Frailty and risk of mortality in older cancer survivors and adults without a cancer history: Evidence from the National Health and Nutrition Examination Survey, 1999-2014.

BACKGROUND: Epidemiologic evidence reporting the role of frailty in survival among older adults with a prior cancer diagnosis is limited. METHODS: A total of 2050 older adults (≥60 years old) surviving for at least 1 year after a cancer diagnosis and 9474 older adults without a cancer history from the National Health and Nutrition Examination Survey (1999-2014) were included for analysis. The exposure variable, a 45-item frailty index (FI), was categorized on the basis of validated cutoffs (FI ≤ 0.10 [fit], 0.10 < FI ≤ 0.21 [prefrail], and FI > 0.21 [frail]). All-cause mortality was ascertained via the National Death Index. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs) and 95% confidence interval (CIs) for the FI, and this was followed by restricted cubic splines depicting dose-response curves. RESULTS: For older cancer survivors, the mean age at the baseline was 72.6 years (SD, 7.1 years); 5.9% were fit, 38.2% were prefrail, and 55.9% were frail. Older adults without a cancer history were slightly younger (mean age, 70.0 years) and less frail (47.9% were frail). At each level of the FI, cancer survivors (1.9 per 100 person-years for FI ≤ 0.10, 3.4 per 100 person-years for 0.10 < FI ≤ 0.21, and 7.5 per 100 person-years for FI > 0.21) had higher mortality than their cancer-free counterparts (1.4 per 100 person-years for FI ≤ 0.10, 2.4 per 100 person-years for 0.10 < FI ≤ 0.21, and 5.4 per 100 person-years for FI > 0.21). The multivariable model suggested a positive association between the FI and all-cause mortality for survivors (aHR for FI > 0.21 vs FI ≤ 0.10, 2.80; 95% CI, 1.73-4.53) and participants without a cancer history (aHR for FI > 0.21 vs FI ≤ 0.10, 2.75; 95% CI, 2.29-3.32). Restricted cubic splines indicated that all-cause mortality risk increased with the FI in a monotonic pattern. CONCLUSIONS: Frailty is associated with a higher risk of death in older cancer survivors and the elderly without a cancer history.

Novel insights on the role of spexin as a biomarker of obesity and related cardiometabolic disease.

Spexin (SPX) is a 14-amino acid neuropeptide, discovered recently using bioinformatic techniques. It is encoded by the Ch12:orf39 gene that is widely expressed in different body tissues/organs across species, and secreted into systemic circulation. Recent reports have highlighted a potentially important regulatory role of SPX in obesity and related comorbidities. SPX is also ubiquitously expressed in human tissues, including white adipose tissue. The circulating concentration of SPX is significantly lower in individuals with obesity compared to normal weight counterparts. SPX's role in obesity appears to be related to various factors, such as the regulation of energy expenditure, appetite, and eating behaviors, increasing locomotion, and inhibiting long-chain fatty acid uptake into adipocytes. Recent reports have also suggested SPX's relationship with novel biomarkers of cardiovascular disease (CVD) and glucose metabolism and evoked the potential role of SPX as a key biomarker/player in the early loss of cardiometabolic health and development of CVD and diabetes later in life. Data on age-related changes in SPX and SPX's response to various interventions are also emerging. The current review focuses on the role of SPX in obesity and related comorbidities across the life span, and its response to interventions in these conditions. It is expected that this article will provide new ideas for future research on SPX and its metabolic regulation, particularly related to cardiometabolic diseases.

Current Epidemiology of Surgical Sepsis: Discordance Between Inpatient Mortality and 1-year Outcomes.

OBJECTIVE: We sought to compare traditional inpatient outcomes to long-term functional outcomes and mortality of surgical intensive care unit (SICU) patients with sepsis. SUMMARY OF BACKGROUND DATA: As inpatient sepsis mortality declines, an increasing number of initial sepsis survivors now progress into a state of chronic critical illness (CCI) and their post-discharge outcomes are unclear. METHODS: We performed a prospective, longitudinal cohort study of SICU patients with sepsis. RESULTS: Among this recent cohort of 301 septic SICU patients, 30-day mortality was 9.6%. Only 13 (4%) patients died within 14 days, primarily of refractory multiple organ failure (62%). The majority (n = 189, 63%) exhibited a rapid recovery (RAP), whereas 99 (33%) developed CCI. CCI patients were older, with greater comorbidities, and more severe and persistent organ dysfunction than RAP patients (all P < 0.01). At 12 months, overall cohort performance status was persistently worse than presepsis baseline (WHO/Zubrod score 1.4 ±â€Š0.08 vs 2.2 ±â€Š0.23, P > 0.0001) and mortality was 20.9%. Of note at 12 months, the CCI cohort had persistent severely impaired performance status and a much higher mortality (41.4%) than those with RAP (4.8%) after controlling for age and comorbidity burden (Cox hazard ratio 1.27; 95% confidence interval, 1.14-1.41, P < 0.0001). Among CCI patients, independent risk factors for death by 12 months included severity of comorbidities and persistent organ dysfunction (sequential organ failure assessment ≥6) at day 14 after sepsis onset. CONCLUSIONS: There is discordance between low inpatient mortality and poor long-term outcomes after surgical sepsis, especially among older adults, increasing comorbidity burden and patients that develop CCI. This represents important information when discussing expected outcomes of surgical patients who experience a complicated clinical course owing to sepsis.

The Development of Chronic Critical Illness Determines Physical Function, Quality of Life, and Long-Term Survival Among Early Survivors of Sepsis in Surgical ICUs.

OBJECTIVES: This study sought to examine mortality, health-related quality of life, and physical function among sepsis survivors who developed chronic critical illness. DESIGN: Single-institution, prospective, longitudinal, observational cohort study assessing 12-month outcomes. SETTING: Two surgical/trauma ICUs at an academic tertiary medical and level 1 trauma center. PATIENTS: Adult critically ill patients that survived 14 days or longer after sepsis onset. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Baseline patient characteristics and function, sepsis severity, and clinical outcomes of the index hospitalization were collected. Follow-up physical function (short physical performance battery; Zubrod; hand grip strength) and health-related quality of life (EuroQol-5D-3L, Short Form-36) were measured at 3, 6, and 12 months. Hospital-free days and mortality were determined at 12 months. We compared differences in long-term outcomes between subjects who developed chronic critical illness (≥ 14 ICU days with persistent organ dysfunction) versus those with rapid recovery. The cohort consisted of 173 sepsis patients; 63 (36%) developed chronic critical illness and 110 (64%) exhibited rapid recovery. Baseline physical function and health-related quality of life did not differ between groups. Those who developed chronic critical illness had significantly fewer hospital-free days (196 ± 148 vs 321 ± 65; p < 0.0001) and reduced survival at 12-months compared with rapid recovery subjects (54% vs 92%; p < 0.0001). At 3- and 6-month follow-up, chronic critical illness patients had significantly lower physical function (3 mo: short physical performance battery, Zubrod, and hand grip; 6 mo: short physical performance battery, Zubrod) and health-related quality of life (3- and 6-mo: EuroQol-5D-3L) compared with patients who rapidly recovered. By 12-month follow-up, chronic critical illness patients had significantly lower physical function and health-related quality of life on all measures. CONCLUSIONS: Surgical patients who develop chronic critical illness after sepsis exhibit high healthcare resource utilization and ultimately suffer dismal long-term clinical, functional, and health-related quality of life outcomes. Further understanding of the mechanisms driving the development and persistence of chronic critical illness will be necessary to improve long-term outcomes after sepsis.

Prognostic value of NT-proBNP levels in the acute phase of sepsis on lower long-term physical function and muscle strength in sepsis survivors.

BACKGROUND: Sepsis survivors often develop chronic critical illness (CCI) and demonstrate the persistent inflammation, immunosuppression, and catabolism syndrome predisposing them to long-term functional limitations and higher mortality. There is a need to identify biomarkers that can predict long-term worsening of physical function to be able to act early and prevent mobility loss. N-terminal pro-brain natriuretic peptide (NT-proBNP) is a well-accepted biomarker of cardiac overload, but it has also been shown to be associated with long-term physical function decline. We explored whether NT-proBNP blood levels in the acute phase of sepsis are associated with physical function and muscle strength impairment at 6 and 12 months after sepsis onset. METHODS: This is a retrospective analysis conducted in 196 sepsis patients (aged 18-86 years old) as part of the University of Florida (UF) Sepsis and Critical Illness Research Center (SCIRC) who consented to participate in the 12-month follow-up study. NT-proBNP was measured at 24 h after sepsis onset. Patients were followed to determine physical function by short physical performance battery (SPPB) test score (scale 0 to12-higher score corresponds with better physical function) and upper limb muscle strength by hand grip strength test (kilograms) at 6 and 12 months. We used a multivariate linear regression model to test an association between NT-proBNP levels, SPPB, and hand grip strength scores. Missing follow-up data or absence due to death was accounted for by using inverse probability weighting based on concurrent health performance status scores. Statistical significance was set at p ≤ 0.05. RESULTS: After adjusting for covariates (age, gender, race, Charlson comorbidity index, APACHE II score, and presence of CCI condition), higher levels of NT-proBNP at 24 h after sepsis onset were associated with lower SPPB scores at 12 months (p < 0.05) and lower hand grip strength at 6-month (p < 0.001) and 12-month follow-up (p < 0.05). CONCLUSIONS: NT-proBNP levels during the acute phase of sepsis may be a useful indicator of higher risk of long-term impairments in physical function and muscle strength in sepsis survivors.

Prevalence of Prediabetes and Abdominal Obesity Among Healthy-Weight Adults: 18-Year Trend.

PURPOSE: Trends in sedentary lifestyle may have influenced adult body composition and metabolic health among individuals at presumably healthy weights. This study examines the nationally representative prevalence of prediabetes and abdominal obesity among healthy-weight adults in 1988 through 2012. METHODS: We analyzed the National Health and Nutrition Examination Survey (NHANES) III (1988-1994) and NHANES for the years 1999 to 2012, focusing on adults aged 20 years and older who have a body mass index (BMI) of 18.5 to 24.99 and do not have diabetes, either diagnosed or undiagnosed. We defined prediabetes using glycated hemoglobin (HbA1c) level ranges from 5.7% to 6.4%, as specified by the American Diabetes Association. Abdominal obesity was measured by waist circumference and waist-to-height ratio. RESULTS: The prevalence of prediabetes among healthy-weight adults, aged 20 years and older and without diagnosed or undiagnosed diabetes, increased from 10.2% in 1988-1994 to 18.5% in 2012. Among individuals aged 45 years and older, the prevalence of prediabetes increased from 22.0% to 33.1%. The percentage of adults aged 20 years and older with an unhealthy waist circumference increased from 5.6% in 1988-1994 to 7.6% in 2012. The percentage of individuals with an unhealthy waist-to-height ratio increased from 27.2% in 1988-1994 to 33.7% in 2012. Adjusted models found that measures of abdominal obesity were not independent predictors of prediabetes among adults with a healthy BMI. CONCLUSIONS: Among individuals within a healthy BMI range, the prevalence of prediabetes and abdominal obesity has substantially increased. Abdominal obesity does not appear to be the primary cause of the increase.

Depressive symptom severity is associated with increased cortical thickness in older adults.

OBJECTIVE: Structural neuroimaging studies in older adults have consistently shown volume reductions in both major and subthreshold depression. Cortical thickness, another measure of brain structure, has not been well studied in this population. We examined cortical thickness in older adults across a range of depressive symptom (DS) severity. METHODS: Forty-three community-dwelling older adults (mean age = 68.80 ± 7.00 years) underwent magnetic resonance imaging. Based on a priori hypotheses, we examined cortical thickness in regions of interest in the rostral anterior cingulate, orbitofrontal cortex, middle frontal gyrus, and isthmus cingulate using multiple linear regressions with depression questionnaire scores as the independent variable and age, sex, and mean hemispheric thickness as covariates. We also performed an exploratory vertex-wise analysis. RESULTS: After correction for multiple comparisons, we found an association between increased DSs and greater cortical thickness in the right isthmus cingulate (F(1, 38) = 8.09, false discovery rate corrected p = 0.028; R(2) = 35.78) in the region of interest analysis and in the left precuneus (cluster size = 413, p = 0.00002) in the vertex-wise analysis. CONCLUSIONS: Older adults with higher DSs also have greater cortical thickness in the isthmus cingulate and precuneus, areas important for emotion regulation and self-referential processing. Additional research is needed to elucidate the mechanisms and potential clinical significance underlying this relationship.

A randomized trial comparing weight loss treatment delivered in large versus small groups.

BACKGROUND: Behavioral interventions for obesity are commonly delivered in groups, although the effect of group size on weight loss has not been empirically evaluated. This behavioral weight loss trial compared the 6- and 12-month weight changes associated with interventions delivered in a large group (LG) or small groups (SG). METHODS: Obese adults (N = 66; mean age = 50 years; mean BMI = 36.5 kg/m2; 47% African American; 86% women) recruited from a health maintenance organization were randomly assigned to: (1) LG treatment (30 members/group), or (2) SG treatment (12 members/group). Conditions were comparable in frequency and duration of treatment, which included 24 weekly group sessions (months 1-6) followed by six monthly extended care contacts (months 7-12). A mixed effects model with unstructured covariance matrix was applied to analyze the primary outcome of weight change while accounting for baseline weight and dependence among participants' measurements over time. RESULTS: SG participants lost significantly more weight than LG participants at Month 6 (-6.5 vs. -3.2 kg; p = 0.03) and Month 12 (-7.0 vs. -1.7 kg; p < 0.002). SG participants reported better treatment engagement and self-monitoring adherence at Months 6 and 12, ps < 0.04, with adherence fully mediating the relationship between group size and weight loss. CONCLUSIONS: Receiving obesity treatment in smaller groups may promote greater weight loss and weight loss maintenance. This effect may be due to improved adherence facilitated by SG interactions. These novel findings suggest that the perceived efficiency of delivering behavioral weight loss treatment to LGs should be balanced against the potentially better outcomes achieved by a SG approach.

Effects of resveratrol on changes in trimethylamine-N-oxide and circulating cardiovascular factors following exercise training among older adults.

PURPOSE: Trimethylamine-N-oxide (TMAO) is a gut-derived metabolite associated with cardiovascular disease (CVD). In preclinical and observational studies, resveratrol and exercise training have been suggested as potential strategies to reduce the systemic levels of TMAO. However, evidence from experimental studies in humans remains unknown. This project examined the dose-dependent effects of a combined resveratrol intervention with exercise training on circulating TMAO and other related metabolite signatures in older adults with high CVD risk. METHODS: Forty-one older adults [mean (±SD) age of 72.1 (6.8) years] participated in a 12-week supervised center-based, multi-component exercise training intervention [2×/week; 80 min/session] and were randomized to one of two resveratrol dosages [Low: 500 vs. High:1000 mg/day] or a cellulose-based placebo. Serum/plasma were collected at baseline and post-intervention and evaluated for TMAO and associated analytes. RESULTS: After the 12-week intervention, TMAO concentration increased over time, regardless of treatment [mean (±SD) Placebo: 11262 (±3970); Low:13252 (±1193); High: 12661(±3359) AUC; p = 0.04]. Each resveratrol dose produced different changes in metabolite signatures. Low dose resveratrol upregulated metabolites associated with bile acids biosynthesis (i.e., glycochenodeoxycholic acid, glycoursodeoxycholic acid, and glycocholic acid). High dose resveratrol modulated metabolites enriched for glycolysis, and pyruvate, propanoate, ß-alanine, and tryptophan metabolism. Different communities tightly correlated to TMAO and resveratrol metabolites were associated with the lipid and vascular inflammatory clinical markers [|r| > 0.4, p < 0.05]. CONCLUSION: These findings suggest a distinct dose-dependent adaptation response to resveratrol supplementation on circulating metabolite signatures but not on TMAO among high-risk CVD older adults when combined with an exercise training intervention.

Does time-restricted eating add benefits to calorie restriction? A systematic review.

OBJECTIVE: A growing body of evidence has supported the health benefits of extended daily fasting, known as time-restricted eating (TRE); however, whether the addition of TRE enhances the known benefits of calorie restriction (CR) remains unclear. METHODS: PubMed, Scopus, the Cochrane Library, and Google Scholar were searched through April 2023. This systematic review includes randomized controlled trials (RCTs) that compared CR + TRE with CR alone in energy-matched conditions of at least 8 weeks in duration that assessed changes in body weight and cardiometabolic disease risk factors in adults with overweight and/or obesity. RESULTS: Seven studies were identified (n = 579). Two studies reported greater weight loss and reductions in diastolic blood pressure with CR + TRE compared with CR alone after 8 to 14 weeks, whereas one study reported greater improvements in triglycerides and glucose tolerance with CR + TRE (3 days/week) compared with CR alone following 26 weeks. One study reported significant increases in homeostatic model assessment of insulin resistance (HOMA-IR) levels with CR + TRE versus CR alone after 8 weeks. There were no statistically significant differences in any other outcome variable between the two interventions. CONCLUSIONS: The addition of TRE to CR regimens resulted in greater weight loss and improvements in cardiometabolic risk factors in some studies; however, the majority of studies did not find additional benefits.

Relationship between Mitochondrial Quality Control Markers, Lower Extremity Tissue Composition, and Physical Performance in Physically Inactive Older Adults.

Altered mitochondrial quality and function in muscle may be involved in age-related physical function decline. The role played by the autophagy-lysosome system, a major component of mitochondrial quality control (MQC), is incompletely understood. This study was undertaken to obtain initial indications on the relationship between autophagy, mitophagy, and lysosomal markers in muscle and measures of physical performance and lower extremity tissue composition in young and older adults. Twenty-three participants were enrolled, nine young (mean age: 24.3 ± 4.3 years) and 14 older adults (mean age: 77.9 ± 6.3 years). Lower extremity tissue composition was quantified volumetrically by magnetic resonance imaging and a tissue composition index was calculated as the ratio between muscle and intermuscular adipose tissue volume. Physical performance in older participants was assessed via the Short Physical Performance Battery (SPPB). Protein levels of the autophagy marker p62, the mitophagy mediator BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), the lysosomal markers transcription factor EB, vacuolar-type ATPase, and lysosomal-associated membrane protein 1 were measured by Western immunoblotting in vastus lateralis muscle biopsies. Older adults had smaller muscle volume and lower tissue composition index than young participants. The protein content of p62 and BNIP3 was higher in older adults. A negative correlation was detected between p62 and BNIP3 and the tissue composition index. p62 and BNIP3 were also related to the performance on the 5-time sit-to-stand test of the SPPB. Our results suggest that an altered expression of markers of the autophagy/mitophagy-lysosomal system is related to deterioration of lower extremity tissue composition and muscle dysfunction. Additional studies are needed to clarify the role of defective MQC in human muscle aging and identify novel biological targets for drug development.

Effect of change of interleukin-6 over time on gait speed response: Results from the lifestyle interventions and independence for elders study.

Interleukin (IL)-6 is a well-accepted biomarker of chronic low-grade inflammation possibly conditioning the effect of physical activity (PA) intervention on physical performance in mobility-limited older adults. We evaluated PA intervention effects on 400 m gait speed by yearly change of IL-6 levels in a post-hoc analysis from Lifestyle Interventions and Independence for Elders (LIFE) Study, a multicenter single-blind randomized clinical trial on 1300 sedentary older adults (mean age:78.85 ± 5.23,65.85 % women) at risk for mobility disability. We compared the intervention effects on 400 m gait speed at 12 months follow-up, according to yearly IL-6 change categorized for 1 pg/ml increase or decrease, and subsequently for larger range of yearly variation. Among subjects with yearly IL-6 change between -1 and + 2 pg/ml, we observed a significant difference of gait speed in PA intervention group compared to healthy educational intervention group [0.041 m/s,95 % confidence interval (CI):0.008-0.074,p = 0.006;Cohen's d:0.26, 95 % CI:0.12-0.41). No effects were observed on 400 m gait speed for wider range of variation of plasma IL-6 levels. Limiting change of IL-6 levels under this specific hormetic window could be an important goal to achieve better benefit from PA intervention in terms of gait speed change and prevention of mobility disability.

Effect of Physical Activity Intervention on Gait Speed by Frailty Condition: A Randomized Clinical Trial.

OBJECTIVES: There is uncertainty about effects of physical activity on physical performance, such as gait speed, among community-dwelling older adults according to their physical frailty status. We determined whether a long-term, moderate-intensity physical activity program was associated with different responses on gait speed over 4 m and 400 m based on physical frailty status. DESIGN: Post hoc analysis from the Lifestyle Interventions and Independence for Elders (LIFE) (NCT01072500), a single-blind randomized clinical trial testing the effect of physical activity intervention compared with health education program. SETTING AND PARTICIPANTS: We analyzed data on 1623 community-dwelling older adults (78.9 ± 5.2 years) at risk for mobility disability. METHODS: Physical frailty was assessed at baseline using the Study of Osteoporotic Fractures frailty index. Gait speed over 4 m and 400 m was measured at baseline, and 6, 12, and 24 months. RESULTS: We estimated significantly better 400-m gait speed at 6, 12, and 24 months for nonfrail older adults in the physical activity group, but not for frail participants. Among frail participants, physical activity showed a potentially clinically meaningful benefit on 400-m gait speed at 6 months (0.055; 95% CI 0.016-0.094; P = .005), compared with the healthy educational intervention, only in those who, at baseline, were able to rise from a chair 5 times without using their arms. CONCLUSIONS AND IMPLICATIONS: A well-structured physical activity program produced a faster 400-m gait speed potentially able to prevent mobility disability among physically frail individuals with preserved muscle strength in lower limbs.

A scalable, virtual weight management program tailored for adults with type 2 diabetes: effects on glycemic control.

BACKGROUND: The objective was to test the efficacy of a scalable, virtually delivered, diabetes-tailored weight management program on glycemic control in adults with type 2 diabetes (T2D). METHODS: This was a single arm, three-site clinical trial. Participants had baseline HbA1c between 7-11% and BMI between 27-50 kg/m2. Primary outcome was change in HbA1c at 24 weeks. Secondary outcomes were changes in body weight, waist circumference, the Diabetes Distress Scale (DDS), quality of life (IWQOL-L), and hunger (VAS). Generalized linear effects models were used for statistical analysis. RESULTS: Participants (n = 136) were 56.8 ± 0.8 y (Mean ± SEM), 36.9 ± 0.5 kg/m2, 80.2% female, 62.2% non-Hispanic white. Baseline HbA1c, weight, and total DDS score were 8.0 ± 0.09%, 101.10 ± 1.47 kg, and 2.35 ± 0.08, respectively. At week 24, HbA1c, body weight, and total DDS decreased by 0.75 ± 0.11%, 5.74 ± 0.50%, 0.33 ± 0.10 units, respectively (all p < 0.001). Also, at week 24, quality of life increased by 9.0 ± 1.2 units and hunger decreased by 14.3 ± 2.4 units, (both p < 0.0001). CONCLUSIONS: The scalable, virtually delivered T2D-tailored weight management program had favorable and clinically meaningful effects on glycemic control, body weight, and psychosocial outcomes.

Low muscle mass is associated with a higher risk of all-cause and cardiovascular disease-specific mortality in cancer survivors.

OBJECTIVES: Individuals with prior cancer diagnosis are more likely to have low muscle mass (LMM) than their cancer-free counterparts. Understanding the effects of LMM on the prognosis of cancer survivors can be clinically important. The aim of this study was to investigate whether risks for all-cause and cardiovascular disease (CVD)-specific mortality differ by status of LMM in cancer survivors and a matched cohort without cancer history. METHODS: We used cohort data from the 1999-2006 and 2011-2014 National Health and Nutrition Examination Survey. Participants included 946 adults surviving for ≥1 since cancer diagnosis and a matched cohort (by age, sex, and race) without cancer history (N = 1857). LMM was defined by appendicular lean mass and body height (men <7.26 kg/m2, women <5.45 kg/m2). Death was ascertained via the National Death Index and cause of death was assessed via International Classification of Diseases, Tenth Revision. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratio (aHR) and 95% confidence interval (CI) of LMM. RESULTS: The mean age of cancer survivors and matched cohort was 60.6 y (SD 15) and 60.2 y (SD 14.9), respectively. The median follow-up was 10.5 y for survivors and 10.9 y for matched cohort. Overall, 22.2% of cancer survivors and 19.7% of the matched cohort had LMM, respectively. In all, 321 survivors (33.9%) and 495 participants (26.7%) in the matched cohort died during follow-up. CVD-specific deaths were identified in 58 survivors (6.1%) and 122 participants in the matched cohort (6.6%). The multivariable Cox model suggested that LMM was positively associated with all-cause (aHR, 1.73; 95% CI, 1.31-2.29) and CVD-specific (aHR, 2.13; 95% CI, 1.14-4.00) mortality in cancer survivors. The associations between LMM and risk for all-cause (aHR, 1.24; 95% CI, 0.98-1.56) and CVD-specific (aHR, 1.21; 95% CI, 0.75-1.93) mortality were not statistically significant in the matched cohort. CONCLUSION: Cancer survivors with LMM have an increased risk for all-cause and CVD-specific mortality. This increase appears to be larger than that in counterparts without cancer history.

Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates.

BACKGROUND: The possible advantage for weight loss of a diet that emphasizes protein, fat, or carbohydrates has not been established, and there are few studies that extend beyond 1 year. METHODS: We randomly assigned 811 overweight adults to one of four diets; the targeted percentages of energy derived from fat, protein, and carbohydrates in the four diets were 20, 15, and 65%; 20, 25, and 55%; 40, 15, and 45%; and 40, 25, and 35%. The diets consisted of similar foods and met guidelines for cardiovascular health. The participants were offered group and individual instructional sessions for 2 years. The primary outcome was the change in body weight after 2 years in two-by-two factorial comparisons of low fat versus high fat and average protein versus high protein and in the comparison of highest and lowest carbohydrate content. RESULTS: At 6 months, participants assigned to each diet had lost an average of 6 kg, which represented 7% of their initial weight; they began to regain weight after 12 months. By 2 years, weight loss remained similar in those who were assigned to a diet with 15% protein and those assigned to a diet with 25% protein (3.0 and 3.6 kg, respectively); in those assigned to a diet with 20% fat and those assigned to a diet with 40% fat (3.3 kg for both groups); and in those assigned to a diet with 65% carbohydrates and those assigned to a diet with 35% carbohydrates (2.9 and 3.4 kg, respectively) (P>0.20 for all comparisons). Among the 80% of participants who completed the trial, the average weight loss was 4 kg; 14 to 15% of the participants had a reduction of at least 10% of their initial body weight. Satiety, hunger, satisfaction with the diet, and attendance at group sessions were similar for all diets; attendance was strongly associated with weight loss (0.2 kg per session attended). The diets improved lipid-related risk factors and fasting insulin levels. CONCLUSIONS: Reduced-calorie diets result in clinically meaningful weight loss regardless of which macronutrients they emphasize. (ClinicalTrials.gov number, NCT00072995.)

Time-Restricted Eating Regimen Differentially Affects Circulatory miRNA Expression in Older Overweight Adults.

Time-restricted eating (TRE), a popular form of intermittent fasting, has been demonstrated to provide multiple health benefits, including an extension of healthy lifespan in preclinical models. While the specific mechanisms remain elusive, emerging research indicates that one plausible mechanism through which TRE may confer health benefits is by influencing the expression of the epigenetic modulator circulatory miRNAs, which serve as intercellular communicators and are dysregulated in metabolic disorders, such as obesity. Therefore, the goal of this pilot study is to examine the effects of a 4-week TRE regimen on global circulatory miRNA from older (≥65 years) overweight participants. Pre- and post-TRE regimen serum samples from nine individuals who participated in the Time to Eat clinical trial (NCT03590847) and had a significant weight loss (2.6 kg, p < 0.01) were analyzed. The expressions of 2083 human miRNAs were quantified using HTG molecular whole transcriptome miRNA assay. In silico analyses were performed to determine the target genes and biological pathways associated with differentially expressed miRNAs to predict the metabolic effects of the TRE regimen. Fourteen miRNAs were differentially expressed pre- and post-TRE regimen. Specifically, downregulated miRNA targets suggested increased expression of transcripts, including PTEN, TSC1, and ULK1, and were related to cell growth and survival. Furthermore, the targets of downregulated miRNAs were associated with Ras signaling (cell growth and proliferation), mTOR signaling (cell growth and protein synthesis), insulin signaling (glucose uptake), and autophagy (cellular homeostasis and survival). In conclusion, the TRE regimen downregulated miRNA, which, in turn, could inhibit the pathways of cell growth and activate the pathways of cell survival and might promote healthy aging. Future mechanistic studies are required to understand the functional role of the miRNAs reported in this study.

Older Adults Demonstrate Biomarker Evidence of the Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) After Sepsis.

BACKGROUND: Hospital deaths after sepsis have decreased substantially and most young adult survivors rapidly recover (RAP). However, many older survivors develop chronic critical illness (CCI) with poor long-term outcomes. The etiology of CCI is multifactorial and the relative importance remains unclear. Sepsis is caused by a dysregulated immune response and biomarkers reflecting a persistent inflammation, immunosuppression, and catabolism syndrome (PICS) have been observed in CCI after sepsis. Therefore, the purpose of this study was to compare serial PICS biomarkers in (i) older (vs young) adults and (ii) older CCI (vs older RAP) patients to gain insight into underlying pathobiology of CCI in older adults. METHOD: Prospective longitudinal study with young (≤45 years) and older (≥65 years) septic adults, who were characterized by (i) baseline predisposition, (ii) hospital outcomes, (iii) serial Sequential Organ Failure Assessment (SOFA) organ dysfunction scores over 14 days, (iv) Zubrod Performance status at 3-, 6-, and 12-month follow-up, and (v) mortality over 12 months, was conducted. Serial blood samples over 14 days were analyzed for selected biomarkers reflecting PICS. RESULTS: Compared to the young, more older adults developed CCI (20% vs 42%) and had markedly worse serial SOFA scores, performance status, and mortality over 12 months. Additionally, older (vs young) and older CCI (vs older RAP) patients had more persistent aberrations in biomarkers reflecting inflammation, immunosuppression, stress metabolism, lack of anabolism, and antiangiogenesis over 14 days after sepsis. CONCLUSION: Older (vs young) and older CCI (vs older RAP) patient subgroups demonstrate early biomarker evidence of the underlying pathobiology of PICS.

Promoting weight-loss maintenance among Black women primary care patients: A cluster RCT of a culturally sensitive versus standard behavioural approach.

The prevalence of obesity is higher among Black women (56.6%) compared to Hispanic women (50%) and non-Hispanic White women (42%). Notably, interventions to reduce obesity typically result in initial weight loss that is not maintained. This study tested (a) the effectiveness of a 6-month Health-Smart Weight Loss (HSWL) Program for Black women patients with obesity implemented by community health workers (CHWs) within primary care clinics and (b) the comparative effectiveness of two 12-month physician-implemented weight loss maintenance programs-a Patient-Centred Culturally Sensitive Weight Loss Maintenance Program (PCCS-WLM Program) and a Standard Behavioural Weight Loss Maintenance Program (SB-WLM Program). Black women patients (N = 683) with obesity from 20 community primary care clinics participated in the HSWL Program and were then randomized to either maintenance program. The HSWL Program led to significant weight loss (i.e., 2.7 pounds, 1.22 kg, p < .01, -1.1%) among the participants. Participants in both the PCCS-WLM Program and the SB-WLM Program maintained their weight loss; however, at month 18, participants in the PCCS-WLM Program had a significantly lower weight than those in the SB-WLM (i.e., 231.9 vs. 239.4 pounds or 105.19 vs. 108.59 kg). This study suggests that (a) the HSWL Program can produce significant weight loss among Black women patients with obesity when implemented in primary care clinics by CHWs, and (b) primary care physicians can be trained to successfully promote weight loss maintenance among their Black women patients.

Control in the middle (CIM) for three-period crossover studies.

Three-period crossover studies can be efficient and convenient methods of conducting Phase II clinical trials. Non-randomly placing control in the middle (CIM) has not been practiced but may be extremely useful in studies testing herbal products for which placebos are not available, or for distinguishing between behavioral and biological effects. Furthermore, this design can serve as a valuable addition to classical studies of either (a) two competing treatments or (b) treatment versus placebo versus an open label "nothing" as the control. Therefore, we propose rigorous designs that will help practitioners efficiently answer research questions where (1) two active treatments need to be compared against each other with treatment vs. placebo comparisons being of secondary importance; (2) a single active treatment needs to be tested where no placebo is available; or (3) the placebo effect is of interest in a treatment vs. placebo trial. For studies where no placebo is available, deception will be required, with participants told that in one randomly selected period (#1 or #3) they will receive the active treatment, and that they will receive a new experimental inert placebo in the other period. Assuming this design is approved by an ethics committee, it can be very useful in biomedical research.