001) and male-CDIV (aOR = 0.87, CI = 0.83-0.91, P < 0.001) interaction terms demonstrated that the increased odds of mortality associated with PASC or CDIV complications/failure-to-rescue were lower in males versus females. CONCLUSIONS: Our study provides a comprehensive analysis of sex-related surgical outcomes across a wide range of procedures and health care systems. Females presenting with PASC or experiencing CDIV complications had higher odds of mortality/failure to rescue suggesting sex-related care differences. Yentl syndrome may be present in surgical patients; possibly related to differences in presenting symptoms, patient care preferences, or less aggressive care in female patients and deserves further study.

Interpreting the risk analysis index of frailty in the context of surgical oncology.

BACKGROUND AND OBJECTIVES: The Risk Analysis Index (RAI) accurately predicts adverse postoperative outcomes but the inclusion of cancer status in the RAI has raised two key concerns about its suitability for use in surgical oncology: (1) the potential over classification of cancer patients as frail, and (2) the potential overestimation of postoperative mortality for patients with surgically curable cancers. METHODS: We performed a retrospective cohort analysis to assess the RAI's power to appropriately identify frailty and predict postoperative mortality in cancer patients. We assessed discrimination for mortality and calibration across five RAI models-the complete RAI and four variants that removed different cancer-related variables. RESULTS: We found that the presence of disseminated cancer was a key variable driving the RAI's power to predict postoperative mortality. The model including only this variable [RAI (disseminated cancer)] was similar to the complete RAI in the overall sample (c = 0.842 vs. 0.840) and outperformed the complete RAI in the cancer subgroup (c = 0.736 vs 0.704, respectively, p < 0.0001, Max R2 = 19.3% vs. 15.1%, respectively). CONCLUSION: The RAI demonstrates somewhat less discrimination when applied exclusively to cancer patients, but remains a strong predictor of postoperative mortality, especially in the setting of disseminated cancer.

Posttraumatic Cognitions and Condomless Sex Among Men Who Have Sex with Men (MSM) with a History of Childhood Sexual Abuse: The Role of Avoidance Coping.

This study explicated associations between trauma-related cognitions and condomless sex, examining avoidance coping style and behavior (i.e., substance use) as intermediate variables, among a group disproportionately affected by both trauma and HIV. Two hundred and ninety HIV-negative MSM with a history of childhood sexual abuse (CSA) completed a cross-sectional psychosocial battery. Trauma-related cognitions were positively associated with more acts of condomless sex. Indirect associations on condomless sex were driven by avoidance coping, but not substance use. Findings indicate a need to address trauma-related cognitions and avoidance coping within interventions for reducing HIV risk among MSM with a history of CSA.

Risk of Tendon Injury in Patients Treated With Fluoroquinolone (FQ) Versus Non-Fluoroquinolone Antibiotics for Community-Acquired Pneumonia (CAP).

BACKGROUND: Fluoroquinolones (FQs) are associated with increased risk of tendon injury but comparative risk versus other antibiotic options for the same indication has yet to be evaluated. OBJECTIVE: Describe the incidence (relative risk) of any tendon injury in patients receiving FQ compared with other (non-FQs) antibiotics for treatment of community-acquired pneumonia (CAP). METHODS: A retrospective propensity score weighted cohort study was performed to evaluate the association between FQ antibiotics and tendon injury risk at 2 time points (within 1 month and within 6 months of use) compared with non-FQ regimens for treatment of CAP. The evaluation was performed using the CCAE (MarketScan Commercial Claims and Encounters) and COB (Medicare Supplemental and Coordination of Benefits) databases from 2014 to 2020. Patients with ICD (International Classification of Diseases) 9/10 coding for outpatient pneumonia who were >18 years and without history of tendon injury were included. Patients with history of tendon injury, who received multiple antibiotic therapies for recurrent pneumonia, or who received both FQ and non-FQ regimens during the study period were excluded. Propensity score weighting was used to adjust for selection bias due to contributing risk factors, including demographics (age, sex), comorbidities (diabetes mellitus, chronic kidney disease), and concurrent medications (corticosteroids). RESULTS: At 1 month, the odds of tendon injury were estimated to be significantly higher (41.9%) in patients receiving FQs compared with those receiving a non-FQ-based regimen (odds ratio [OR] = 1.419, 95% confidence interval [CI] = [1.188-1.698]). The odds of tendon injury were also estimated to be higher (OR = 1.067, 95% CI = [0.975-1.173]) in the FQ population within 180 days, but this effect was not statistically significant. The most frequent sites of tendon injuries were rotator cuff, shoulder, and patellar tendon. CONCLUSIONS AND RELEVANCE: Prescribers should recognize the risk of tendon injury within 1 month of FQ use when considering treatment regimens for CAP and use alternative options with lower risk whenever possible.

MetfOrmin BenefIts Lower Extremities with Intermittent Claudication (MOBILE IC): randomized clinical trial protocol.

BACKGROUND: Peripheral artery disease (PAD) affects over 230 million people worldwide and is due to systemic atherosclerosis with etiology linked to chronic inflammation, hypertension, and smoking status. PAD is associated with walking impairment and mobility loss as well as a high prevalence of coronary and cerebrovascular disease. Intermittent claudication (IC) is the classic presenting symptom for PAD, although many patients are asymptomatic or have atypical presentations. Few effective medical therapies are available, while surgical and exercise therapies lack durability. Metformin, the most frequently prescribed oral medication for Type 2 diabetes, has salient anti-inflammatory and promitochondrial properties. We hypothesize that metformin will improve function, retard the progression of PAD, and improve systemic inflammation and mitochondrial function in non-diabetic patients with IC. METHODS: 200 non-diabetic Veterans with IC will be randomized 1:1 to 180-day treatment with metformin extended release (1000 mg/day) or placebo to evaluate the effect of metformin on functional status, PAD progression, cardiovascular disease events, and systemic inflammation. The primary outcome is 180-day maximum walking distance on the 6-min walk test (6MWT). Secondary outcomes include additional assessments of functional status (cardiopulmonary exercise testing, grip strength, Walking Impairment Questionnaires), health related quality of life (SF-36, VascuQoL), macro- and micro-vascular assessment of lower extremity blood flow (ankle brachial indices, pulse volume recording, EndoPAT), cardiovascular events (amputations, interventions, major adverse cardiac events, all-cause mortality), and measures of systemic inflammation. All outcomes will be assessed at baseline, 90 and 180 days of study drug exposure, and 180 days following cessation of study drug. We will evaluate the primary outcome with linear mixed-effects model analysis with covariate adjustment for baseline 6MWT, age, baseline ankle brachial indices, and smoking status following an intention to treat protocol. DISCUSSION: MOBILE IC is uniquely suited to evaluate the use of metformin to improve both systematic inflammatory responses, cellular energetics, and functional outcomes in patients with PAD and IC. TRIAL REGISTRATION: The prospective MOBILE IC trial was publicly registered (NCT05132439) November 24, 2021.

Representation of race and ethnicity among cancer survivors in trials of cognitive behavioral therapy for insomnia (CBT-I): A systematic review.

PURPOSE: For cancer survivors, insomnia is highly prevalent and debilitating. Although cognitive behavioral therapy for insomnia (CBT-I) is recognized as a gold standard treatment, it is unclear whether benefits of treatment generalize to racial and ethnic minorities in the USA. This systematic review characterizes the representation of racial and ethnic diversity among cancer survivors in CBT-I clinical trials and provides recommendations for research in sleep/cancer survivorship. METHODS: Literature searches were conducted in five electronic databases (PubMed, Cochrane Library via Ovid, PsycINFO via Ovid, Embase, Web of Science Core Collection) using concepts of CBT, insomnia, and cancer survivors. Information about CBT-I intervention details, sample racial demographics, and whether authors explicitly analyzed race and ethnicity were recorded. RESULTS: A total of 1673 citations were retrieved, and 967 citations were uploaded to Covidence. Of these, 135 articles went through full-text review and 13 studies were included. Race and ethnicity were reported in 11/13 trials (84.6%). Of those reporting race and ethnicity, 8/11 (72.7%) trials were comprised of samples that were ≥ 85% non-Hispanic White. Among the trials that explicitly analyzed race and ethnicity, CBT-I was more effective among cancer survivors who were White and highly educated, and non-White cancer survivors were less likely to have private insurance and ability to participate in clinical trials. CONCLUSION: Non-Hispanic White cancer survivors are overrepresented in CBT-I trials, the best available treatment for insomnia. Underrepresentation of racial and ethnic minorities likely contributes to barriers in access and uptake. Recommendations include implementing sustained efforts to expand diversity in CBT-I clinical trials for cancer survivors.

Do cancer curvivors and metavivors have distinct needs for stress management intervention? Retrospective analysis of a mind-body survivorship program.

PURPOSE: Cancer "curvivors" (completed initial curative intent treatment with surgery, radiation, chemotherapy, and/or other novel therapies) and "metavivors" (living with metastatic or chronic, incurable cancer) experience unique stressors, but it remains unknown whether these differences impact benefits from mind-body interventions. This study explored differences between curvivors and metavivors in distress (depression, anxiety, worry) and resiliency changes over the course of an 8-week group program, based in mind-body stress reduction, cognitive-behavioral therapy (CBT), and positive psychology. METHODS: From 2017-2021, 192 cancer survivors (83% curvivors; 17% metavivors) completed optional online surveys of resiliency (CES) and distress (PHQ-8, GAD-7, PSWQ-3) pre- and post- participation in an established clinical program. Mixed effect regression models explored curvivor-metavivor differences at baseline and in pre-post change. RESULTS: Compared to curvivors, metavivors began the program with significantly more resilient health behaviors (B = 0.99, 95% CI[0.12, 1.86], p = .03) and less depression (B = -2.42, 95%CI[-4.73, -0.12], p = .04), with no other significant differences. Curvivors experienced significantly greater reductions in depression (curvivor-metavivor difference in strength of change = 2.12, 95% CI [0.39, 3.83], p = .02) over the course of the program, with no other significant differences. Neither virtual delivery modality nor proportion of sessions attended significantly moderated strength of resiliency or distress change. CONCLUSION: Metavivors entering this mind-body program had relatively higher well-being than did curvivors, and both groups experienced statistically comparable change in all domains other than depression. Resiliency programming may thus benefit a variety of cancer survivors, including those living with incurable cancer.

Hypothalamus-pituitary-interrenal (HPI) axis signaling in Atlantic sturgeon (Acipenser oxyrinchus) and sterlet (Acipenser ruthenus).

In vertebrates, the hypothalamic-pituitaryadrenal/interrenal (HPA/HPI) axis is a highly conserved endocrine axis that regulates glucocorticoid production via signaling by corticotropin releasing hormone (CRH) and adrenocorticotropic hormone (ACTH). Once activated by ACTH, Gs protein-coupled melanocortin 2 receptors (Mc2r) present in corticosteroidogenic cells stimulate expression of steroidogenic acute regulatory protein (Star), which initiates steroid biosynthesis. In the present study, we examined the tissue distribution of genes involved in HPI axis signaling and steroidogenesis in the Atlantic sturgeon (Acipenser oxyrinchus) and provided the first functional characterization of Mc2r in sturgeon. Mc2r of A. oxyrinchus and the sterlet sturgeon (Acipenser ruthenus) are co-dependent on interaction with the melanocortin receptor accessory protein 1 (Mrap1) and highly selective for human (h) ACTH over other melanocortin ligands. A. oxyrinchus expresses key genes involved in HPI axis signaling in a tissue-specific manner that is indicative of the presence of a complete HPI axis in sturgeon. Importantly, we co-localized mc2r, mrap1, and star mRNA expression to the head kidney, indicating that this is possibly a site of ACTH-mediated corticosteroidogenesis in sturgeon. Our results are discussed in the context of other studies on the HPI axis of basal bony vertebrates, which, when taken together, demonstrate a need to better resolve the evolution of HPI axis signaling in vertebrates.

PIM-induced phosphorylation of Notch3 promotes breast cancer tumorigenicity in a CSL-independent fashion.

Dysregulation of the developmentally important Notch signaling pathway is implicated in several types of cancer, including breast cancer. However, the specific roles and regulation of the four different Notch receptors have remained elusive. We have previously reported that the oncogenic PIM kinases phosphorylate Notch1 and Notch3. Phosphorylation of Notch1 within the second nuclear localization sequence of its intracellular domain (ICD) enhances its transcriptional activity and tumorigenicity. In this study, we analyzed Notch3 phosphorylation and its functional impact. Unexpectedly, we observed that the PIM target sites are not conserved between Notch1 and Notch3. Notch3 ICD (N3ICD) is phosphorylated within a domain, which is essential for formation of a transcriptionally active complex with the DNA-binding protein CSL. Through molecular modeling, X-ray crystallography, and isothermal titration calorimetry, we demonstrate that phosphorylation of N3ICD sterically hinders its interaction with CSL and thereby inhibits its CSL-dependent transcriptional activity. Surprisingly however, phosphorylated N3ICD still maintains tumorigenic potential in breast cancer cells under estrogenic conditions, which support PIM expression. Taken together, our data indicate that PIM kinases modulate the signaling output of different Notch paralogs by targeting distinct protein domains and thereby promote breast cancer tumorigenesis via both CSL-dependent and CSL-independent mechanisms.