Impact of a digital employer-based weight loss program on individuals age 65 or older.

Introduction: Older adults are not protected from obesity, which has been linked to frailty, cognitive impairment, and other aging-related factors. Intensive lifestyle interventions have been shown to be effective for weight loss in older adults; however, these have typically been highly intensive and less feasible for dissemination. This analysis describes weight loss in a large-scale, commercially available, digital intervention in a subset of older adults. Methods: Older adults (N = 20,443, males = 6,238; females = 14,205) between 65 and 85 years of age with overweight (43.3%) or obesity (46.7%) participated in an online, self-directed weight loss program. Behavioral-based content was delivered through weekly video lessons within an online platform that included weight and physical activity tracking, an online community, a reference library, and access to coaching support. Self-reported measures taken at the time of entry into the program were used for this analysis (demographics, height, body weight, and health status). Weight was reported across weeks of engagement in the curriculum. Results: The average weight loss was -3.15 kg (95% CI: [-3.20, -3.11]) at 15.5 weeks. Weight loss was significantly greater in male individuals (-3.79 kg [95% CI: -3.89, -3.71]) versus female individuals (-2.87 kg [95% CI: -2.94, -2.82]) (p < 0.001), with a similar engagement in curriculum weeks. Percent weight loss was statistically significant for all age categories (p < 0.05) and self-reported health conditions (p < 0.05). Discussion: Short-term weight loss was observed in older adults exposed to a low-touch, self-guided, and digital behavioral-based weight loss program. Weight loss was also observed even in the presence of various chronic health conditions.

Effects of aerobic and resistance exercise for 9 months on serum free light chains in type 2 diabetes.

Background and aims: Serum polyclonal free light chains (FLCs) levels are associated with overall survival in the general population, reflecting their utility as a biomarker of underlying immune activation and inflammation. Regular exercise is known to ameliorate low-grade inflammation in chronic diseases such as type 2 diabetes; however, the effects of different exercise training modalities on FLCs in adults with type 2 diabetes is unknown. This study investigated the effects of 9-month of aerobic, resistance or combined supervised exercise on serum FLCs in 164 patients with type 2 diabetes (age 58 ± 8 years; 63% female). Methods: 164 participants from the Health Benefits of Aerobic and Resistance Training in individuals with type 2 diabetes trial (HART-D) were randomly assigned to no exercise (n = 27), aerobic exercise alone (n = 41), resistance exercise alone (n = 49), or a combination of aerobic and resistance exercise (n = 47). Fasting serum samples were collected before and after completion of the intervention to quantify changes in kappa and lambda FLCs, and serum creatinine, using commercially-available ELISAs. Results: At baseline, combined kappa and lambda FLCs (FLC sum; calculated as kappa + lambda FLCs) were positively correlated with high-sensitive C-reactive protein (hs-CRP) (r = 0.237, p < 0.05) and fat mass (r = 0.162, p < 0.05), and negatively associated with aerobic fitness (r = -0.238, p < 0.05). While non-exercise controls exhibited an increase in FLCs over the 9-month study, exercise training blunted this increase (Δ FLC sum control arm: 3.25 ± 5.07 mg∙L-1 vs. all exercise arms: -0.252 ± 6.60 mg∙L-1, p < 0.05), regardless of exercise modality. Conclusion: Serum FLCs were associated with physical fitness and body composition in patients with type 2 diabetes. 9-month of exercise training prevented the accumulation of FLCs, regardless of exercise modality. Unlike hs-CRP-which did not change during the trial-serum FLCs may serve as a more sensitive biomarker of chronic low-grade inflammation in this population.

Projected Colorectal Cancer Incidence and Mortality Based on Observed Adherence to Colonoscopy and Sequential Stool-Based Screening.

INTRODUCTION: Modeling supporting recommendations for colonoscopy and stool-based colorectal cancer (CRC) screening tests assumes 100% sequential participant adherence. The impact of observed adherence on the long-term effectiveness of screening is unknown. We evaluated the effectiveness of a program of screening colonoscopy every 10 years vs annual high-sensitivity guaiac-based fecal occult blood testing (HSgFOBT) using observed sequential adherence data. METHODS: The MIcrosimulation SCreening ANalysis (MISCAN) model used observed sequential screening adherence, HSgFOBT positivity, and diagnostic colonoscopy adherence in HSgFOBT-positive individuals from the National Colonoscopy Study (single-screening colonoscopy vs ≥4 HSgFOBT sequential rounds). We compared CRC incidence and mortality over 15 years with no screening or 10 yearly screening colonoscopy vs annual HSgFOBT with 100% and differential observed adherence from the trial. RESULTS: Without screening, simulated incidence and mortality over 15 years were 20.9 (95% probability interval 15.8-26.9) and 6.9 (5.0-9.2) per 1,000 participants, respectively. In the case of 100% adherence, only screening colonoscopy was predicted to result in lower incidence; however, both tests lowered simulated mortality to a similar level (2.1 [1.6-2.9] for screening colonoscopy and 2.5 [1.8-3.4] for HSgFOBT). Observed adherence for screening colonoscopy (83.6%) was higher than observed sequential HSgFOBT adherence (73.1% first round; 49.1% by round 4), resulting in lower simulated incidence and mortality for screening colonoscopy (14.4 [10.8-18.5] and 2.9 [2.1-3.9], respectively) than HSgFOBT (20.8 [15.8-28.1] and 3.9 [2.9-5.4], respectively), despite a 91% adherence to diagnostic colonoscopy with FOBT positivity. The relative risk of CRC mortality for screening colonoscopy vs HSgFOBT was 0.75 (95% probability interval 0.68-0.80). Findings were similar in sensitivity analyses with alternative assumptions for repeat colonoscopy, test performance, risk, age, and projection horizon. DISCUSSION: Where sequential adherence to stool-based screening is suboptimal and colonoscopy is accessible and acceptable-as observed in the national colonoscopy study, microsimulation, comparative effectiveness, screening recommendations.

Multilevel Interventions to Improve Colorectal Cancer Screening in an Urban Native American Community: A Pilot Randomized Clinical Trial.

Native Americans have the highest burden of colorectal cancer (CRC) and the lowest rates of CRC screening across the United States.1 The disparities in CRC screening were made worse during the pandemic, creating an unmet need to implement evidence-based, multilevel interventions to improve CRC screening uptake. This can be achieved through an organized outreach program with identification of screen-eligible individuals using health records from the clinic; and a screening program with the following: (1) a mailed invitation, (2) a package of materials so patients can complete a fecal immunochemical test (FIT) kit from their homes, (3) reminder calls and a letter, and (4) navigation to a diagnostic colonoscopy.2-5 We conducted a pilot randomized controlled trial of a program of outreach vs usual care for completion of CRC screening at an urban clinic serving the Native American community. Applying the Consolidated Framework for Implementation Research (CFIR),6 we also conducted patient and provider interviews to understand barriers and facilitators to the organized program and CRC screening in general.

Mortality and cancer incidence in perfluorooctanesulfonyl fluoride production workers.

BACKGROUND: Exposure to per- and polyfluoroalkyl substances (PFAS) has been associated with several health outcomes, though few occupationally-exposed populations have been studied. We evaluated mortality and cancer incidence in a cohort of perfluorooctanesulfonyl fluoride-based specialty chemical manufacturing workers. METHODS: The cohort included any employee who ever worked at the facility from 1961 to 2010 (N = 4045), with a primary interest in those who had 365 cumulative days of employment (N = 2659). Vital status and mortality records were obtained through 2014 and the cohort was linked to state cancer registries to obtain incident cancer cases from 1995 to 2014. Cumulative exposure was derived from a comprehensive exposure reconstruction that estimated job-specific perfluorooctanesulfonate (PFOS)-equivalents (mg/m3 ) exposure. Overall and exposure-specific standardized mortality ratios (SMR) were estimated in reference to the US population. Hazard ratios (HRs) and 95% confidence interval (CI) for cumulative PFOS-equivalent exposure (log2 transformed) were estimated within the cohort for specific causes of death and incident cancers using a time-dependent Cox model. RESULTS: Death rates were lower than expected except for cerebrovascular disease (SMR = 2.42, 95% CI = 1.25-4.22) and bladder cancer (SMR = 3.91, 95% CI = 1.07-10.02) in the highest exposure quartile. Within the cohort, the incidence of bladder, colorectal, and pancreatic cancer were positively associated with exposure, however except for lung cancer (HR = 1.05, 95% CI = 1.00-1.11) the CIs did not exclude an HR of 1. CONCLUSIONS: This study provides some evidence that occupational exposure to PFOS is associated with bladder and lung cancers and with cerebrovascular disease.

Effect of ginger supplementation on the fecal microbiome in subjects with prior colorectal adenoma.

Ginger has been associated with a decreased incidence of colorectal cancer (CRC) through reduction in inflammatory pathways and inhibition of tumor growth. Recent pre-clinical models have implicated changes in the gut microbiome as a possible mediator of the ginger effect on CRC. We hypothesized that, in adults previously diagnosed with a colorectal adenoma, ginger supplementation would alter the fecal microbiome in the direction consistent with its CRC-inhibitory effect. Sixty-eight adults were randomized to take either ginger or placebo daily for 6 weeks, with a 6-week washout and longitudinal stool collection throughout. We performed 16S rRNA sequencing and evaluated changes in overall microbial diversity and the relative abundances of pre-specified CRC-associated taxa using mixed-effects logistic regression. Ginger supplementation showed no significant effect on microbial community structure through alpha or beta diversity. Of 10 pre-specified CRC-associated taxa, there were significant decreases in the relative abundances of the genera Akkermansia (p < 0.001), Bacteroides (p = 0.018), and Ruminococcus (p = 0.013) after 6-week treatment with ginger compared to placebo. Ginger supplementation led to decreased abundances of Akkermansia and Bacteroides, which suggests that ginger may have an inhibitory effect on CRC-associated taxa. Overall, ginger supplementation appears to have a limited effect on gut microbiome in patients with colorectal adenomas.

Internal-state-dependent control of feeding behavior via hippocampal ghrelin signaling.

Hunger is an internal state that not only invigorates feeding but also acts as a contextual cue for higher-order control of anticipatory feeding-related behavior. The ventral hippocampus is crucial for differentiating optimal behavior across contexts, but how internal contexts such as hunger influence hippocampal circuitry is unknown. In this study, we investigated the role of the ventral hippocampus during feeding behavior across different states of hunger in mice. We found that activity of a unique subpopulation of neurons that project to the nucleus accumbens (vS-NAc neurons) increased when animals investigated food, and this activity inhibited the transition to begin eating. Increases in the level of the peripheral hunger hormone ghrelin reduced vS-NAc activity during this anticipatory phase of feeding via ghrelin-receptor-dependent increases in postsynaptic inhibition and promoted the initiation of eating. Together, these experiments define a ghrelin-sensitive hippocampal circuit that informs the decision to eat based on internal state.

Screening for lung cancer: 2023 guideline update from the American Cancer Society.

Lung cancer is the leading cause of mortality and person-years of life lost from cancer among US men and women. Early detection has been shown to be associated with reduced lung cancer mortality. Our objective was to update the American Cancer Society (ACS) 2013 lung cancer screening (LCS) guideline for adults at high risk for lung cancer. The guideline is intended to provide guidance for screening to health care providers and their patients who are at high risk for lung cancer due to a history of smoking. The ACS Guideline Development Group (GDG) utilized a systematic review of the LCS literature commissioned for the US Preventive Services Task Force 2021 LCS recommendation update; a second systematic review of lung cancer risk associated with years since quitting smoking (YSQ); literature published since 2021; two Cancer Intervention and Surveillance Modeling Network-validated lung cancer models to assess the benefits and harms of screening; an epidemiologic and modeling analysis examining the effect of YSQ and aging on lung cancer risk; and an updated analysis of benefit-to-radiation-risk ratios from LCS and follow-up examinations. The GDG also examined disease burden data from the National Cancer Institute's Surveillance, Epidemiology, and End Results program. Formulation of recommendations was based on the quality of the evidence and judgment (incorporating values and preferences) about the balance of benefits and harms. The GDG judged that the overall evidence was moderate and sufficient to support a strong recommendation for screening individuals who meet the eligibility criteria. LCS in men and women aged 50-80 years is associated with a reduction in lung cancer deaths across a range of study designs, and inferential evidence supports LCS for men and women older than 80 years who are in good health. The ACS recommends annual LCS with low-dose computed tomography for asymptomatic individuals aged 50-80 years who currently smoke or formerly smoked and have a ≥20 pack-year smoking history (strong recommendation, moderate quality of evidence). Before the decision is made to initiate LCS, individuals should engage in a shared decision-making discussion with a qualified health professional. For individuals who formerly smoked, the number of YSQ is not an eligibility criterion to begin or to stop screening. Individuals who currently smoke should receive counseling to quit and be connected to cessation resources. Individuals with comorbid conditions that substantially limit life expectancy should not be screened. These recommendations should be considered by health care providers and adults at high risk for lung cancer in discussions about LCS. If fully implemented, these recommendations have a high likelihood of significantly reducing death and suffering from lung cancer in the United States.

Physical activity in the new era of antiobesity medications.

Contemporary antiobesity medications (AOMs) are highly efficacious for the treatment of obesity and obesity-related comorbidities. Given this effectiveness, lifestyle factors within the context of AOM treatments need to refocus and move away from efforts to enhance weight loss. Rather, lifestyle considerations should pivot to being complementary to the benefits realized with AOM treatment and be redirected to enhancing holistic patient health and well-being. Physical activity is an important lifestyle behavior that contributes to many health benefits both in conjunction with, and in the absence of, weight loss. Physical activity improves cardiorespiratory fitness, muscle strength, and physical function. Physical activity may attenuate the loss of lean mass that is observed with AOM treatments and may enhance the quality and function of muscle. Physical activity is a key behavior for holistic health within this era of contemporary AOMs that warrants appropriate attention within the clinical care of patients.

Strength training is more effective than aerobic exercise for improving glycaemic control and body composition in people with normal-weight type 2 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: Type 2 diabetes in people in the healthy weight BMI category (<25 kg/m2), herein defined as 'normal-weight type 2 diabetes', is associated with sarcopenia (low muscle mass). Given this unique body composition, the optimal exercise regimen for this population is unknown. METHODS: We conducted a parallel-group RCT in individuals with type 2 diabetes (age 18-80 years, HbA1c 47.5-118.56 mmol/mol [6.5-13.0%]) and BMI <25 kg/m2). Participants were recruited in outpatient clinics or through advertisements and randomly assigned to a 9 month exercise programme of strength training alone (ST), aerobic training alone (AER) or both interventions combined (COMB). We used stratified block randomisation with a randomly selected block size. Researchers and caregivers were blinded to participants' treatment group; however, participants themselves were not. Exercise interventions were conducted at community-based fitness centres. The primary outcome was absolute change in HbA1c level within and across the three groups at 3, 6 and 9 months. Secondary outcomes included changes in body composition at 9 months. Per adherence to recommended exercise protocol (PP) analysis included participants who completed at least 50% of the sessions. RESULTS: Among 186 individuals (ST, n=63; AER, n=58; COMB, n=65) analysed, the median (IQR) age was 59 (53-66) years, 60% were men and 83% were Asian. The mean (SD) HbA1c level at baseline was 59.6 (13.1) mmol/mol (7.6% [1.2%]). In intention-to-treat analysis, the ST group showed a significant decrease in HbA1c levels (mean [95% CI] -0.44 percentage points [-0.78, -0.12], p=0.002), while no significant change was observed in either the COMB group (-0.35 percentage points, p=0.13) or the AER group (-0.24 percentage points, p=0.10). The ST group had a greater improvement in HbA1c levels than the AER group (p=0.01). Appendicular lean mass relative to fat mass increased only in the ST group (p=0.0008), which was an independent predictor of HbA1c change (beta coefficient -7.16, p=0.01). Similar results were observed in PP analysis. Only one adverse event, in the COMB group, was considered to be possibly associated with the exercise intervention. CONCLUSIONS/INTERPRETATION: In normal-weight type 2 diabetes, strength training was superior to aerobic training alone, while no significant difference was observed between strength training and combination training for HbA1c reduction. Increased lean mass relative to decreased fat mass was an independent predictor of reduction in HbA1c level. TRIAL REGISTRATION: ClinicalTrials.gov NCT02448498. FUNDING: This study was funded by the National Institutes of Health (NIH; R01DK081371).

Modeled residual current cancer risk after clinical investigation of a positive multicancer early detection test result.

BACKGROUND: Positive results of a multi-cancer early detection (MCED) test require confirmatory diagnostic workup. Here, residual current cancer risk (RR) during the process of diagnostic resolution, including situations where the initial confirmatory test does not provide resolution, was modeled. METHODS: A decision-tree framework was used to model conditional risk in a patient's journey through confirmatory diagnostic options and outcomes. The diagnostic journey assumed that cancer signal detection (a positive MCED test result) had already led to a transition from screening to diagnosis and began with an initial positive predictive value (PPV) from the positive result. Evaluation of a most probable (top) predicted cancer signal origin (CSO) and then a second-most probable predicted CSO followed. Under the assumption that the top- and second-predicted CSOs were each followed by a targeted confirmatory test, the RR was estimated for each subsequent scenario. RESULTS: For an initial MCED test result with typical performance characteristics modeled (PPV, 40%; top-predicted CSO accuracy, 90%), after a negative initial confirmatory test (sensitivity, 70%, 90%, or 100%) the RR ranged from 6% to 20%. A second-predicted CSO (accuracy, 50%), after a negative second confirmatory test, still provided a significant RR (3%-18%) in comparison with the National Institute for Health and Care Excellence-recommended cancer risk threshold warranting investigation in symptomatic individuals (3%). With a 40% PPV for an MCED test and 90% specificity for a confirmatory test, the risk of incidental findings after one or two confirmatory tests was 6% and 12%, respectively. CONCLUSIONS: These results may illustrate the impact of a positive MCED test on follow-up decision-making.

Randomized Trial of Facilitated Adherence to Screening Colonoscopy vs Sequential Fecal-Based Blood Test.

BACKGROUND & AIMS: Colorectal cancer (CRC) screening guidelines include screening colonoscopy and sequential high-sensitivity fecal occult blood testing (HSgFOBT), with expectation of similar effectiveness based on the assumption of similar high adherence. However, adherence to screening colonoscopy compared with sequential HSgFOBT has not been reported. In this randomized clinical trial, we assessed adherence and pathology findings for a single screening colonoscopy vs sequential and nonsequential HSgFOBTs. METHODS: Participants aged 40-69 years were enrolled at 3 centers representing different clinical settings. Participants were randomized into a single screening colonoscopy arm vs sequential HSgFOBT arm composed of 4-7 rounds. Initial adherence to screening colonoscopy and sequential adherence to HSgFOBT, follow-up colonoscopy for positive HSgFOBT tests, crossover to colonoscopy, and detection of advanced neoplasia or large serrated lesions (ADN-SERs) were measured. RESULTS: There were 3523 participants included in the trial; 1761 and 1762 participants were randomized to the screening colonoscopy and HSgFOBT arms, respectively. Adherence was 1473 (83.6%) for the screening colonoscopy arm vs 1288 (73.1%) for the HSgFOBT arm after 1 round (relative risk [RR], 1.14; 95% CI, 1.10-1.19; P ≤ .001), but only 674 (38.3%) over 4 sequential HSgFOBT rounds (RR, 2.19; 95% CI, 2.05-2.33). Overall adherence to any screening increased to 1558 (88.5%) in the screening colonoscopy arm during the entire study period and 1493 (84.7%) in the HSgFOBT arm (RR, 1.04; 95% CI, 1.02-1.07). Four hundred thirty-six participants (24.7%) crossed over to screening colonoscopy during the first 4 rounds. ADN-SERs were detected in 121 of the 1473 participants (8.2%) in the colonoscopy arm who were adherent to protocol in the first 12 months of the study, whereas detection of ADN-SERs among those who were not sequentially adherent (n = 709) to HSgFOBT was subpar (0.6%) (RR, 14.72; 95% CI, 5.46-39.67) compared with those who were sequentially adherent (3.3%) (n = 647) (RR, 2.52; 95% CI, 1.61-3.98) to HSgFOBT in the first 4 rounds. When including colonoscopies from HSgFOBT patients who were never positive yet crossed over (n = 1483), 5.5% of ADN-SERs were detected (RR, 1.50; 95% CI, 1.15-1.96) in the first 4 rounds. CONCLUSIONS: Observed adherence to sequential rounds of HSgFOBT was suboptimal compared with a single screening colonoscopy. Detection of ADN-SERs was inferior when nonsequential HSgFOBT adherence was compared with sequential adherence. However, the greatest number of ADN-SERs was detected among those who crossed over to colonoscopy and opted to receive a colonoscopy. The effectiveness of an HSgFOBT screening program may be enhanced if crossover to screening colonoscopy is permitted. CLINICALTRIALS: gov, Number: NCT00102011.

Link for Equity, a community-engaged waitlist randomized controlled trial of a culturally responsive trauma-informed care program for BIPOC students: Design features and characteristics of baseline sample.

BACKGROUND: Link for Equity is a multi-tiered, school-based program of trauma-informed care and cultural humility designed to reduce the impact of Adverse Child Experiences among Black Indigenous and other children of color (BIPOC). This report describes the program, its trial design, and the study participants' baseline characteristics. METHODS: We designed a nested waitlist-controlled trial to evaluate Link for Equity's effectiveness in reducing school violence among BIPOC students. Three pairs of school districts, matched on suspension rates and enrollment of Black/African American, Hispanic/Latinx, and American Indian/Alaska Native children, were randomized into either an intervention or delayed intervention (waitlist control) group. A community-engaged approach guided the development of protocols. Within intervention sites, BIPOC students who screened positive for ACEs or posttraumatic stress were also randomized into an immediate and waitlist control group to receive additional one-on-one support from trained school staff. RESULTS: The trial was implemented from 2019 to 2021, which overlapped with the pandemic and civil unrest in Minnesota. At baseline, 444 staff and 188 students enrolled in the study. Over a quarter of American Indian/Alaska Native students, 18% of multiple race, 12% of Black/African American, 14% of Hispanic/Latinx students reported 4+ ACEs. Between 44 and 53% of all the BIPOC students in the study were symptomatic for PTSD. Of the enrolled students, 78.7% qualified for one-on-one Link support. CONCLUSION: We implemented a multilevel waitlist-controlled trial of Link for Equity using community-engaged methods. Despite school closures during the pandemic, the study persisted with its methods now being employed in an expanded cohort of middle schools. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04026477, NCT04026490).

Exercise Training, Cardiac Biomarkers, and Cardiorespiratory Fitness in Type 2 Diabetes: The HART-D Study.

Background: High-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are cardiac biomarkers commonly detected in adults with type 2 diabetes (T2D) and are associated with heart failure risk. Objectives: The purpose of this study was to evaluate the effects of exercise training (ET) on hs-cTnT and NT-proBNP and evaluate the associations of these biomarkers with cardiorespiratory fitness among adults with T2D. Methods: Participants of the HART-D (Health Benefits of Aerobic and Resistance Training in Individuals with Type 2 Diabetes) trial who were randomly assigned to one of 3 ET groups or a non-exercise control group were included. Cardiac biomarkers and cardiorespiratory fitness (evaluated by peak oxygen uptake [VO2peak]) were assessed at baseline and after 9 months. The effects of ET (3 ET groups pooled) vs non-exercise control on hs-cTnT and NT-proBNP were assessed using separate analysis of covariance models. Multivariable-adjusted linear regression was performed to identify factors associated with follow-up biomarkers and ΔVO2peak. Results: The present study included 166 participants randomized to the ET (n = 135) and non-exercise control (n = 31) groups. Compared with the non-exercise control, ET did not significantly change hs-cTnT or NT-proBNP. In adjusted analysis, each ET group and ΔVO2peak were not significantly associated with hs-cTnT or NT-proBNP levels on follow-up. Among individuals in the ET group, baseline hs-cTnT was inversely associated with ΔVO2peak [per 1 SD higher log (hs-cTnT): ß = -0.08 (95% CI = -0.15 to -0.01)]. Conclusions: Among individuals with T2D, ET did not modify cardiac biomarkers. Higher baseline hs-cTnT was associated with blunted cardiorespiratory fitness improvement in response to exercise.

Tau isoform-specific enhancement of L-type calcium current and augmentation of afterhyperpolarization in rat hippocampal neurons.

Accumulation of tau is observed in dementia, with human tau displaying 6 isoforms grouped by whether they display either 3 or 4 C-terminal repeat domains (3R or 4R) and exhibit no (0N), one (1N) or two (2N) N terminal repeats. Overexpression of 4R0N-tau in rat hippocampal slices enhanced the L-type calcium (Ca2+) current-dependent components of the medium and slow afterhyperpolarizations (AHPs). Overexpression of both 4R0N-tau and 4R2N-tau augmented CaV1.2-mediated L-type currents when expressed in tsA-201 cells, an effect not observed with the third 4R isoform, 4R1N-tau. Current enhancement was only observed when the pore-forming subunit was co-expressed with CaVß3 and not CaVß2a subunits. Non-stationary noise analysis indicated that enhanced Ca2+ channel current arose from a larger number of functional channels. 4R0N-tau and CaVß3 were found to be physically associated by co-immunoprecipitation. In contrast, the 4R1N-tau isoform that did not augment expressed macroscopic L-type Ca2+ current exhibited greatly reduced binding to CaVß3. These data suggest that physical association between tau and the CaVß3 subunit stabilises functional L-type channels in the membrane, increasing channel number and Ca2+ influx. Enhancing the Ca2+-dependent component of AHPs would produce cognitive impairment that underlie those seen in the early phases of tauopathies.

Interindividual Differences in Trainability and Moderators of Cardiorespiratory Fitness, Waist Circumference, and Body Mass Responses: A Large-Scale Individual Participant Data Meta-analysis.

Although many studies have assumed variability reflects variance caused by exercise training, few studies have examined whether interindividual differences in trainability are present following exercise training. The present individual participant data (IPD) meta-analysis sought to: (1) investigate the presence of interindividual differences in trainability for cardiorespiratory fitness (CRF), waist circumference, and body mass; and (2) examine the influence of exercise training and potential moderators on the probability that an individual will experience clinically important differences. The IPD meta-analysis combined data from 1879 participants from eight previously published randomized controlled trials. We implemented a Bayesian framework to: (1) test the hypothesis of interindividual differences in trainability by comparing variability in change scores between exercise and control using Bayes factors; and (2) compare posterior predictions of control and exercise across a range of moderators (baseline body mass index (BMI) and exercise duration, intensity, amount, mode, and adherence) to estimate the proportions of participants expected to exceed minimum clinically important differences (MCIDs) for all three outcomes. Bayes factors demonstrated a lack of evidence supporting a high degree of variance attributable to interindividual differences in trainability across all three outcomes. These findings indicate that interindividual variability in observed changes are likely due to measurement error and external behavioural factors, not interindividual differences in trainability. Additionally, we found that a larger proportion of exercise participants were expected to exceed MCIDs compared with controls for all three outcomes. Moderator analyses identified that larger proportions were associated with a range of factors consistent with standard exercise theory and were driven by mean changes. Practitioners should prescribe exercise interventions known to elicit large mean changes to increase the probability that individuals will experience beneficial changes in CRF, waist circumference and body mass.

Computer-Aided Detection Improves Adenomas per Colonoscopy for Screening and Surveillance Colonoscopy: A Randomized Trial.

BACKGROUND & AIMS: Colonoscopy for colorectal cancer screening is endoscopist dependent, and colonoscopy quality improvement programs aim to improve efficacy. This study evaluated the clinical benefit and safety of using a computer-aided detection (CADe) device in colonoscopy procedures. METHODS: This randomized study prospectively evaluated the use of a CADe device at 5 academic and community centers by US board-certified gastroenterologists (n = 22). Participants aged ≥40 scheduled for screening or surveillance (≥3 years) colonoscopy were included; exclusion criteria included incomplete procedure, diagnostic indication, inflammatory bowel disease, and familial adenomatous polyposis. Patients were randomized by endoscopist to the standard or CADe colonoscopy arm using computer-generated, random-block method. The 2 primary endpoints were adenomas per colonoscopy (APC), the total number of adenomas resected divided by the total number of colonoscopies; and true histology rate (THR), the proportion of resections with clinically significant histology divided by the total number of polyp resections. The primary analysis used a modified intention-to-treat approach. RESULTS: Between January and September 2021, 1440 participants were enrolled to be randomized. After exclusion of participants who did not meet the eligibility criteria, 677 in the standard arm and 682 in the CADe arm were included in a modified intention-to-treat analysis. APC increased significantly with use of the CADe device (standard vs CADe: 0.83 vs 1.05, P = .002; total number of adenomas, 562 vs 719). There was no decrease in THR with use of the CADe device (standard vs CADe: 71.7% vs 67.4%, P for noninferiority < .001; total number of non-neoplastic lesions, 284 vs 375). Adenoma detection rate was 43.9% and 47.8% in the standard and CADe arms, respectively (P = .065). CONCLUSIONS: For experienced endoscopists performing screening and surveillance colonoscopies in the United States, the CADe device statistically improved overall adenoma detection (APC) without a concomitant increase in resection of non-neoplastic lesions (THR). CLINICALTRIALS: gov registration: NCT04754347.