UNASSIGNED: Frailty is a significant public health issue facing aging societies and can be reduced by physical activity (PA), but the dose-response relationship between PA and frailty is not clear. This systematic review and dose-response meta-analysis aimed to assess the effect of PA on frailty in adults by aggregating data from observational studies.
UNASSIGNED: PubMed, Embase, Web of Science, Cochrane Library, Scopus, SAGE Reference Online, SinoMed, CINAHL and CNKI were retrieved for articles published before May 2024. After quality evaluation, data on PA and the risk of frailty were extracted. Stata/MP 17.0 was used for dose-response meta-analysis.
UNASSIGNED: A total of 15 articles were included, involving 34,754 participants, including 4250 subjects with frailty or pre-frailty. The consequence of the dose-response meta-analysis revealed that compared with those who were not active at all, a 22 % (95 % CI, 16 %-28 %) reduction in the risk of frailty in individuals with 11.25 MET h/week of cumulative activity and a 55 % (95 % CI, 44 %-63 %) reduction in the risk of frailty in those with 22.5 MET h/week of cumulative activity; for higher activity levels (36.75 MET h/week), the risk of frailty was reduced by 68 % (95 % CI, 58 %-76 %) and continued to be reduced as PA volum increased.
UNASSIGNED: There is a non-linear dose-response relationship between PA and frailty risk. Even small amounts of PA could reduce the risk of frailty. Meeting the minimum recommended PA target could reduce some risks, and doubling the recommended PA volumes could reduce most risks, which continue to increase as the volum of PA accumulates.

UNASSIGNED: To synthesize the knowledge about the association of total physical activity (TPA), leisure-time physical activity (LTPA), occupational physical activity (OPA) and lung cancer risk and explore the dose-response relationship between LTPA level and lung cancer.
UNASSIGNED: PubMed and Web of Science were searched up to 17 November 2021. The summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated by random-effects or fixed-effects model. The dose-response analysis was conducted with restricted cubic splines.
UNASSIGNED: We identified 25 articles (42 cohort studies) that assessed the physical activity-lung cancer association, including 9,983,295 study participants and 85,988 incident cases of lung cancer. When comparing the highest to the lowest level of TPA and LTPA, lung cancer risk reduced 22% (RR, 0.78; 95% CI: 0.70, 0.86) and 12% (RR, 0.88; 95% CI: 0.83, 0.93), respectively. We found an approximately U-shaped association between LTPA and lung cancer (P non-linearity < 0.001), with the lowest risk at 15 metabolic equivalent of task hours per week (h/wk) of LTPA. Compared to participants with sitting occupations, lung cancer risk significantly increased among those being unemployed (RR, 1.33; 95% CI: 1.17, 1.51) or with standing occupations (RR, 1.37; 95% CI: 1.15, 1.63), but not among those with light or high OPA.
UNASSIGNED: Our meta-analysis supported a protective effect of TPA and LTPA, but not OPA, on lung cancer risk. The novel finding of a U-shaped association between LTPA and lung cancer risk warrants further investigation.

UNASSIGNED: To evaluate and rank the effectiveness of specific non-pharmacological treatments (NPTs) in improving the global cognitive function in individuals with Alzheimer\'s disease (AD) and to examine the dose-response relationship.
UNASSIGNED: We conducted a systematic search in PubMed, MEDLINE, Embase, PsycINFO, CENTRAL, WOS, and CNKI from their inception to 15 February 2023. Standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated for outcomes using random effects models.
UNASSIGNED: We included 68 studies involving 5053 participants in this meta-analysis. The treatments with the highest cumulative probabilities for improving global cognitive function were transcranial direct current stimulation (tDCS), followed by physical exercise (PE), and repetitive transcranial magnetic stimulation (rTMS). Additionally, cognitive stimulation (CS), cognitive training CT), multidisciplinary program (MD), and reminiscence treatment (RT) also significantly improve the global cognitive function of people with AD. A non-linear dose-response association was observed for tDCS, PE, rTMS, CS, and CT with global cognitive improvement. Notably, no minimal threshold was identified for the beneficial effects of PE on cognition. The estimated minimal doses for clinically relevant changes in cognition were 33 min per week for tDCS, 330 MET-min per week for PE, and 8000 pulses per week for rTMS.
UNASSIGNED: tDCS, PE, and rTMS are the better effective NPTs for enhancing global cognitive function in individuals with AD. Properly dosing these treatments can yield significant clinical benefits. Our findings support the clinical utility of low-dose exercise in improving cognition in people with AD.

Depression is a growing public health concern, and exercise is an adjunctive treatment modality to improve depression, but the optimal form of exercise and the optimal dose are still unclear. This systematic review examined the efficacy of four major types of exercise (aerobic, resistance, mixed, and mind-body) on depression, as well as the dose-response relationship between total and specific exercise and depressive symptoms. We included randomized controlled trials that included participants aged 18 years or older with a diagnosis of major depressive disorder or a depressive symptom score above a threshold as determined by a validated screening measure, implemented one or more exercise therapy groups, and assessed depressive symptoms at baseline and follow-up. Forty-six studies (3164 patients) were included in the meta-analysis. Aerobic (standardised mean difference (SMD) = -0.93; 95% CI: -1.25 to -0.62) and mind-body exercise (SMD) = -0.81; 95% CI: -1.19 to -0.42) improved depressive symptoms better compared to controls, followed by mixed (SMD = -0.77; 95% CI: -1.20 to -0.34) and resistance exercise (SMD = -0.76; 95% CI: -1.24 to -0.28). This dose-response meta-analysis showed a U-shaped curve between exercise dose and depressive symptoms. The minimum effective dose was estimated to be 320 metabolic equivalent (METs) -min per week and the optimal response was 860 METs-min per week. These findings lead us to advocate that clinicians carefully select the appropriate dose of exercise based on the patient\'s individual characteristics and needs, in conjunction with psychological care interventions.

BACKGROUND: Mesenchymal stem cells (MSCs) have emerged as living biodrugs for myocardial repair and regeneration. Recent randomized controlled trials (RCTs) have reported that MSC-based therapy is safe and effective in heart failure patients; however, its dose-response relationship has yet to be established. We aimed to determine the optimal MSC dose for treating HF patients with reduced ejection fraction (EF) (HFrEF).
METHODS: The preferred reporting items for systematic reviews and meta-analyses (PRISMA) and Cochrane Handbook guidelines were followed. Four databases and registries, i.e., PubMed, EBSCO, clinicaltrials.gov, ICTRP, and other websites, were searched for RCTs. Eleven RCTs with 1098 participants (treatment group, n = 606; control group, n = 492) were selected based on our inclusion/exclusion criteria. Two independent assessors extracted the data and performed quality assessments. The data from all eligible studies were plotted for death, major adverse cardiac events (MACE), left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and 6-minute walk distance (6-MWD) as safety, efficacy, and performance parameters. For dose-escalation assessment, studies were categorized as low-dose (< 100 million cells) or high-dose (≥ 100 million cells).
RESULTS: MSC-based treatment is safe across low and high doses, with nonsignificant effects. However, low-dose treatment had a more significant protective effect than high-dose treatment. Subgroup analysis revealed the superiority of low-dose treatment in improving LVEF by 3.01% (95% CI; 0.65-5.38%) compared with high-dose treatment (-0.48%; 95% CI; -2.14-1.18). MSC treatment significantly improved the 6-MWD by 26.74 m (95% CI; 3.74-49.74 m) in the low-dose treatment group and by 36.73 m (95% CI; 6.74-66.72 m) in the high-dose treatment group. The exclusion of studies using ADRCs resulted in better safety and a significant improvement in LVEF from low- and high-dose MSC treatment.
CONCLUSIONS: Low-dose MSC treatment was safe and superior to high-dose treatment in restoring efficacy and functional outcomes in heart failure patients, and further analysis in a larger patient group is warranted.

OBJECTIVE: This study aimed to clarify the effectiveness of tart cherries on anthropometric, lipid, and glycemic indices. We also aimed to clarify the appropriate dosage for this effect and suggest directions for future studies.
METHODS: PubMed, Scopus, and Web of Science were searched until May 2022. Twelve eligible trials were included. The pooled results were reported as weighted mean differences (WMD) and 95 % confidence intervals (CIs). The Cochrane risk of bias and GRADE tools were used to assess the risk of bias and certainty of the evidence, respectively.
RESULTS: Tart cherry generally showed no significant effects on cardiometabolic risk factors. But subgroup analysis revealed that tart cherry significantly lowered total cholesterol (WMD: -0.33 mmol/l; 95 % CI: -0.55, -0.10), triglyceride (WMD: -0.19 mmol/l; 95 % CI: -0.26, -0.12), and low-density lipoprotein cholesterol (WMD: -0.36 mmol/l; 95 % CI: -0.58, -0.14), in unhealthy populations. Additionally, subgroup analysis indicated that the favorable effects of tart cherry were more pronounced in a single dose, longer duration, elderly, and obese individuals. Dose-response analysis revealed that 20 ml concentrate has the greatest effect in reducing total cholesterol (WMD: -0.40 mmol/l; 95 % CI: -0.61, -0.19), triglyceride (WMD: -0.23 mmol/l; 95 % CI: -0.33, -0.13), and elevating high-density lipoprotein cholesterol (WMD: 0.20 mmol/l; 95 % CI: 0.17, 0.22).
CONCLUSIONS: Tart cherry supplementation did not have significant effects on anthropometric and glycemic indices, but can improve lipid profile, especially in a single dose, longer duration, and in elderly, obese, and unhealthy individuals.

OBJECTIVE: Whole grains have recently been promoted as beneficial to diabetes prevention. However, the evidence for the glycemic benefits of whole grains seems to conflict between the cohort studies and randomized control trials (RCTs). To fill the research gap, we conducted a meta-analysis to determine the effects of whole grains on diabetes prevention and to inform recommendations.
METHODS: We searched PubMed, Clarivate Web of Science, and Cochrane Library until March 2024. We used the risk ratio (RR) of type 2 diabetes to represent the clinical outcomes for cohort studies, while the biomarkers, including fasting blood glucose and insulin, HbA1C, and HOMA-IR, were utilized to show outcomes for RCTs. Dose-response relationships between whole grain intakes and outcomes were tested with random effects meta-regression models and restricted cubic splines models. This study is registered with PROSPERO, CRD42021281639.
RESULTS: Ten prospective cohort studies and 37 RCTs were included. Cohort studies suggested a 50 g/day whole grain intake reduced the risk of type 2 diabetes (RR = 0.761, 95% CI: 0.700 to 0.828, I2 = 72.39%, P < 0.001) and indicated a monotonic inverse relationship between whole grains and type 2 diabetes rate. In RCTs, whole grains significantly reduced fasting blood glucose (Mean difference (MD) = -0.103 mmol/L, 95% CI: -0.178 to -0.028; I2 = 72.99%, P < 0.01) and had modest effects on HbA1C (MD = -0.662 mmol/mol (-0.06%), 95% CI: -1.335 to 0.010; I2 = 64.55%, P = 0.05) and HOMA-IR (MD = -0.164, 95% CI: -0.342 to 0.013; I2 = 33.38%, P = 0.07). The intake of whole grains and FBG, HbA1C, and HOMA-IR were significantly dose-dependent. The restricted spline curves remained flat up to 150 g/day and decreased afterward. Subgroup analysis showed that interventions with multiple whole-grain types were more effective than those with a single type.
CONCLUSIONS: Our study findings suggest that a daily intake of more than 150 g of whole grain ingredients is recommended as a population approach for diabetes prevention.

OBJECTIVE: To verify the dose-response relationship between body mass index (BMI) and multimorbidity risk.
METHODS: PubMed, CINAHL, and Embase were systematically studied until January 25, 2023. Original articles on BMI and multimorbidity risk were included. Random effects model and dose-response meta-analysis were used to estimate the pooled odds ratio (OR) with 95 % confidence interval (CI). Subgroup analysis was performed to explore potential heterogeneity.
RESULTS: A total of 43 studies involving 969,130 patients (94,978 with multimorbidity) were involved in the meta-analysis. In the longitudinal studies, the pooled results showed that, compared to being a normal BMI, being overweight was much similar with 1.32 times possibility of getting multimorbidity; in persons with obesity the risk was 1.93 times higher; and the risk decreased 0.80 times among underweight persons. Additionally, obesity was 1.75 times as likely to be multimorbidity than those non-obese persons. In the cross-sectional studies, the pooled results demonstrated that persons with overweight and obesity had a 1.38-fold and 2.38-fold risk for multimorbidity, respectively; and the risk decreased 0.90 times among underweight persons compared to those with normal BMI. Besides, obese people are 1.89 times more likely to have multimorbidity than non-obese people. Dose response analysis found the linear connection between BMI and multimorbidity risk (Pnon-linearity=0.762), that for each 1 kg/m2 and 5 kg/m2 increase in BMI, the multimorbidity risk increased by 6 % and 35 %, respectively.
CONCLUSIONS: Multimorbidity increased linearly with an increase in BMI. Clinicians should pay attention to persons with abnormal weight, to help them achieve normal BMI.

UNASSIGNED: Emerging evidence suggests the potential relationship between vitamin D deficiency and risk of cognitive impairment or dementia. To what extent the excess risk of dementia conferred by vitamin D deficiency is less clear.
UNASSIGNED: We summarized the current evidence from several aspects and further quantified these associations.
UNASSIGNED: We collected relevant prospective cohort studies by searching PubMed, Embase and Cochrane up to July 2023. The pooled relative risks (RR) were evaluated by random-effects models. Dose-response analyses were conducted by the method of two-stage generalized least squares regression.
UNASSIGNED: Of 9,267 identified literatures, 23 were eligible for inclusion in the meta-analyses, among which 9 and 4 literatures were included in the dose-response analyses for the risk of dementia and Alzheimer\'s disease (AD). Vitamin D deficiency exhibited a 1.42 times risk for dementia (95% confidence interval (CI) = 1.21-1.65) and a 1.57-fold excess risk for AD (95% CI = 1.15-2.14). And vitamin D deficiency was associated with 34% elevated risk with cognitive impairment (95% CI = 1.19-1.52). Additionally, vitamin D was non-linearly related to the risk of dementia (pnonlinearity = 0.0000) and AD (pnonlinearity = 0.0042). The approximate 77.5-100 nmol/L 25-hydroxyvitamin D [25(OH)D] was optimal for reducing dementia risk. And the AD risk seemed to be decreased when the 25(OH)D level >40.1 nmol/L.
UNASSIGNED: Vitamin D deficiency was a risk factor for dementia, AD, and cognitive impairment. The nonlinear relationships may further provide the optimum dose of 25(OH)D for dementia prevention.

OBJECTIVE: To quantify the dose-response relationship between overall and specific exercise modalities and pain, in patients with nonspecific chronic low back pain (LBP). DESIGN: Systematic review with Bayesian network meta-analysis. LITERATURE SEARCH: We searched the Medline, Embase, Web of Science, Cochrane Library, Scopus, and SPORTDiscus databases from inception to June 2023. STUDY SELECTION CRITERIA: We included randomized controlled trials of exercise interventions in adults with nonspecific chronic LBP and at least 1 pain outcome reported at the main trial end point. DATA SYNTHESIS: A random-effects network meta-analysis was conducted. We assessed risk of bias using the Cochrane Risk of Bias Tool 2.0, and used the GRADE approach to judge the certainty of evidence for each outcome. RESULTS: Eighty-two trials were included (n = 5033 participants). We found a nonlinear dose-response relationship between total exercise and pain in patients with nonspecific chronic LBP. The maximum significant response was observed at 920 MET minutes (standardized mean difference = -1.74; 95% credible intervals: -2.43, -1.04). The minimal clinically important difference for achieving meaningful pain improvement was 520 MET minutes per week. The dose to achieve minimal clinically important difference varied by type of exercise; Pilates was the most effective. The certainty of the evidence was very low to moderate for all outcomes. CONCLUSION: The dose-response relationship of different exercise modalities to improve pain in patients with nonspecific chronic LBP had a U-shaped trajectory and low- to moderate-certainty evidence. The clinical effect was most pronounced with Pilates exercise. J Orthop Sports Phys Ther 2024;54(5):1-13. Epub 8 March 2024. doi:10.2519/jospt.2024.12153.