Folic acid supplementation for stroke prevention: A systematic review and meta-analysis of 21 randomized clinical trials worldwide.

BACKGROUND & AIMS: The AHA/ASA guidelines for primary stroke prevention are almost a decade old. The current recommendation regarding folic acid supplementation is based on only 8 clinical trials, and an additional 13 folate trials have been published since then. This meta-analysis aims to fill in critical evidence gaps by comprehensively evaluating 21 published trials with particular attention given to identifying the true influences through stratification. METHODS: PubMed, the Cochrane Central Register of Controlled Trials, and Embase were searched from inception to April 4, 2023. This study included all randomized controlled trials (RCTs) of folic acid with stroke as one of the reporting endpoints. Relative risks and 95% confidence intervals were used to assess the association between folic acid supplementation and the risk of stroke in a random-effects model. RESULTS: Results from the 21 pooled RCTs totaling 115,559 participants showed that folic acid supplementation significantly reduced the risk of stroke by 10% (RR 0.90, 95%CI 0.83 to 0.98). Subgroup analyses showed that folic acid efficacy was greater in areas without fortified grain or with partially-fortified grain (RR = 0.83, 95% CI 0.75 to 0.93; RR = 1.04 in areas with grain fortification, P-interaction = 0.003). In this group, folic acid supplementation was most efficacious in those without a history of stroke or myocardial infarction (RR = 0.77, 95% CI 0.68 to 0.86; RR = 0.94 for participants with a history of stroke or myocardial infarction, P-interaction = 0.008). The efficacy of folic acid remained consistent regardless of baseline folate levels, folic acid dosage, baseline vitamin B12 levels, vitamin B12 dosage, homocysteine reduction, intervention duration, and whether folic acid was taken alone or in combination (all P-interaction>0.05). All 21 trials were free of attrition bias and reporting bias, and there was no significant publication bias. CONCLUSIONS: This is by far the largest meta-analysis of RCTs regarding folic acid supplementation and stroke, demonstrating the overall benefit of folic acid for stroke prevention. Grain fortification and history of stroke or myocardial infarction may be the most important influences on the efficacy of folic acid for stroke prevention.

Tea Consumption, Milk or Sweeteners Addition, Genetic Variation in Caffeine Metabolism, and Incident Venous Thromboembolism.

OBJECTIVE: The association between tea consumption and venous thromboembolism (VTE) remains unknown. We aimed to evaluate the association between tea consumption with different additives (milk and/or sweeteners) and incident VTE, and the modifying effects of genetic variation in caffeine metabolism on the association. METHODS: A total of 190,189 participants with complete dietary information and free of VTE at baseline in the UK Biobank were included. The primary outcome was incident VTE, including incident deep vein thrombosis and pulmonary embolism. RESULTS: During a median follow-up of 12.1 years, 4,485 (2.4%) participants developed incident VTE. Compared with non-tea drinkers, tea drinkers who added neither milk nor sweeteners (hazard ratio [HR]: 0.85; 95% confidence interval [95% CI]: 0.76-0.94), only milk (HR: 0.86; 95% CI: 0.80-0.93), and both milk and sweeteners to their tea (HR: 0.90; 95% CI: 0.81-0.99) had a lower risk of VTE, while those who added only sweeteners to their tea did not (HR: 0.94; 95% CI: 0.75-1.17). Moreover, there was an L-shaped relationship between tea consumption and incident VTE among tea drinkers who added neither milk nor sweeteners, only milk, and both milk and sweeteners to their tea, respectively. However, a nonsignificant association was found among tea drinkers who added only sweeteners to their tea. Genetic variation in caffeine metabolism did not significantly modify the association (p-interaction = 0.659). CONCLUSION: Drinking unsweetened tea, with or without added milk, was associated with a lower risk of VTE. However, there was no significant association between drinking tea with sweeteners and incident VTE.

Associations between brachial-ankle pulse wave velocity and hypertensive retinopathy in treated hypertensive adults: Results from the China Stroke Primary Prevention Trial (CSPPT).

Although the association between persistent hypertension and the compromise of both micro- and macro-circulatory functions is well recognized, a significant gap in quantitative investigations exploring the interplay between microvascular and macrovascular injuries still exists. In this study, the authors looked into the relationship between brachial-ankle pulse wave velocity (baPWV) and hypertensive retinopathy in treated hypertensive adults. The authors conducted a cross-sectional study of treated hypertensive patients with the last follow-up data from the China Stoke Primary Prevention Trial (CSPPT) in 2013. With the use of PWV/ABI instruments, baPWV was automatically measured. The Keith-Wagener-Barker classification was used to determine the diagnosis of hypertensive retinopathy. The odds ratio (OR) and 95% confidence interval (CI) for the connection between baPWV and hypertensive retinopathy were determined using multivariable logistic regression models. The OR curves were created using a multivariable-adjusted restricted cubic spline model to investigate any potential non-linear dose-response relationships between baPWV and hypertensive retinopathy. A total of 8514 (75.5%) of 11,279 participants were diagnosed with hypertensive retinopathy. The prevalence of hypertensive retinopathy increased from the bottom quartile of baPWV to the top quartile: quartile 1: 70.7%, quartile 2: 76.1%, quartile 3: 76.7%, quartile 4: 78.4%. After adjusting for potential confounders, baPWV was positively associated with hypertensive retinopathy (OR = 1.05, 95% CI, 1.03-1.07, p < .001). Compared to those in the lowest baPWV quartile, those in the highest baPWV quartile had an odds ratio for hypertensive retinopathy of 1.61 (OR = 1.61, 95% CI: 1.37-1.89, p < .001). Two-piece-wise logistic regression model demonstrated a nonlinear relationship between baPWV and hypertensive retinopathy with an inflection point of 17.1 m/s above which the effect was saturated .

Relationship of serum total cholesterol and triglyceride with risk of mortality in maintenance hemodialysis patients: a multicenter prospective cohort study.

OBJECTIVE: The relationship between serum total cholesterol (TC) and triglyceride (TG) levels and mortality in maintenance hemodialysis (MHD) patients remains inconsistent. We aimed to explore the individual and combined association of TC and TG levels with the risk of mortality in Chinese MHD patients. METHODS: 1036 MHD patients were enrolled in this multicenter, prospective cohort study. The serum levels of total cholesterol and triglycerides were measured at baseline. The primary outcome was all-cause mortality and secondary outcome was cardiovascular disease (CVD) mortality. RESULTS: During a median follow-up duration of 4.4 years (IQR= 2.0-7.9 years), 549 (53.0%) patients died, and 297 (28.7%) deaths were attributed to CVD. Compared with patients with TC levels in the first three quartiles (<182.5 mg/dL), a significantly higher risk of all-cause mortality was found in participants with TC in the fourth quartile (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.17-1.76). However, a significantly lower risk of all-cause mortality was observed in participants with TG in the fourth quartile (≥193.9 mg/dL) (HR, 0.78; 95%CI: 0.63-0.98), compared with participants with TG in the first three quartiles. Similar trends were observed in CVD mortality. When analyzed jointly, patients with lower TC (<182.5 mg/dL) and higher TG (≥193.9 mg/dL) levels had the lowest risk of all-cause mortality and CVD mortality.Conclusions: In MHD patients in southern China, higher TC levels were associated with higher risk of mortality, while higher TG levels were related to lower risk of mortality. Patients with lower TC and higher TG levels had the best survival prognosis.

Evaluation of plasma vitamin E and development of proteinuria in hypertensive patients.

Background: The prospective relationship between plasma vitamin E levels and proteinuria remains uncertain. We aimed to evaluate the association between baseline plasma vitamin E levels and the development of proteinuria and examine any possible effect modifiers in patients with hypertension. Methods: This was a post hoc analysis of the renal sub-study of the China Stroke Primary Prevention Trial (CSPPT). In total, 780 participants with vitamin E measurements and without proteinuria at baseline were included in the current study. The study outcome was the development of proteinuria, defined as a urine dipstick reading of a trace or ≥ 1+ at the exit visit. Results: During a median follow-up duration of 4.4 years, the development of proteinuria occurred in 93 (11.9%) participants. Overall, there was an inverse relationship between plasma vitamin E and the development of proteinuria (per standard deviation [SD] increment; odds ratio [OR]: 0.73, 95% confidence interval [CI]: 0.55-0.96). Consistently, when plasma vitamin E was assessed as quartiles, lower risk of proteinuria development was found in participants in quartiles 2-4 (≥ 7.3 µg/mL; OR: 0.57, 95% CI: 0.34-0.96) compared to those in quartile 1. None of the variables, including sex, age, and body mass index, significantly modified the association between vitamin E and proteinuria development. Conclusion: There was a significant inverse association between plasma vitamin E levels and the development of proteinuria in patients with hypertension. The results were consistent among participants with different baseline characteristics.

Optimal folic acid dosage in lowering homocysteine: Precision Folic Acid Trial to lower homocysteine (PFAT-Hcy).

BACKGROUND: While folic acid (FA) is widely used to treat elevated total homocysteine (tHcy), promoting vascular health by reducing vascular oxidative stress and modulating endothelial nitric oxide synthase, the optimal daily dose and individual variation by MTHFR C677T genotypes have not been well studied. Therefore, this study aimed to explore the efficacy of eight different FA dosages on tHcy lowering in the overall sample and by MTHFR C677T genotypes. METHODS: This multicentered, randomized, double-blind, controlled clinical trial included 2697 eligible hypertensive adults with elevated tHcy (≥ 10 mmol/L) and without history of stroke and cardiovascular disease. Participants were randomized into eight dose groups of FA combined with 10 mg enalapril maleate, taken daily for 8 weeks of treatment. RESULTS: The intent to treat analysis included 2163 participants. In the overall sample, increasing FA dosage led to steady tHcy reduction within the FA dosing range of 0-1.2 mg. However, a plateau in tHcy lowering was observed in FA dose range of 1.2-1.6 mg, indicating a ceiling effect. In contrast, FA doses were positively and linearly associated with serum folate levels without signs of plateau. Among MTHFR genotype subgroups, participants with the TT genotype showed greater efficacy of FA in tHcy lowering. CONCLUSIONS: This randomized trial lent further support to the efficacy of FA in lowering tHcy; more importantly, it provided critically needed evidence to inform optimal FA dosage. We found that the efficacy of FA in lowering tHcy reaches a plateau if the daily dosage exceeds 1.2 mg, and only has a small gain by increasing the dosage from 0.8 to 1.2 mg. GOV IDENTIFIER: NCT03472508 (Registration Date: March 21, 2018).

J-shaped association between dietary thiamine intake and the risk of cognitive decline in cognitively healthy, older Chinese individuals.

Background: The prospective association of dietary thiamine intake with the risk of cognitive decline among the general older adults remains uncertain. Aims: To investigate the association between dietary thiamine intake and cognitive decline in cognitively healthy, older Chinese individuals. Methods: The study included a total of 3106 participants capable of completing repeated cognitive function tests. Dietary nutrient intake information was collected through 3-day dietary recalls and using a 3-day food-weighed method to assess cooking oil and condiment consumption. Cognitive decline was defined as the 5-year decline rate in global or composite cognitive scores based on a subset of items from the Telephone Interview for Cognitive Status-modified. Results: The median follow-up duration was 5.9 years. There was a J-shaped relationship between dietary thiamine intake and the 5-year decline rate in global and composite cognitive scores, with an inflection point of 0.68 mg/day (95% confidence interval (CI): 0.56 to 0.80) and a minimal risk at 0.60-1.00 mg/day of dietary thiamine intake. Before the inflection point, thiamine intake was not significantly associated with cognitive decline. Beyond the inflection point, each unit increase in thiamine intake (mg/day) was associated with a significant decrease of 4.24 (95% CI: 2.22 to 6.27) points in the global score and 0.49 (95% CI: 0.23 to 0.76) standard units in the composite score within 5 years. A stronger positive association between thiamine intake and cognitive decline was observed in those with hypertension, obesity and those who were non-smokers (all p<0.05). Conclusions: This study revealed a J-shaped association between dietary thiamine intake and cognitive decline in cognitively healthy, older Chinese individuals, with an inflection point at 0.68 mg/day and a minimal risk at 0.60-1.00 mg/day of dietary thiamine intake.

Systemic immune-inflammation index predicts first stroke and affects the efficacy of folic acid in stroke prevention.

Background: Systemic immune-inflammation index (SII) is a novel biomarker of growing interest in predicting stroke. The aim of this study was to investigate its predictive value and explore its effect modification on folic acid supplement for stroke primary prevention in a Chinese population with hypertension. Methods: A total of 10,013 participants from the China Stroke Primary Prevention Trial with available neutrophil, platelet and lymphocyte count were included, including 5,019 subjects in the enalapril group and 4,994 in the enalapril-folic acid group. SII was calculated as (platelet × neutrophil)/lymphocyte. The primary endpoint was first stroke. Cox proportional hazards models were used to evaluate the association between SII and first stroke. Results: A U-shape association between SII and first stroke risk was observed in enalapril group. Compared with the reference group (Quartile 2: 335.1 to <443.9 × 109 cell/L), the adjusted HRs were 1.68 (95 % CI: 1.06-2.66, P = 0.027) in Quartile 1 (<335.1 × 109 cell/L), 1.43 (95 % CI: 0.90-2.27, P = 0.126) in Quartile 3 (443.9 to <602.6 × 109 cell/L), and 1.61 (95 % CI: 1.03-2.51, P = 0.035) in Quartile 4 (≥602.6 × 109 cell/L). There was no significant association between SII and first stroke in the enalapril-folic acid group, with adjusted HR of 0.92 (95%CI: 0.54-1.56, P = 0.749) in Quartile 1(<334.7 × 109 cell/L), 1.36 (95%CI: 0.84-2.21, P = 0.208) in Quartile 3 (446.2 to <595.2 × 109 cell/L), and 1.41 (95%CI: 0.87-2.27, P = 0.163) in Quartile 4 (≥595.2 × 109 cell/L). A remarkable interaction between baseline SII and folic acid supplement for stroke prevention was observed, with particularly reduced risk by 44 % (HR: 0.56; 95 % CI: 0.34-0.90; P = 0.018) in the lowest SII group (P for interaction = 0.041). Conclusions: Among Chinese adults with hypertension, both low and high SII at baseline predicted increased first stroke risk. And compensatory folic acid particularly reduced first stroke risk in the lowest SII subgroup.

Association of accelerometer-measured physical activity and its change with progression to chronic kidney disease in adults with type 2 diabetes and overweight/obesity.

OBJECTIVE: To examine the long-term association of objectively measured moderate-to-vigorous physical activity (MVPA) and its longitudinal changes with progression to chronic kidney disease (CKD) in patients with type 2 diabetes (T2D) and overweight/obesity. METHODS: This study included 1746 participants in the Look AHEAD trial with baseline estimated glomerular filtration rate (eGFR)≥60 mL/min/1.73 m2. MVPA was measured at baseline, year 1, year 4 and year 8 using an RT3 accelerometer. The outcome was progression to CKD, defined as eGFR<60 mL/min per 1.73 m2 with a drop of ≥30% or end-stage kidney disease. Cox hazards models were fitted to examine the association between MVPA and outcomes. RESULTS: Over a median follow-up of 12.0 years, 567 participants experienced progression to CKD. Overall, there was a linear inverse association of cumulative average total MVPA (per 100 min/week higher amount, HR: 0.91; 95% CI: 0.86 to 0.96) and MVPA accumulated in bouts of ≥10 min (per 100 minutes/week higher amount, HR: 0.81; 95% CI: 0.72 to 0.91) with progression to CKD. Moreover, an increase in total MVPA from baseline to year 4 (the fourth quartile, ≥63.2 min/week) was associated with a 33% lower risk of progression to CKD compared with the largest MVPA reduction (the first quartile, <-198.3 min/week). A lower risk of progression to CKD was also observed for increases in MVPA accumulated in bouts of both <10 min and ≥10 min. CONCLUSIONS: Longer MVPA time and increases in MVPA was associated with a reduced risk of progression to CKD in adults with overweight/obesity and T2D.

Relationship among serum 25-hydroxyvitamin D, fibrosis stage, genetic susceptibility, and risk of severe liver disease.

OBJECTIVES: The prospective association between vitamin D and new-onset severe liver disease is still uncertain. The aim of this study was to assess the association of serum 25-hydroxyvitamin D (25(OH)D) with new-onset severe liver disease and to evaluate whether fibrosis stage, as assessed by the fibrosis- 4 (FIB-4) scores and genetic risk for liver cirrhosis may modify this association. METHODS: The study included 439 807 participants without liver diseases at baseline from the UK Biobank. Serum 25(OH)D concentrations were measured using the chemiluminescent immunoassay method. The primary outcome was new-onset severe liver disease, a composite definition of compensated or decompensated liver cirrhosis, liver failure, hepatocellular carcinoma, and liver-related death. RESULTS: During a median follow-up of 12 y, 4510 participants developed new-onset severe liver disease. Overall, there was an inverse association of serum 25(OH)D with new-onset severe liver disease (per SD increment, adjusted hazard ratio [HR], 0.87; 95% confidence interval, 0.84-0.91). Similarly, serum 25(OH)D (per SD increment) was significantly and inversely associated with new-onset compensated cirrhosis, decompensated cirrhosis, liver failure, and liver-related death, respectively, with HRs ranging from 0.75 to 0.87. No significant association was found for hepatocellular carcinoma. Furthermore, there was a stronger inverse association between serum 25(OH)D and severe liver disease among those with a higher FIB-4 score (≥2.67, 1.3 to <2.67, and <1.3; Pinteraction < 0.001). However, the genetic risks for liver cirrhosis, calculated using 12 related single nucleotide polymorphisms, did not significantly modify the association between serum 25(OH)D and severe liver disease (Pinteraction = 0.216). CONCLUSIONS: Lower serum 25(OH)D concentrations were significantly associated with a greater risk for new-onset severe liver disease, especially in participants with higher FIB-4 scores.

Social isolation, loneliness, and the risk of incident type 2 diabetes mellitus by glycemic status.

AIM: The modifying effect of prediabetic status on the association of social isolation and loneliness with the risk of type 2 diabetes mellitus (T2DM) remains uncertain. We aimed to explore whether prediabetic status modifies the association of social isolation and loneliness with incident T2DM. METHODS: 358,951 participants with random blood glucose < 11.1 mmol/l, hemoglobin A1c < 6.5 % and without diagnosis of diabetes from the UK Biobank were included. Prediabetes was defined by hemoglobin A1c level at 5.7-6.4 %. Social isolation and loneliness were assessed using self-reported questionnaires. The study outcome was incident T2DM. RESULTS: During a median follow-up of 12.5 years, 13,213 (3.7 %) incident T2DM cases were documented. Social isolation and loneliness in subjects with normoglycemia (adjusted HR [95 %CI]: social isolation: 1.14 [1.07;1.23]; loneliness: 1.33 [1.20;1.47]) were more strongly associated with increased risk of T2DM than in those with prediabetes (adjusted HR [95 %CI]: social isolation: 0.97 [0.91;1.03]; loneliness: 1.04 [0.95;1.13]) (Both P for interaction < 0.001). Among individuals with prediabetes, alcoholic consumption (30.9 %), household income (23.3 %), healthy sleep (17.1 %), loneliness (14.9 %), and physical activity (12.6 %) mediated most of the variance in the association between social isolation and incident T2DM, while body mass index (17.9 %) and healthy sleep (17.6 %) mediated most of the variance in the association between loneliness and incident T2DM. CONCLUSION: Social isolation and loneliness were independently associated with a higher risk of T2DM among individuals without prediabetes. Among those with prediabetes, the association of social isolation and loneliness with incident T2DM were mainly mediated by some socioeconomic and lifestyle factors.

Serum 25-Hydroxyvitamin D, Vitamin D Receptor, and Vitamin-D-Binding Protein Gene Polymorphisms and Risk of Dementia Among Older Adults With Prediabetes.

BACKGROUND: The association between vitamin D and dementia risk in those with prediabetes remains uncertain. We aimed to evaluate the association of serum 25-hydroxyvitamin D (25OHD) with incident dementia among older adults with prediabetes, and examine whether apolipoprotein E (APOE) genotypes, vitamin D receptor (VDR), and vitamin-D-binding protein (VDBP) gene polymorphisms may modify this association. METHODS: A total of 34 237 participants aged ≥60 with prediabetes (HbA1c <6.5% and ≥5.7%) and without dementia at baseline were included from the UK Biobank. Serum 25-hydroxyvitamin D (25OHD) was measured using chemiluminescent immunoassay method. The primary outcome was incident all-cause dementia. Secondary outcomes included incident Alzheimer's disease (AD) and vascular dementia, respectively. The VDR and VDBP gene polymorphisms included single nucleotide polymorphisms of rs7975232, rs1544410, rs2228570, rs731236, and rs7041, rs4588, respectively. RESULTS: During a median follow-up of 11.8 years, 941 (2.7%) participants developed incident all-cause dementia. Overall, serum 25OHD was inversely associated with all-cause dementia (per standard deviation increment, adjusted hazard ratio: 0.82; 95% confidence interval: 0.75, 0.89). Similar trends were found for incident AD and vascular dementia. Furthermore, there was a stronger inverse relationship between serum 25OHD and all-cause dementia among VDR rs7975232 C allele noncarriers (p-interaction < 0.05). However, APOE Ɛ4, other VDR, and VDBP gene polymorphisms did not significantly modify the relation of serum 25OHD with incident all-cause dementia (all p-interactions >.05). CONCLUSIONS: There was an inverse association between serum 25OHD and incident dementia among older adults with prediabetes, especially in VDR rs7975232 AA allele carriers.

Social isolation, loneliness, and the risk of incident acute kidney injury in middle-aged and older adults: A prospective cohort study.

OBJECTIVE: The relationships of social isolation and loneliness with acute kidney injury (AKI) risk remained uncertain. We aimed to investigate the associations of social isolation and loneliness with incident AKI. METHODS: 450,868 participants without prior AKI were included from the UK Biobank. The social isolation index was constructed based on living alone, social contact, and participation in social activities. Loneliness was assessed by asking about "Do you often feel lonely?". The study outcome was incident AKI. RESULTS: During a median follow-up of 12.0 years, 18,679 (4.1%) participants developed AKI, including 18,428 participants ascertained by hospital admission records with a median duration of hospitalization of 3 (25th-75th, 1-8) days. The hazard ratio for incident AKI for social isolation compared with no social isolation was 1.50 (95% CI: 1.44-1.55) after adjusting for age and race (minimally adjusted), and was 1.10 (95% CI: 1.06-1.14) after further adjusting for socioeconomic factors, health behaviors, biological and health-related factors, psychologic factors, and loneliness (fully adjusted). The minimally adjusted and fully adjusted hazard ratios for incident AKI for loneliness compared with no loneliness was 1.57 (95% CI: 1.52-1.62), and 1.10 (95% CI: 1.06-1.15), respectively. In the fully adjusted models, the highest risk of AKI was found in those with both social isolation and loneliness. Living alone and less social contact, rather than less participation in social activities, were significantly associated with a higher risk of incident AKI. CONCLUSIONS: Both social isolation and loneliness were independently and significantly associated with a higher risk of incident AKI.

L-shaped association between dietary zinc intake and cognitive decline in Chinese older people.

BACKGROUND AND OBJECTIVE: The prospective association between dietary zinc (Zn) intake and cognitive decline remains uncertain. We aimed to assess the relationship of dietary Zn intake with the risk of cognitive decline in the Chinese older people, and examine the possible effect modifiers on this association. METHODS: A total of 3,106 older Chinese adults aged 55 years or older from China Health and Nutrition Survey were included. Dietary nutrients intake information was collected by combined 24-h dietary recalls with weighing food inventory. The cognitive decline was defined as the 5-year decline rate in global and composite cognitive scores, based on a subset of items from the Telephone Interview for Cognitive Status-modified. RESULTS: The median follow-up duration was 5.9 years. There was an L-shaped association between dietary Zn intake and the 5-year decline rates in global and composite cognitive scores, with an inflection point at 8.8 mg/day of dietary Zn. For the composite cognitive scores, compared with the first quantile (<7.9 mg/day) of dietary Zn intake, quantiles 2-6 (≥7.9 mg/day) had a significantly slower cognitive decline rate (ß: -0.24; 95% confidence interval: -0.40 to -0.07). Similar results were found for the global cognitive scores. Moreover, the inverse association between dietary Zn intake and cognitive decline in composite cognitive scores was significantly stronger in those with lower levels of physical activity (P-interactions = 0.041). CONCLUSION: Dietary Zn intake was negatively associated with cognitive decline in the older people. Maintaining appropriate dietary Zn levels may prevent cognitive decline.

Relationship of dietary intake of food folate and synthetic folic acid intake from fortified foods with all-cause mortality in individuals with chronic kidney disease.

OBJECTIVE: To evaluate the association of the dietary intake of food folate (natural folate) and synthetic folic acid intake from fortified foods with the risk of all-cause mortality and end-stage kidney disease (ESKD) among the chronic kidney disease (CKD) population in regions with folic acid fortification. METHODS: 4028 individuals with established CKD in Chronic Renal Insufficiency Cohort (CRIC) were included. Diet was assessed using a validated diet history questionnaire at the baseline, year 2, and year 4, and nutrient intake, including food folate and folic acid from fortified foods, was estimated using the National Nutrient Database. The outcomes were all-cause mortality and ESKD. The results for all-cause mortality were further validated using the data from National Health and Nutrition Examination Surveys (NHANES). RESULTS: During a median follow-up of 11.1 years, 1155 deaths and 938 ESKD cases occurred. Compared with the first quartile of food folate intake, the third (HR: 0.74; 95% CI: 0.62, 0.90) and fourth (HR: 0.79; 95% CI: 0.63, 0.98) quartiles had a lower risk of all-cause mortality. Nevertheless, there was no significant association of synthetic folic acid intake from fortified foods with all-cause mortality. Similar results were observed for ESKD. Consistently, in NHANES, food folate intake and serum 5-methyltetrahydrofolate, but not folic acid intake, were inversely associated with all-cause mortality, while serum unmetabolized folic acid was positively associated with all-cause mortality in CKD participants. CONCLUSIONS: Higher intake of dietary natural folate, but not synthetic folic acid intake from fortified foods, was associated with lower risks of all-cause mortality and ESKD among CKD participants.

Association of Body Weight Time in Target Range With the Risk of Kidney Outcomes in Patients With Overweight/Obesity and Type 2 Diabetes Mellitus.

OBJECTIVE: We assessed the relationship of body weight time in target range (TTR) with composite kidney outcome in people with overweight/obesity and type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: Included in this study were 3,601 participants with baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 from the Look AHEAD (Action for Health in Diabetes) trial. Body weight TTR was defined as the proportion of time during the first 4 years that body weight was within the weight loss target (a weight loss of ≥7% from baseline). The primary outcome was composite kidney outcome, defined as eGFR decline ≥30% from baseline and to a level <60 mL/min/1.73 m2 at follow-up visit, or end-stage kidney disease. RESULTS: During a median follow-up of 8.0 years, 435 cases of composite kidney outcome were documented. Body weight TTR during the first 4 years was inversely associated with the subsequent risk of composite kidney outcome (per SD increment; adjusted hazard ratio [HR] 0.81; 95% CI 0.70-0.93). Accordingly, the adjusted HRs (95% CI) of composite kidney outcome were 1.00 (reference), 0.73 (0.54-1.00), 0.71 (0.52-0.99), and 0.54 (0.36-0.80) for participants with body weight TTR of 0%, >0% to <29.9%, 29.9% to <69.7%, and 69.7% to <100%, respectively. Similar results were found for a doubling of the urine albumin to creatinine ratio (secondary outcome). CONCLUSIONS: A higher body weight TTR, with a weight loss target of losing ≥7% of initial weight, was associated with a lower risk of kidney outcomes in participants with overweight/obesity and T2DM.

Habitual fish oil supplementation, genetic susceptibility of kidney stones and the risk of new-onset kidney stones.

OBJECTIVE: We aimed to assess the association between habitual fish oil use and new-onset kidney stones in participants with different levels of genetic risks of kidney stones. METHODS: 477,311 participants free of kidney stones at baseline from the UK Biobank cohort were included. Fish oil use was collected by both food frequency questionnaires and 24-h dietary recalls. A genetic risk score (GRS) for kidney stones was calculated based on 20 single-nucleotide polymorphisms associated with kidney stones. The primary outcome was new-onset kidney stones. RESULTS: During a median follow-up of 12.0 years, 5,637 cases of kidney stones were documented. Participants with high genetic risks of kidney stones had a higher risk of new-onset kidney stones (vs. low or intermediate risks; adjusted HR, 1.52; 95 %CI:1.44-1.60). Compared with non-users, habitual use of fish oil was associated with a lower risk of new-onset kidney stones (adjusted HR, 0.84, 95 %CI, 0.78-0.92) in participants with low or intermediate genetic risks, but not in those with high genetic risks of kidney stones (adjusted HR, 1.02, 95 %CI, 0.93-1.12; P-interaction =0.001). Among those with low or intermediate genetic risks of kidney stones, compared with fish oil constant nonusers, the adjusted HRs (95 %CI) for kidney stones were 0.89 (0.75-1.06), 0.72 (0.58-0.90), and 0.79 (0.64-0.97), for fish oil occasional users, modestly constant users, and moderately and highly constant users (P for trend = 0.001), respectively. CONCLUSIONS: Habitual fish oil use was associated with a lower risk of new-onset kidney stones in participants with low or intermediate genetic risk of kidney stones.

Different sedentary behaviors, genetic susceptibility of hypertension, and new-onset hypertension: Mediating effects of body mass index and grip strength.

BACKGROUND: The association between different sedentary behaviors and hypertension risk remains unclear. We aimed to explore the relationship between different domains of sedentary behaviors and new-onset hypertension, investigate whether genetic susceptibility to hypertension modifies the relationship, and examine the extent to which the relationship is mediated by body mass index (BMI) and grip strength. METHODS: 212 714 participants without baseline hypertension in the UK Biobank were enrolled. The three major sedentary behaviors (TV-watching, nonoccupational computer use, and driving) were measured using touch screen questionnaires. The primary outcome was new-onset hypertension. RESULTS: During a median follow-up of 11.9 years, 13 983 participants developed hypertension. There was a linear positive association between TV-watching time and new-onset hypertension (p for nonlinearity =0.868). A J-shaped association was found for nonoccupational computer use time and driving time with new-onset hypertension, with an inflection point of 0.5 h/day for both (both p for nonlinearity <0.001). Polygenetic risk scores for hypertension (based on 118 related single-nucleotide polymorphisms) did not significantly modify these associations (all p-interactions >0.05). Furthermore, the detrimental effects of long-term sedentary behaviors on hypertension were mediated by BMI by 21%-30%, and the beneficial effects of limited sitting time (within 0.5 h/day) for driving and nonoccupational computer use were mediated by grip strength by 6-25%. CONCLUSIONS: There was a positive association for hands-independence sedentary behavior (TV-watching), and a J-shaped association for hands-dependence sedentary behaviors (nonoccupational computer use and driving) with new-onset hypertension, regardless of genetic risks of hypertension. These relationships were partly mediated by BMI and grip strength.

Mobile Phone Use and Risks of Overall and 25 Site-Specific Cancers: A Prospective Study from the UK Biobank Study.

BACKGROUND: The association between mobile phone use and incident cancers remains uncertain. We aimed to investigate the relationships of mobile phone use with incident overall and 25 site-specific cancers in men and women. METHODS: A total of 431,861 participants ages 38 to 73 years without prior cancers were included from the UK Biobank. Of these, 46.7% were male. Participants who used a mobile phone at least once per week to make or receive calls were defined as mobile phone users. The study outcomes were incident overall and 25 site-specific cancers. RESULTS: During a median follow-up of 10.7 years, 35,401 (17.5%) men and 30,865 (13.4%) women developed overall cancer. Mobile phone use was significantly associated with higher risks of incident overall cancer [HR, 1.09; 95% confidence interval (CI): 1.06-1.12], nonmelanoma skin cancer (NMSC; HR, 1.08; 95% CI: 1.03-1.14), urinary tract cancer (HR, 1.18; 95% CI:1.05-1.32), and prostate cancer (HR, 1.19; 95% CI: 1.13-1.25) in men, and incident overall cancer (HR, 1.03; 95% CI: 1.00-1.06), NMSC (HR, 1.07; 95% CI: 1.01-1.13), and vulva cancer (HR, 1.74; 95% CI: 1.00-3.02) in women, but not with other cancers. Among mobile phone users, there was a dose-response relationship of length of mobile phone use with incident NMSC in men and women, and prostate cancer in men (all Ptrend < 0.05). CONCLUSIONS: There was a dose-response relationship of length of mobile phone use with incident NMSC in men and women, and prostate cancer in men. IMPACT: Our findings underscore the importance of limiting mobile phone use or keeping a distance from mobile phone for primary prevention of NMSC and prostate cancer.

Relationship of serum 25-hydroxyvitamin D, obesity with new-onset obstructive sleep apnea.

OBJECTIVE: The prospective association between vitamin D and obstructive sleep apnea (OSA) remains uncertain. We aimed to assess the association between serum 25-hydroxyvitamin D (25(OH)D), a major circulating form of vitamin D, and new-onset OSA, and examine the modifying effect of obesity. MATERIALS AND METHODS: This prospective cohort study included 444,975 participants from UK Biobank without prior OSA. The primary outcome was new-onset OSA. RESULTS: During a median follow-up duration of 12.0 years, 6051 (1.4%) participants occurred new-onset OSA. Overall, there was an inverse relation of serum 25(OH)D concentrations with the risk of new-onset OSA (per SD increment, HR, 0.92; 95%CI: 0.89-0.95). In the analysis of the interactions of serum 25(OH)D with the combination of BMI (<25, 25- < 30, and ≥30 kg/m2) and waist circumference (WC) (<90 and ≥90 cm) categories on new-onset OSA, the significantly inverse association of serum 25(OH)D and new-onset OSA was mainly found in participants with both BMI ≥ 25 kg/m2 and WC ≥ 90 cm (BMI 25-30 kg/m2 and WC ≥ 90 cm: per SD increment, HR, 0.90; 95%CI: 0.84-0.95; BMI ≥ 30 kg/m2 and WC ≥ 90 cm: per SD increment, HR, 0.85; 95%CI: 0.81-0.88), but not in other four groups with BMI < 25 kg/m2 or WC < 90 cm (P -interaction = 0.004). CONCLUSIONS: There was an inverse relation of serum 25(OH)D with the risk of new-onset OSA in participants with both BMI ≥ 25 kg/m2 and WC ≥ 90 cm. Our findings suggest the importance of maintaining a higher serum 25(OH)D concentration for primary prevention of OSA in a population with obesity.