Nathan R. Weeldreyer

Background: Weight loss results in losses of fat mass and fat-free mass/lean body mass loss with accompanying high recidivism and weight regain. Prior studies demonstrated that most weight regain is in the fat mass compartment; however, comprehensive studies utilizing meta-analytical methodologies are need. Therefore, we aimed to synthesize data from randomized controlled weight-loss trials using direct measures of body composition to determine the implications for body composition during weight regain. Methods: The objectives of this systematic review and meta-analysis were to (1) systematically summarize data for body composition during periods of follow-up after weight loss in adults, (2) conduct meta-analyses for body compositional changes during follow-up periods ≥ 6 months, following weight-loss interventions ≥ 12 weeks, and (3) explore potential moderators of weight regain. Embase, PubMed, Scopus, and CINAHL were searched through June 2025. Inclusion criteria comprised randomized controlled trials directly quantifying body composition changes after weight-loss interventions lasting ≥ 12-weeks with ≥ 6-months follow-up. Trial Registration: PROSPERO CRD420251046692. Findings: Thirty-four studies including 4024 participants (female n = 2670) were included· After completion of the weight-loss intervention, body mass (mean difference (MD) 2·99 kg, 95% CI 1·93 to 4·05; p < 0·001) and fat mass (MD 2·56 kg, 95% CI 1·74 to 3·37; p < 0·001) significantly increased at follow-up. No regain was observed for fat-free mass (MD 0·27, 95% CI -0·06 to 0·61; p = 0·11) or lean body mass (MD 0·18, 95% CI -0·15 to 0·50; p = 0·25). Intervention type and follow-up time were not related to outcomes. Interpretation: Weight regain following weight-loss intervention primarily reflects FM recovery, not fat-free mass or lean body mass. The findings of this systematic review and meta-analyses may have implications for cardiometabolic health and physical function following weight loss and weight regain.

Menopause increases coronary heart disease risk, in part through reduced oestrogen-mediated nitric oxide (NO) bioavailability. The Buckberg ratio, an index of myocardial oxygen supply-demand balance, in which higher values reflect more favourable myocardial perfusion, is lower in postmenopausal females (PMFs) than in age-matched males. High-intensity exercise enhances NO production and endothelial function more than moderate-intensity exercise, yet PMFs often exhibit blunted vascular adaptations. Inorganic nitrate (NO₃ ^-) supplementation increases NO bioavailability and improves endothelial function, but its effect on the Buckberg ratio is unknown. We hypothesised that the Buckberg ratio would decline after exercise in an intensity-dependent manner and that this reduction would be attenuated by NO₃ ^- supplementation. In a double-blind, randomized design, 24 PMFs (60 ± 5 years; 27.5 ± 5.9 kg/m²; 10 ± 5 years postmenopausal; peak oxygen consumption = 23.9 ± 4.5 mL/kg/min) consumed nitrate-rich beetroot juice (BRJ; n = 12) or nitrate-depleted placebo (PL; n = 12) for ∼2 days, with a final dose 2 h before testing. The Buckberg ratio was measured at rest and every 30 min for 3 h following calorically matched high-intensity exercise (HIE), moderate-intensity exercise (MIE) and non-exercise control (CON) conditions using pulse wave analysis (SphygmoCor) and was calculated from the derived central aortic pressure waveform as the ratio of diastolic to systolic pressure-time integrals, reflecting myocardial oxygen supply relative to demand. Venous blood collected pre- and post-supplementation assessed plasma NO₃ ^- and nitrite (NO₂ ^-). BRJ increased plasma NO₃ ^- (64.9 ± 20.8 vs. 1114.2 ± 176.2 µM, P < 0.001) and NO₂ ^- (118.3 ± 57.9 vs. 356.8 ± 114.0 nM, P < 0.001). The Buckberg ratio was unchanged during CON but declined after MIE (P < 0.001) and HIE (P < 0.001). BRJ attenuated this decline following HIE (P < 0.001), but not MIE. These findings indicate that acute exercise reduces the Buckberg ratio in PMFs in an intensity-dependent manner, and NO₃ ^- supplementation might help to preserve coronary perfusion during higher-intensity exercise stress.

Background: Peak oxygen uptake (V̇O ₂ peak) is a strong predictor of survival in breast cancer survivors (BCS), with values ≤1.09 L/min associated with increased mortality. The relative contributions of convective oxygen delivery (QO ₂ ) and muscle oxygen diffusing capacity (D _M O ₂ ) to reduced V̇O ₂ peak in BCS remain unclear. Materials and Methods: In 49 BCS, we measured V̇O ₂ peak from cycle ergometry with gas-exchange analysis, and derived QO ₂ and D _M O ₂ using Fick-based calculations and computational modeling. BCS were stratified by mortality risk: High-Risk (V̇O ₂ peak ≤1.09 L/min; n=11) and Lower-Risk (n=38), and compared using t-tests, Mann-Whitney U tests and ANCOVA. Dominance analysis quantified the relative contributions of QO ₂ and D _M O ₂ to V̇O ₂ peak within each group. Results: The High-Risk group was older (72±6 vs. 69±5 years), had longer time since treatment (17±5 vs. 13±6 years), and higher cumulative doxorubicin-equivalent doses (291±134 vs. 163±120 mg/m²)(all p≤0.05). After ANCOVA, the High-Risk group had lower V̇O ₂ peak (1.0±0.1 vs. 1.4±0.2 L/min), QO ₂ (1.8±0.3 vs. 2.5±0.5 L/min), and D _M O ₂ (28.2±4.8 vs. 41.5±9.0 mL/min/mmHg) (all p≤0.001). Dominance analysis revealed D _M O ₂ as the strongest contributor to V̇O ₂ peak with 81.7% and 66.0% of explained variance in High-Risk and Lower-Risk groups while QO ₂ accounted for 14.1% and 30.3%, respectively. Conclusions: In older, long-term BCS with reduced V̇O ₂ peak (≤1.09 L/min), impairments in both QO ₂ and D _M O ₂ contribute to reduced exercise tolerance. However, D _m O ₂ emerged as the strongest modeled contributor in the high-risk group. Interventions prioritizing skeletal muscle–vascular function, alongside complementary targeting of QO ₂ , may have greater impact on V̇O ₂ peak improvements and survival in this high-risk population.

Breast cancer is a common, survivable malignancy affecting women. With improved survival, the off‐target effects of chemotherapy, such as a decline in cardiorespiratory fitness and worse cardiovascular outcomes, have been recognized. Exercise training may help mitigate these effects. In this study, patients with breast cancer ( N = 24) scheduled to undergo chemotherapy were randomized to either remotely administered high‐intensity interval training (HIIT) or moderate‐intensity exercise (MOD) based on ACSM guidelines for cancer survivors. HIIT involved three weekly sessions using the 4 × 4 protocol at 85%–90% peak heart rate (PHR), while MOD consisted of 150 min per week at 70%–75% PHR. Exercise training began 1–2 weeks before chemotherapy and continued throughout treatment. Baseline testing was conducted prior to chemotherapy and follow‐up testing 7–10 days after completion. Assessments included VO _2peak , echocardiography, vascular function, and blood biomarkers. VO _2peak significantly declined in MOD ( n = 8; 1.50 ± 0.23 to 1.27 ± 0.28 L/min; p = 0.013, d = 1.2), while remaining stable in HIIT ( n = 7; 1.58 ± 0.24 to 1.52 ± 0.28 L/min; p = 0.445, d = 0.3), with a large between‐group effect size ( p = 0.109, d = 0.9). NTproBNP levels significantly increased in MOD (104.3 ± 35.1 to 158.1 ± 56.0; p = 0.018), but not in HIIT. The study was underpowered due to greater than anticipated dropout to detect significant between‐group differences in VO _2peak . These data have implications for the design of scalable exercise interventions in patients undergoing chemotherapy for breast cancer.

Reduced cardiorespiratory fitness is common among breast cancer survivors and, although traditionally attributed to cardiac dysfunction, might also be related to peripheral skeletal muscle abnormalities. We examined peak and submaximal plantar‐flexion exercise and recovery kinetics for lower‐leg oxygen uptake (), blood flow and arteriovenous O ₂ difference in 35 older, female long‐term breast cancer survivors (age, 70 ± 5 years; 14 ± 6 years post‐treatment) and 19 age‐ and sex‐matched healthy control subjects using MRI. The calf intermuscular fat to skeletal muscle ratio was evaluated using fat‐ and water‐separated MRI to quantify myosteatosis. No significant differences were found between groups for lower‐leg , blood flow or arteriovenous O ₂ difference at peak or during submaximal plantar‐flexion exercise. Recovery kinetics for these measures were similar between groups (all P  > 0.05). No differences were found in calf muscle mass between breast cancer survivors and control subjects. A higher intermuscular fat to skeletal muscle ratio was significantly associated with reduced peak (cycle exercise) pulmonary ( r = −0.37, P = 0.01), lower plantar‐flexion power output ( r = −0.325, P = 0.012) and delayed muscle recovery kinetics in both groups ( r = −0.325, P = 0.015). Older, female long‐term breast cancer survivors have comparable lower‐limb skeletal muscle oxidative capacity to control subjects. However, myosteatosis represents a key determinant of exercise performance and recovery kinetics regardless of breast cancer history. Interventions targeting skeletal muscle quality might be effective in improving both submaximal and maximal exercise tolerance and recovery kinetics in older women with or without a breast cancer diagnosis.

Ghrelin circulates in acylated (AG) and deacylated (DAG) isoforms and both may impact endothelial function (EF). Although acute exercise has been shown to modulate ghrelin levels and EF, data on the impact of exercise intensity on these parameters are scarce. To investigate the effect of exercise intensity and sex on EF and ghrelin levels, nine males (age: 43.8 ± 10.3 y; BMI: 22.5 ± 1.8 kg/m²) and eight females (age: 33.75 ± 10.2 y; BMI: 22.4 ± 1.6 kg/m²) completed a maximal cycle ergometer lactate threshold (LT)/VO_2peak test. This test determined the exercise intensity for three visits: (a) CON, no exercise; (b) MOD, the power output (PO) at LT; (c) HIGH, the PO associated with 75% of the difference between LT and VO_2peak. Ghrelin levels and EF [flow‐mediated dilation (FMD), shear rate (SR)] were measured at baseline and then 30–120 min post‐exercise. HIGH and MOD increased FMD (p < 0.0001). Each ghrelin isoform was suppressed by HIGH; only females exhibited reduced DAG levels in HIGH compared to MOD and CON (p < 0.0001–0.004). FMD was associated with ghrelin levels in females (r = −0.26–0.47). High‐intensity exercise is key for ghrelin suppression and appears to only be weakly/moderately related to EF.

Background: To analyze the effect of type 2 diabetes (T2D) on cardiorespiratory fitness. Methods: A multilevel model using restricted maximum likelihood method was used to analyze pooled data. Inclusion criteria included adults aged >18 years, one group of individuals needed to have been diagnosed with T2D, the control group must not have had insulin resistance, the study must report peak oxygen uptake, there was no exercise training before tests of functional capacity, and subjects may not have had overt cardiovascular disease, cancer, transplant surgery, or bariatric surgery. Moderators assessed were sample demographics (age, body mass index, sex, and time since T2D diagnosis) and cardiovascular outcomes (eg, echocardiographic variables, blood pressure). Results: Absolute (cohorts n=30; subjects n=1152; mean difference, −0.29 L/min [95% CI, −0.37 to −0.22 L/min]; P P =0.001) were significantly reduced in the T2D group compared with control. Time since T2D diagnosis (β coefficient=−0.04, P =0.05) was a significant moderator of the absolute peak oxygen uptake pooled outcome. Early mitral inflow velocity/early mitral annulus velocity (β coefficient=−1.72, P =0.004) and left atrial volume index (β coefficient=−1.41, P =0.02) were significant moderators of the relative peak oxygen uptake model. Conclusions: Markers of cardiac diastolic function (early mitral inflow velocity/early mitral annulus velocity and left atrial volume index) and time since diabetes diagnosis may contribute to exercise intolerance in T2D, although there is a lack of data in young/older adults and newly diagnosed individuals. As cardiorespiratory fitness predicts both all‐cause mortality and cardiovascular morbidity and mortality, these data have important implications for risk reduction in individuals with T2D.

Type 2 diabetes (T2D) is a common metabolic disorder in which only 25% of patients meet management targets. While the primary care setting is positioned to provide lifestyle management education, studies are lacking which integrate behavior interventions in this setting utilizing clinic staff. Thus, we evaluated a 90‐day lifestyle intervention for management of glycemia at a family practice clinic administered by clinic medical assistants. Twenty patients with non‐insulin‐dependent T2D completed a 90‐day intervention driven by patient choices of nutrition and physical activity. Medical assistants were trained by members of the study team and administered the intervention under nurse practitioner supervision. HbA1c trended toward significant reduction 8.59 ± 0.9% to 8.15 ± 1.2% (p = 0.051, 95% CI: −0.88 to 0.003). Modest reductions were observed for waist circumference (115.5 ± 12.6 vs. 112.5 ± 15.2 cm; p = 0.014, 95% CI: −5.66 to −0.26), body weight (97.7 ± 21.9 vs. 95.6 ± 23.9 kg; p = 0.016. 95% CI: −3.84 to −0.31), and BMI (33.7 ± 7.2 vs. 32.8 ± 7.5 kg/m²; p = 0.028, 95% CI: −1.29 to −0.12). This 90‐day, patient choice‐intervention was successful at lowering HbA1c in patients with T2D. Our study is limited by a lack of control group, and results should be interpreted as such. These data have implications for team‐based care models in clinic settings to improve health outcomes in patients with T2D.

Objective: The purpose of this review was to assess the joint relationship of cardiorespiratory fitness (CRF) and Body Mass Index (BMI) on both cardiovascular disease (CVD) and all-cause mortality risk.Design: A systematic review and meta-analysis was conducted. Pooled HR and 95% CI were calculated using a three-level restricted maximum likelihood estimation random-effects model with robust variance estimation. The reference group was normal weight-fit and was compared with normal weight-unfit, overweight-unfit and fit, and obese-unfit and fit.Data sources: Electronic databases (PubMed/MEDLINE, Web of Science and SportDiscus) were searched following registration on PROSPERO.Eligibility criteria: Articles meeting the following criteria were included: (1) published between January 1980 and February 2023, (2) prospective cohort study, (3) CRF assessed using a maximal or VO₂peak exercise test, (4) BMI reported and directly measured, (5) joint impact of CRF and BMI on all-cause mortality or CVD mortality were analysed, and (6) the reference group was normal weight, fit individuals.Results: 20 articles were included in the analysis resulting in a total of 398 716 observations. Compared with the reference group, overweight-fit (CVD HR (95% CI): 1.50 (0.82–2.76), all-cause HR: 0.96 (0.61–1.50)) and obese-fit (CVD: 1.62 (0.87–3.01), all-cause: 1.11 (0.88–1.40)) did not have a statistically different risk of mortality. Normal weight-unfit (CVD: 2.04 (1.32–3.14), all-cause: 1.92 (1.43–2.57)), overweight-unfit (CVD: 2.58 (1.48–4.52), all-cause: 1.82 (1.47–2.24)) and obese-unfit (CVD: 3.35 (1.17–9.61), all-cause: 2.04 (1.54–2.71)) demonstrated 2–3-fold greater mortality risks.Conclusions: CRF is a strong predictor of CVD and all-cause mortality and attenuates risks associated with overweight and obesity. These data have implications for public health and risk mitigation strategies.