UNASSIGNED: Dietary components can influence the incidence of colorectal cancer (CRC). Folate is one of the compounds that plays an essential role in the formation of DNA structures, which can lead to or prevent tumorigenesis. The present study is the first systematic review and dose-response meta-analysis of cohort studies evaluating the association between dietary folate intake and the risk of CRC.
UNASSIGNED: The PubMed/Medline, Scopus, and ISI Web of Science databases were systematically searched for cohort studies that assessed the association between folate intake and CRC up to January 2024. Summary relative risks (RRs) and 95 % confidence intervals (CIs) were calculated using a random effects model. Also, linear and nonlinear dose-response analyses were conducted for the dose-response associations between folate intake and risk of CRC.
UNASSIGNED: Eighteen prospective cohort studies with 931,469 participants, 14,860 CRC patients, 3536 colon cancer (CC) patients, and 1075 rectal cancer (RC) patients were included in the analysis. The summary RR of CRC for each 100-μg increase in dietary folate intake was 0.97 (95 % CI: 0.95-0.99, I2: 0.0 %, P-heterogeneity: 0.616), which can be related to BMI (0.97 (95 % CI: 0.95-0.99)); a more protective effect was also observed in subjects who drank alcohol (0.97 (95 % CI: 0.95-0.99)) and those who smoked (0.97 (95 % CI: 0.95-0.99)). Additionally, it was positively related to a 7 % lower risk of CC (0.93 (95 % CI: 0.87-0.99, I2: 33.7 %, P-heterogeneity: 0.159)), and the null relation for RC was 0.98 (95 % CI: 0.90-1.08), I2: 16.6 %, P-heterogeneity: 0.309). There was evidence of nonlinearity in which up to 500 μg/day dietary folate intake was inversely associated with CC (P nonlinearity = 0.04).
UNASSIGNED: The findings showed an inverse association between dietary folate intake and the risk of CRC, especially in high-risk persons, those who have a higher BMI, alcohol drinkers, and smokers.

OBJECTIVE: This study aimed to describe the variability in estimates of the association of daily steps and all-cause mortality in systematic reviews with meta-analyses, to identify the factors potentially responsible for it, and to provide an updated estimate.
METHODS: Five databases were systematically searched up to May 2024 to identify systematic reviews with meta-analyses and prospective cohort studies. A qualitative synthesis of previous reviews and an updated meta-analysis of cohort studies were performed. Pooled hazard ratios (HRs) with their 95% confidence intervals (CIs) were calculated using a random-effects model.
RESULTS: Eleven systematic reviews with meta-analyses and 14 cohort studies were included, revealing considerable variability in result presentation. Our updated meta-analysis showed a nonlinear association, indicating a lower risk of all-cause mortality with increased daily steps, with a protective threshold at 3143 steps/day, and a pooled HR of 0.91 (95% CI: 0.87, 0.95) per 1000 steps/day increment. Physical activity categories consistently indicated progressively reduced mortality risk, with the highly active category (>12,500 steps/day) exhibiting the lowest risk (0.35 (95% CI: 0.29, 0.42)).
CONCLUSIONS: Systematic reviews and meta-analyses showed considerable variability in effect estimates due to different methods of quantifying exposure. Despite it, our study underscores the importance of increased daily steps in reducing all-cause mortality, with a minimum protective dose of 3000 steps/day, although the optimal dose differed according to age and sex. It is recommended that future studies categorise daily steps by physical activity category, perform dose-response analyses, and use increments of 1000 steps/day.

BACKGROUND: Cannabinoids are being used by patients to help with chronic pain management and to address the 2 primary chronic pain comorbidities of anxiety and sleep disturbance. It is necessary to understand the biphasic effects of cannabinoids to improve treatment of this symptom triad.
METHODS: A scoping review was conducted to identify whether biphasic effects of cannabinoids on pain severity, anxiolysis, and sleep disturbance have been reported. The search included the Embase, Biosis, and Medline databases of clinical literature published between 1970 and 2021. The inclusion criteria were (1) adults more than 18 years of age, (2) data or discussion of dose effects associated with U-shaped or linear dose responses, and (3) measurements of pain and/or anxiety and/or sleep disturbance. Data were extracted by 2 independent reviewers (with a third reviewer used as a tiebreaker) and subjected to a thematic analysis.
RESULTS: After the database search and study eligibility assessment, 44 publications met the final criteria for review. Eighteen publications that specifically provided information on dose response were included in the final synthesis: 9 related to pain outcomes, 7 measuring anxiety, and 2 reporting sleep effects.
CONCLUSIONS: This scoping review reports on biphasic effects of cannabinoids related to pain, sleep, and anxiety. Dose-response relationships are present, but we found gaps in the current literature with regard to biphasic effects of cannabinoids in humans. There is a lack of prospective research in humans exploring this specific relationship.

Empirical evidence has shown that light therapy (LT) can reduce depression symptoms by stimulating circadian rhythms. However, there is skepticism and inconclusive results, along with confusion regarding dosing. The purpose of this study is to quantify light as a stimulus for the circadian system and create a dose-response relationship that can help reduce maladies among adolescents and young adults (AYAs). This will provide a reference for light exposure and neural response, which are crucial in the neuropsychological mechanism of light intervention. The study also aims to provide guidance for clinical application.
The latest quantitative model of CLA (circadian light) and CSt,f (circadian stimulus) was adopted to quantify light dose for circadian phototransduction in youth depression-related light therapy. Articles published up to 2023 through Web of Science, Cochrane Library, Medline (OVID), CINAHL, APA PsycINFO, Embase, and Scholars were retrieved. A meta-analysis of 31 articles (1,031 subjects) was performed using Stata17.0, CMA3.0 (comprehensive meta-analysis version 3.0) software, and Python 3.9 platform for light therapy efficacy comparison and dose-response quantification.
Under various circadian stimulus conditions (0.1 < CSt,f < 0.7) of light therapy (LT), malady reductions among AYAs were observed (pooled SMD = -1.59, 95%CI = -1.86 to -1.32; z = -11.654, p = 0.000; I2 = 92.8%), with temporal pattern (p = 0.044) and co-medication (p = 0.000) suggested as main heterogeneity sources. For the efficacy advantage of LT with a higher circadian stimulus that is assumed to be influenced by visualization, co-medication, disease severity, and time pattern, sets of meta-analysis among random-controlled trials (RCTs) found evidence for significant efficacy of circadian-active bright light therapy (BLT) over circadian-inactive dim red light (SMD = -0.65, 95% CI = -0.96 to -0.34; z = -4.101, p = 0.000; I2 = 84.9%) or circadian-active dimmer white light (SMD = -0.37, 95% CI = -0.68 to -0.06; z = -2.318, p = 0.02; I2 = 33.8%), whereas green-blue, circadian-active BLT showed no significant superiority over circadian-inactive red/amber light controls (SMD = -0.21, 95% CI = -0.45 to 0.04; z = -2.318, p = 0.099; I2 = 0%). Overall, circadian-active BLT showed a greater likelihood of clinical response than dim light controls, with increased superiority observed with co-medication. For pre-to-post-treatment amelioration and corresponding dose-response relationship, cumulative duration was found more influential than other categorical (co-medication, severity, study design) or continuous (CSt,f) variables. Dose-response fitting indicated that the therapeutic effect would reach saturation among co-medicated patients at 32-42 days (900-1,000 min) and 58-59 days (1,100-1,500 min) among non-medicated AYAs. When exerting high circadian stimulus of light therapy (0.6 < CSt,f < 0.7), there was a significantly greater effect size in 1,000-1,500 min of accumulative duration than <1,000 or >1,500 min of duration, indicating a threshold for practical guidance.
The results have been based on limited samples and influenced by a small sample effect. The placebo effect could not be ignored.
Although the superiority of LT with higher circadian stimulus over dimmer light controls remains unproven, greater response potentials of circadian-active BLT have been noticed among AYAs, taking co-medication, disease severity, time pattern, and visual characteristics into consideration. The dose-response relationship with quantified circadian stimulus and temporal pattern had been elaborated under various conditions to support clinical depression treatment and LT device application in the post-pandemic era.

BACKGROUND: Effects of ketone supplements as well as relevant dose-response relationships and time effects on blood β-hydroxybutyrate (BHB), glucose and insulin are controversial.
OBJECTIVE: This study aimed to summarize the existing evidence and synthesize the results, and demonstrate underlying dose-response relationships as well as sustained time effects.
METHODS: Medline, Web of Science, Embase, and Cochrane Central Register of Controlled Trials were searched for relevant randomized crossover/parallel studies published until 25th November 2022. Three-level meta-analysis compared the acute effects of exogenous ketone supplementation and placebo in regulating blood parameters, with Hedge\'s g used as measure of effect size. Effects of potential moderators were explored through multilevel regression models. Dose-response and time-effect models were established via fractional polynomial regression.
RESULTS: The meta-analysis with 327 data points from 30 studies (408 participants) indicated that exogenous ketones led to a significant increase in blood BHB (Hedge\'s g = 1.4994, 95% CI [1.2648, 1.7340]), reduction in glucose (Hedge\'s g = -0.3796, 95% CI [-0.4550, -0.3041]), and elevation in insulin of non-athlete healthy population (Hedge\'s g = 0.1214, 95%CI [0.0582, 0.3011]), as well as insignificant change in insulin of obesity and prediabetes. Nonlinear dose-response relationship between ketone dosage and blood parameter change was observed in some time intervals for BHB (30-60 min; >120 min) and insulin (30-60 min; 90-120 min), with linear relationship observed for glucose (>120 min). Nonlinear associations between time and blood parameter change were found in BHB (>550 mg/kg) and glucose (450-550 mg/kg), with linear relationship observed in BHB (≤250 mg/kg) and insulin (350-550 mg/kg).
CONCLUSIONS: Dose-response relationships and sustained time effects were observed in BHB, glucose and insulin following ketone supplementation. Glucose-lowering effect without increasing insulin load among population of obesity and prediabetes was of remarkable clinical implication.
UNASSIGNED: PROSPERO (CRD42022360620).

There is emerging evidence of associations between intake of sugar-sweetened beverages (SSBs), those that include various forms of added sugar, and increased risk of cardiovascular disease (CVD) but whether consumption of other dietary sources of fructose affects CVD is unclear. In this study, we conducted a meta-analysis to examine potential dose-response relationships between such foods and CVD, coronary heart disease (CHD), and stroke morbidity and mortality. We systematically searched the literature indexed in PubMed, Embase, and the Cochrane Library from the inception of each database to February 10, 2022. We included prospective cohort studies analyzing the association between at least 1 dietary source of fructose and CVD, CHD, and stroke. Based on data from 64 included studies, summary HRs and 95% CIs were calculated for the highest intake category compared with the lowest, and dose-response analyses were performed. Of all fructose sources examined, only SSB intakes showed positive associations with CVD, giving summary HRs per 250 mL/d increase of 1.10 (95% CI: 1.02, 1.17) for CVD, 1.11 (95% CI: 1.05, 1.17) for CHD, 1.08 (95% CI: 1.02, 1.13) for stroke morbidity, and 1.06 (95% CI: 1.02, 1.10) for CVD mortality. Conversely, 3 dietary sources showed protective associations: between fruits and CVD morbidity (HR: 0.97; 95% CI: 0.96, 0.98), fruits and CVD mortality (HR: 0.94; 95% CI: 0.92, 0.97), yogurt and CVD mortality (HR: 0.96; 95% CI: 0.93, 0.99), and breakfast cereals and CVD mortality (HR: 0.80; 95% CI: 0.70, 0.90). All these relationships were linear except for fruit, which was J-shaped: CVD morbidity was the lowest at 200 g/d and there was no protective association above 400 g/d. These findings indicate that the adverse associations between SSBs and CVD, CHD, and stroke morbidity and mortality do not extend to other dietary sources of fructose. The food matrix seemed to modify the association between fructose and cardiovascular outcomes.

We aimed to summarize the associations between food sources of fructose and cardiovascular diseases (CVD), cancer, and all-cause mortality risk using a systematic review and meta-analysis. We searched PubMed, Scopus, and Web of Science up to November 2020. We included cohort studies that investigated the relationship between mortality risk (all-cause, CVD, specific CVD, and total and site-specific cancers) and intake of ≥1 food source of fructose (fruit, fruit juice, breakfast cereals, sugar-sweetened beverages (SSBs), sweets, and yogurt) in general adult population. Summary hazard ratios and 95% CIs were estimated using a random-effects model for linear and nonlinear relationships. Findings indicated that each 100 g/d increase in fruit intake was associated with 8-13% lower risk of CVDs, stroke, gastrointestinal, and lung cancer mortality. For all-cause mortality, there was a beneficial relationship up to 200 g/d fruit, and then plateaued. For ischemic heart disease and cancer mortality, there was a beneficial relationship up to 300 g/d followed by a slight increase. Ingestion of breakfast cereals and sweets was also associated with lower risk of all-cause mortality. For yogurt, a non-linear marginal decrease in all-cause mortality was found. Ingestion of each 200 g/d yogurt was associated with a 14% lower risk of CVD mortality. Every 60 g/d increase in sweet intake was linked to a 5% lower risk of all-cause mortality. Contrariwise, every 250 g/d increase in SSBs intake was associated with 7-10% higher risk of all-cause and CVD mortality. In conclusion, beneficial associations were found between fruit, breakfast cereals, sweets, and yogurt with all-cause and/or CVD mortality risk. Fruit intake had also an inverse link with cancer mortality. Conversely, SSBs had a harmful relationship with all-cause and CVD mortality.Supplemental data for this article is available online at https://doi.org/10.1080/10408398.2021.2000361 .Registry number: CRD42019144956.

BACKGROUND: The time-course response after a single injection of botulinum toxin (BoNT) for post-stroke spasticity is debated. We addressed this issue by conducting a systematic review and a pharmacodynamic model-based meta-analysis.
METHODS: We searched Medline, PeDro and Google Scholar databases up to March 2020, selecting randomized controlled trials of post-stroke and traumatic brain injury patients with arm or leg muscle hypertonia, comparing BoNT to placebo, or different BoNT preparations. The main outcome was change in Modified Ashworth Scale (MAS) score. A non-linear mixed effect model was used to estimate maximal toxin and placebo effects (Emax and EPlacebo), the effect disappearance half-life (T1/2off) of BoNT and the doses achieving 50 and 80% of Emax (D50 and D80). The equivalence ratios between different BoNT preparations were calculated from D50 values. Adverse events were recorded.
RESULTS: Altogether, 2,236 unique records were screened by 2 independent reviewers: 35 eligible trials including 3011 patients (95% post-stroke) were identified. For all BoNT preparations, the BoNT Emax of -1.11 (95% credible interval -1.31; -0.29) was reached at 5 weeks; the maximal placebo effect was -0.30 (-0.37; -0.22). Both D50 and D80 differed significantly by muscle volume. At D50, the equivalence ratio was significantly higher for abobotulinumtoxinA (3.35) than onabotulinumtoxinA and lower for letibotulinumtoxinA (0.41). T1/2off was longer for abobotulinumtoxinA than for onabotulinumtoxinA and the other preparations (13.1 weeks [95% credible interval 7.7; 19.3] vs 8.6 weeks [7.1; 10.1]). Adverse events were minor, with a weak, but significant, dose-response relation for muscle weakness.
CONCLUSIONS: This first pharmacodynamic model-based meta-analysis of individuals with stroke revealed that for all BoNT-A preparations, BoNT-A injections to treat spasticity have maximal effect at 5 weeks. The T1/2off was longer for abobotulinumtoxinA than other preparations. Differences between certain BoNT unit scales were also confirmed.

Antipsychotics acting as antagonists at dopamine D2 receptors concentrated in the striatum are the cornerstone of effective treatment of psychosis. Substantial progress in treating persons with schizophrenia could be achieved by the identification of biomarkers which reliably determine the lowest efficacious dose of antipsychotics. Prolactin levels have been considered a promising treatment-response biomarker due to dopamine\'s regulation of serum prolactin levels through D2 receptors in the hypothalamic-pituitary pathway. Prolactin secretion in response antipsychotic administration is associated with the antipsychotics affinity for D2 receptors. This review assesses the available literature on the use of serum prolactin levels as an antipsychotic-response biomarker. Articles were identified through PubMed as well as the reference lists of full text articles available online. Relevant publications were summarized briefly to define the limitations and utility of serum prolactin levels as a tool for improving antipsychotic dosing. Serum prolactin levels in combination with prolactin-inducing potencies for each antipsychotic may help identify the lowest effective dose of antipsychotic medications. , In addition to the fact that prolactin secretion is dependent on serum antipsychotic levels and not brain levels, recent findings show that prolactin release is independent of the β-arrestin-2 pathway and GSK3β regulation, one branch of the pathway that has been implicated in antipsychotic efficacy. Therefore, serum prolactin is an indirect biomarker for treatment response. Further investigations are warranted to characterize prolactin-antipsychotic dose-response curves and systematically test the utility of measuring prolactin levels in patients to identify a person\'s lowest efficacious dose.

To investigate the association between lactation and maternal risk of type 2 diabetes, including a potential graded association according to lactation duration.
A systematic review and meta-analysis of observational studies that investigated the reported association between lactation (irrespective of duration, intensity or mode) and maternal risk of type 2 diabetes was conducted.
A total of 22 studies (17 cohort studies and five cross-sectional studies) were included in this systematic review, and 16 contributed to the meta-analysis. Studies that investigated the association of lactation with risk of type 2 diabetes in the first months after birth in women with gestational diabetes reported conflicting results. Studies with a longer follow-up showed a graded protective association for lactation and the risk of type 2 diabetes, with a potentially larger risk reduction in women with gestational diabetes than in those without gestational diabetes. Overall, ever versus never lactation was associated with a 27% lower risk of type 2 diabetes (RR 0.73, 95% CI [0.65, 0.83]). Each additional month of lactation was associated with a 1% lower risk of type 2 diabetes (RR 0.99, 95% CI [0.98, 0.99]). However, the overall quality of the studies was modest.
Lactation is associated with a significantly reduced risk of maternal type 2 diabetes over the life course, particularly in women with gestational diabetes. The protective effect seems to increase with longer duration of lactation. Further research is warranted to understand whether this association is modified by exposure to other risk factors.