Combined microfocused ultrasound and delicate pulsed light for facial rejuvenation: A prospective, randomized, and split-face study.

OBJECTIVES: Public's interest in noninvasive skin rejuvenation treatments continues to grow. The advantage of combination therapy lies in that it can target different aspects of skin rejuvenation. This study aimed to assess the efficacy and safety of microfocused ultrasound (MFU) combined with delicate pulsed light (DPL) for facial rejuvenation. METHODS: Twenty-one patients with facial relaxation were enrolled. All patients received whole-face MFU treatment, and one side of the face was randomly assigned to receive DPL. MFU treatment was performed at Months 0 and 3, while DPL treatment was performed at Months 1, 2, 4, and 5. The length and angle of the nasolabial fold and perioral wrinkles, melanin index (MI), erythema index (EI), transepidermal water loss (TEWL), and follow-up time were recorded at Months 0, 3, and 6. Side effects were recorded during treatment and each follow-up visit. RESULTS: Twenty patients successfully completed the study. At the sixth month, the average length of perioral wrinkles and nasolabial folds on the combined side decreased by 11.5% (pwithin < 0.001) and 6.5% (pwithin = 0.011), while 8.3% (pwithin = 0.012) and 3.8% (pwithin = 0.02) on the MFU side. Compared with MFU treatment alone, the combined treatment also showed significant improvements in nasolabial fold angle (from 28.8 ± 3.4° to 32.7 ± 5.0°) and perioral wrinkle angle (from 39.3 ± 5.0° to 43.7 ± 5.1°). In addition, the combined side had greater benefits than the MFU side in improving MI, EI, TEWL, and skin elasticity (pbetween < 0.05). Except for one patient who withdrew due to increased skin sensitivity after MFU treatment, other subjects did not experience permanent or serious side effects. CONCLUSIONS: The combination of MFU and DPL for facial rejuvenation treatment is safe and effective. The combined treatment has better efficacy in skin firmness, and improving skin tone.

Inverse Association Between Baseline Plasma Selenium Concentrations and Risks of Renal Function Decline in Hypertensive Adults.

BACKGROUND: The kidney has the highest level of selenium (Se) in the body, but the role of plasma Se in chronic kidney disease is uncertain. OBJECTIVE: We aimed to investigate the longitudinal association between baseline plasma Se and renal function decline in adults with hypertension and to explore possible effect modifiers. METHODS: This was a post hoc analysis of 935 men and women with hypertension aged 40 to 75 years from a folic-acid intervention trial (the China Stroke Primary Prevention Trial) in China. The baseline plasma Se was analyzed both as a continuous variable and as tertiles. The primary outcome was a rapid decline in renal function, defined as a mean decline in the estimated glomerular filtration rate of ≥ 5 mL/(min × 1.73 m2) per year. RESULTS: The median follow-up duration from baseline to outcome was 4.4 years. After multivariate adjustment, there was an inverse association between plasma Se and a rapid decline in renal function (per 10-unit increment; OR: 0.85; 95% CI: 0.73, 0.99). When the baseline plasma Se was assessed as tertiles, compared to the lowest tertile (<74.5 µg/L), a lower trend of the primary outcome was found in the second tertile (74.5 to < 89.4 µg/L; OR: 0.60; 95% CI: 0.34, 1.07) and the highest tertile (89.4 to <150 µg/L; OR: 0.42; 95% CI: 0.22, 0.80; Ptrend = 0.006). Furthermore, the Se-renal association was more pronounced among participants with folic acid treatment or with a higher baseline folate concentration (both Pinteraction values < 0.05). CONCLUSIONS: In this sample of Chinese adults with hypertension, baseline plasma Se concentrations were inversely associated with the risk of renal function decline. The China Stroke Primary Prevention Trial was registered at clinicaltrials.gov as NCT00794885.

Efficacy and safety of low-dose oral isotretinoin monotherapy versus combined therapy with picosecond laser for the treatment of acne scars in Asian population.

PURPOSE: Acne scars are common in patients with moderate to severe acne. Isotretinoin is the first-line treatment for those patients, but whether oral isotretinoin can improve acne scar is not clear. Picosecond lasers (FxPico) has been reported to improve acne scars. In the present study, we evaluated the clinical efficacy of low-dose isotretinoin with or without FxPico treatment for acne scars. MATERIALS AND METHODS: A total of 48 patients with acne scars were enrolled and were randomly assigned to receive low dose oral isotretinoin or not. For all the patients in both treatment groups, one side of face were randomly assigned to be treated with picosecond laser. Assessments, including photos, échelle d'évaluation clinique des cicatrices d'acné (ECCA) and Global Acne Grading System (GAGS) score, the number of lesions, melanin and erythema indexes, transepidermal water loss were assessed at 0, 1, 2, and 3 month. Side effects, Dermatology Life Quality Index (DLQI) and satisfaction were recorded before and after the study. RESULTS: A total of 44 patients completed the study (24 received oral low dose isotretinoin and 20 did not). Low dose oral isotretinoin treated group showed significant improvement on ECCA (from 112.5 [50-180] to 105 [50-160]), GAGS score (from 12.6 ± 3.3 to 10.1 ± 3.0), the count of papules (from 4.3 ± 3.7 to 1.0 ± 1.5) than the blank group, and higher improvement were noticed after isotretinoin combined with FxPico. All the side effects were temporary and tolerable, no adverse effects were observed. Higher DLQI and patients' satisfaction were achieved by oral isotretinoin alone and isotretinoin combined with FxPico. CONCLUSIONS: This is the first paper showing the improvement of scars by early low dose-isotretinoin intervention with or without the combination of picosecond laser. Early intervention with oral low-dose isotretinoin is effective for the treatment and prevention of acne scars, the combined therapy with FxPico can achieve better outcome.

1927nm fractional thulium fiber laser combined with 30% salicylic acid for the treatment of acne and acne scars: A prospective, randomized, and split-face study.

OBJECTIVES: Patients with acne usually develops acne scars subsequently, early intervention of scars is crucial in acne management. 1927nm fractional thulium fiber laser (TFL) is effective in scars improvement and chemical peels with 30% supramolecular salicylic acid (SSA) can be applied for the treatment of acne. The purpose of this study is to evaluate and compare the efficacy and safety of TFL monotherapy versus the concomitant application of TFL and 30% SSA on acne and acne scars. MATERIALS AND METHODS: Thirty-three patients with acne and acne scars were enrolled, and two sides of the face were randomly divided to receive either TFL and SSA chemical peeling or TFL. Four sessions of TFL treatments were applied with 4-week intervals for both sides, SSA combined treatment side received eight SSA chemical peels with 2-week intervals additionally. GAGS, ECCA score, the number of acne lesions, melanin index (MI) and erythema index (EI), transepidermal water loss (TEWL), and side effects were recorded at Weeks 0, 4, 8, 12, and 18. Satisfaction of patients was recorded on both sides at the end of the study. RESULTS: Thirty patients completed the study. Both control group (TFL monotherapy) and SSA group (TFL combined with SSA chemical peeling) significantly improved GAGS and ECCA score. SSA group showed higher efficacy in terms of GAGS and ECCA score, acne lesion count, TEWL, MI, EI, and satisfaction than control group. All the side effects were temporary and tolerable, no adverse effects were observed. CONCLUSIONS: Both TFL and the TFL combined with 30% SSA chemical peeling are safe and effective for the treatment and prevention of acne and acne scars, though the combined group has higher efficacy.

Early acne scar intervention with 1064 nm picosecond laser in patients receiving oral isotretinoin: a randomized split-face controlled pilot study.

Early acne scar intervention is important. Oral isotretinoin is widely used in patients with moderate to severe acne. Picosecond laser has shown a promising effect on scar clearance. However, there is a lack of reports on the efficacy and safety of early acne scar management by using 1064-nm picosecond laser in patients receiving low-dose oral isotretinoin. Twenty-four patients with atrophic acne scars of Fitzpatrick skin type III to V were enrolled. All patients were receiving low-dose oral isotretinoin (0.12-0.22 mg/kg/day) during the treatment. The face of the participants was randomly assigned to receive 2 sessions of fractional picosecond 1064 nm Nd: YAG laser (FxPico) treatment and 2 follow-ups, with an interval of 1 month (month 0-3). Clinical efficacy and safety were assessed by photographs, ECCA grading scale, the number of scar lesions melanin and erythema indexes (MI and EI), TEWL, DLQI, and patient satisfaction and the adverse events were recorded on every visit. FxPico significantly decreased the ECCA score and showed higher improvement in the ECCA score. FxPico treated side achieved a significant reduction in all acne scar types, while only boxcar scars and rolling scars showed higher improvement. TEWL but not MI or EI were significantly improved. DLQI and patient satisfaction were higher with the FxPico-treated side than control side. No adverse effects were observed and all the side effects observed were temporary and tolerable. Early intervention by FxPico on patients receiving low-dose oral isotretinoin is a safe and effective modality to improve atrophic acne scars.

Identification and functional characterization of safflower cysteine protease 1 as negative regulator in response to low-temperature stress in transgenic Arabidopsis.

MAIN CONCLUSION: We performed genome-wide and heterologous expression analysis of the safflower cysteine protease family and found that inhibition of CtCP1 expression enhanced plant cold resistance. Cysteine protease (CP) is mainly involved in plant senescence and stress responses. However, the molecular mechanism of endogenous cysteine protease inhibition in plant stress tolerance is yet unknown. Here, we report the discovery and functional characterization of a candidate CP1 gene from safflower. The conserved structural topology of CtCPs revealed important insights into their possible roles in plant growth and stress responses. The qRT-PCR results implied that most of CtCP genes were highly expressed at fading stage suggesting that they are most likely involved in senescence process. The CtCP1 expression was significantly induced at different time points under cold, NaCl, H2O2 and PEG stress, respectively. The in-vitro activity of heterologously expressed CtCP1 protein showed highest protease activity for casein and azocasein substrates. The expression and phenotypic data together with antioxidant activity and physiological indicators revealed that transgenic plants inhibited by CtCP1-anti showed higher tolerance to low temperature than WT and CtCP1-OE plants. Our findings demonstrated the discovery of a new Cysteine protease 1 gene that exerted a detrimental effect on transgenic Arabidopsis under low-temperature stress.

Efficacy and safety of low-level light therapy by delicate pulsed light combined with low-dose oral isotretinoin for the treatment of acne vulgaris: a randomized split-face study.

Acne vulgaris (AV) is a common dermatosis that causes psychological problems. Isotretinoin is the first-line treatment for moderate-to-severe AV, but its onset of effect is delayed. Although light-based therapy is widely used in the treatment of AV, there is a lack of reports on delicate pulsed light (DPL) which has a narrow therapeutic spectrum (500-600 nm). Low-level light therapy (LLLT) has shown an emerging role in anti-inflammatory effects and skin repair. This study investigates the efficacy and safety of low-dose oral isotretinoin combined with LLLT using DPL in patients with moderate-to-severe AV. Thirty-six patients with moderate-to-severe AV were enrolled and received low-dose oral isotretinoin (10-20 mg/day). The two sides of the face were randomly assigned to receive DPL (6-9 J/cm2) or not at an interval of 2 weeks for 4 treatment sessions (weeks 0, 2, 4, 6). Photos, GAGS score, counts of papules, pustules, comedones, TEWL, melanin and erythema index, side effects, efficacy, and satisfactory score were recorded at each visit and at 4 weeks after the final treatment (week 10). Thirty-three patients completed the study. DPL and oral isotretinoin combined therapy exhibited significantly improved GAGS score as well as the number of the lesions from week 2 and maintained until week 10. At the end of the observation, the improvement of GAGS was 70.88% on the DPL and isotretinoin combined side versus 62.12% on the side with isotretinoin monotherapy (p = 0.0009). The improvement for papule number was 61.58% on the DPL combined side versus 43.33% on the control side (p < 0.0001), for comedone was 63.15% versus 43.30% (p = 0.0008). TEWL and indexes of melanin and erythema also had better outcomes with DPL combined therapy at week 10. All the side effects were temporary and tolerable; no adverse effects were observed. Oral low-dose isotretinoin combined with LLLT by DPL offers a combination with reduced side effects and better outcomes within a limited treatment duration, which advances the onset of effect of isotretinoin monotherapy and improves lesion clearance.

Dietary Plant Protein and Mortality Among Patients Receiving Maintenance Hemodialysis: A Cohort Study.

RATIONALE & OBJECTIVE: Although greater dietary intake of protein has been associated with beneficial health effects among patients receiving maintenance hemodialysis (MHD), the effects of plant protein intake are less certain. We studied the association of the proportion of protein intake derived from plant sources with the risk of mortality among patients receiving MHD and explored factors that may modify these associations. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: 1,119 Chinese hemodialysis patients aged over 18 years receiving MHD in 2014-2015. PREDICTORS: The proportion of plant protein intake to total protein intake. OUTCOMES: All-cause mortality and cardiovascular disease (CVD) mortality. ANALYTICAL APPROACH: Segmented regression models were fit to examine the association of plant protein intake proportion with the risk of all-cause mortality and CVD mortality. Multivariable-adjusted Cox proportional and cause-specific hazards models were used to estimate the hazard ratios (HR) and 95% CI for these outcomes. RESULTS: The means of plant protein intake normalized to ideal body weight and plant protein intake proportion were 0.6±0.2 (SD) g/kg per day and 0.538±0.134, respectively. During a median follow-up period of 28.0 months, 249 deaths occurred, with 146 of these deaths resulting from CVD. Overall, there was a U-shaped association between plant protein intake proportion and the risk of all-cause mortality, with an inflection point at 45%. Among patients with a plant protein intake proportion<45%, there was a 17% lower rate of mortality with each 5% greater plant protein intake proportion (HR, 0.83 [95% CI, 0.73-0.96]). Among patients with plant protein intake proportion≥45%, there was a 9% greater rate of mortality with each 5% greater plant protein intake proportion. A similar U-shaped association was observed for CVD mortality, with an inflection point at 44%. LIMITATIONS: Observational study, potential unmeasured confounding. CONCLUSIONS: There was a U-shaped association between plant protein intake proportion and the risk of all-cause and cardiovascular mortality in MHD patients. If confirmed, these findings suggest a potential avenue to improve outcomes in this patient population.

Higher dietary fibre intake is associated with lower CVD mortality risk among maintenance haemodialysis patients: a multicentre prospective cohort study.

High fibre intake is associated with reduced mortality risk in both general and chronic kidney disease populations. However, in dialysis patients, such data are limited. Therefore, the association between dietary fibre intake (DFI) and the risk of all-cause and CVD mortality was examined in this study. A total of 1044 maintenance haemodialysis (MHD) patients from eight outpatient dialysis centres in China were included in this study. Data on DFI were collected using 24-h dietary recalls for 3 d in a week and were normalised to actual dry weight. The study outcomes included all-cause and CVD mortality. Over a median of 46 months of follow-up, 354 deaths were recorded, of which 210 (59 %) were due to CVD. On assessing DFI as tertiles, the CVD mortality risk was significantly lower in patients in tertiles 2-3 (≥0·13 g/kg per d; hazard ratio (HR) 0·71; 95 % CI 0·51, 0·97) compared with those in tertile 1 (<0·13 g/kg per d). A similar but non-significant trend was found for the association between DFI (tertiles 2-3 v. tertile 1; HR 0·83; 95 % CI 0·64, 1·07) and all-cause mortality. In summary, higher DFI was associated with lower CVD mortality risk among Chinese MHD patients. This study emphasises the significance of DFI in MHD patients and provides information that is critical for the improvement of dietary guidelines for dialysis patients.

Effect of Vitamin B12 Levels on the Association Between Folic Acid Treatment and CKD Progression: A Post Hoc Analysis of a Folic Acid Interventional Trial.

RATIONALE & OBJECTIVE: In populations with folic acid fortification or supplementation, the main nutritional determinant of total homocysteine levels is vitamin B12 (B12) status. We aimed to evaluate the modifying effect of B12 levels on the association between folic acid treatment and chronic kidney disease (CKD) progression. STUDY DESIGN: A post hoc analysis of an interventional trial. SETTING & PARTICIPANTS: This is a post hoc analysis of 1,374 hypertensive adults with mild to moderate CKD and B12 measurements at baseline from the kidney disease substudy of the China Stroke Primary Prevention Trial (CSPPT), conducted in 20 communities in Jiangsu province in China, a region with low folate consumption. INTERVENTIONS: Assignments to a double-blinded daily treatment of enalapril, 10mg, and folic acid, 0.8mg; or enalapril, 10mg, alone. OUTCOMES: The primary outcome was progression of CKD (defined as a decrease in estimated glomerular filtration rate [eGFR] ≥ 30% and to a level of<60mL/min/1.73m2 if baseline eGFR was≥60mL/min/1.73m2; or a decrease in eGFR≥50% if baseline eGFR was<60mL/min/1.73m2; or kidney failure). RESULTS: Mean baseline eGFR in this study was 86.1±20.5 (SD) mL/min/1.73m2. Median treatment duration was 4.4 years. Among participants with higher baseline B12 levels (≥248pmol/L), compared to enalapril alone, enalapril-folic acid treatment was associated with an 83% reduction in the odds of the primary outcome (OR, 0.17; 95% CI, 0.07-0.40). However, among those with baseline B12 levels<248pmol/L (metabolic B12 deficiency), there was no significant group difference in the primary outcome (OR, 1.21; 95% CI, 0.51-2.85). The interaction between B12 level and folic acid treatment was significant (P = 0.001). LIMITATIONS: The analysis is post hoc and event rate is low. CONCLUSIONS: Folic acid treatment was associated with a greater reduction in the odds of CKD progression among patients with mild to moderate CKD and higher B12 levels. FUNDING: Government funding (National Key Research and Development Program of China).

Relationship between Serum Uric Acid and Mortality Risk in Hemodialysis Patients: A Multicenter Prospective Cohort Study.

BACKGROUND: Several studies have reported that low serum uric acid (SUA) levels are related to increased risk of mortality in maintenance hemodialysis (MHD) patients. However, the possible detrimental effects of high SUA on the mortality risk have not been well examined. Moreover, the possible effect modifiers for the SUA-mortality association have not been fully investigated. To address the aforementioned gap, we aimed to explore the nonlinear relationship between SUA levels and all-cause and cardiovascular disease (CVD) mortality risk, and to examine any possible effect modifiers in MHD patients. METHODS: We conducted a multicenter, prospective cohort study among 1,018 MHD patients from 8 hemodialysis centers. The primary outcome was all-cause mortality, and the secondary outcomes were CVD mortality and non-CVD mortality. RESULTS: The mean value for SUA in the total population was 8.5 ± 1.9 mg/dL. The lowest and highest quintiles of SUA were <7.0 and >10.1 mg/dL, respectively. Over a median follow-up of 45.6 months, 343 deaths were recorded, of which 202 (58.9%) were due to CVD. When SUA was assessed as quintiles, a significantly higher risk of all-cause mortality was found in patients in quintile 1 (<7.0 mg/dL; hazard ratio [HR], 1.33; 95% confidence interval [CI]: 1.02-1.73) or quintile 5 (≥10.1 mg/dL; HR, 1.47; 95% CI: 1.09-2.00), compared to those in quintiles 2-4 (7-10.1 mg/dL). Moreover, the U-shaped SUA-mortality association was mainly found in those with lower C-reactive protein levels (<3 compared with ≥3 mg/L; p for interaction = 0.018). Similar trends were found for CVD mortality and non-CVD mortality. CONCLUSION: There was a U-shaped relationship between SUA levels and the risk of all-cause mortality, CVD mortality, and non-CVD mortality in MHD patients.

Visit-to-visit variability in blood pressure and the development of chronic kidney disease in treated general hypertensive patients.

BACKGROUND: Data on the association between visit-to-visit variability (VVV) in blood pressure (BP) and the risk of chronic kidney disease (CKD) in general treated hypertensive patients were limited. We aimed to evaluate the relation of VVV in BP with the development of CKD, and examine any possible effect modifiers in hypertensive patients without prior cardiovascular diseases (CVDs) or CKD. METHODS: This is a post hoc analysis of the Renal Sub-study of the China Stroke Primary Prevention Trial (CSPPT). A total of 10 051 hypertensives without CVD and CKD and with at least six visits of BP measurements from randomization to the 24-month visit were included. The main VVV in BP was expressed as standard deviation (SD). The primary outcome was the development of CKD, defined as a decrease in estimated glomerular filtration rate ≥30% and to a level of <60 mL/min/1.73 m2, or end-stage renal disease. RESULTS: The median treatment duration was 4.4 years. After multivariable adjustment, including baseline systolic blood pressure (SBP) and mean SBP during the first 2-year treatment period, there was a significantly positive relationship of SD of SBP with the risk of CKD development (per SD increment; odds ratio, 1.27; 95% confidence interval: 1.10-1.46). The results were similar for coefficient of variation (CV) of SBP. Results across various subgroups, including age, sex, SBP at baseline, treatment compliance, concomitant antihypertensive medications and mean SBP during the first 24-month treatment period, were consistent. CONCLUSIONS: SBP variability, irrespective of mean BP level, was significantly associated with the development of CKD in general treated hypertensive patients.

The association between dietary energy intake and the risk of mortality in maintenance haemodialysis patients: a multi-centre prospective cohort study.

Maintenance haemodialysis (MHD) is the use of a machine to filter wastes, salts and fluid from blood for at least 3 months to prolong the life of patients with advanced kidney failure. Although low dietary energy intake (DEI) has been observed in MHD patients, few studies have related DEI to the risk of mortality. To explore this relationship, a study included 1039 MHD patients from eight centres was conducted. DEI was assessed by three 24-h diet recalls and was normalised to ideal body weight (IBW). All-cause mortality and CVD mortality were the primary and secondary outcomes, respectively. During a median follow-up of 28 months, a U-shaped relationship was observed between DEI and all-cause or CVD mortality. The risk of all-cause mortality decreased significantly with the increase of DEI in participants with DEI <167·4 kJ/kg IBW per d (hazard ratio (HR) 0·98; 95 % CI 0·96, 1·00) and increased significantly with the increase of DEI in those with DEI ≥167·4 kJ/kg IBW per d (HR 1·12; 95 % CI 1·04, 1·20). Similarly, the risk of CVD mortality decreased with the increase of DEI in participants with DEI <152·7 kJ/kg IBW per d (HR 0·96; 95 % CI 0·93, 0·99) and increased with the increase of DEI in participants with DEI ≥152·7 kJ/kg IBW per d (HR 1·11; 95 % CI 1·04, 1·18). In summary, there was a U-shaped association between DEI and all-cause or CVD mortality, with a turning point at about 167·4 and 152·7 kJ/kg IBW per d, respectively, in MHD patients.

Positive association between baseline brachial-ankle pulse wave velocity and the risk of new-onset diabetes in hypertensive patients.

BACKGROUND: There is no clearly defined temporal relationship between arterial stiffness and diabetes. We aimed to investigate the prospective association between baseline brachial-ankle pulse wave velocity (baPWV) and the risk of new-onset diabetes during follow-up, and examined whether there were effect modifiers, in hypertensive patients. METHODS: We included 2429 hypertensive patients with all the pertinent data but without diabetes at the baseline, who were part of the China Stroke Primary Prevention Trial (CSPPT), a randomized, double-blind, actively controlled trial conducted in 32 communities in Anhui and Jiangsu provinces in China. The primary outcome was new-onset diabetes, defined as physician-diagnosed diabetes or use of glucose-lowering drugs during follow-up, or fasting glucose (FG) ≥ 126.0 mg/dL at the exit visit. RESULTS: During a median follow-up duration of 4.5 years, 287 (11.8%) participants developed diabetes. There was a significant positive association between baseline baPWV and the risk of new-onset diabetes (per SD increment; OR, 1.33; 95% CI 1.13, 1.56). Consistently, when baPWV was assessed as quartiles, a significantly higher risk of new-onset diabetes was found in participants in quartiles 2-4 (≥ 15.9 m/s; OR, 1.80; 95% CI 1.22, 2.65) compared with those in quartile 1 (< 15.9 m/s). The positive association was consistent in participants with (per SD increment; OR, 1.29; 95% CI 1.06, 1.56) or without (per SD increment; OR, 1.40; 95% CI 1.15, 1.71) impaired fasting glucose (IFG, FG ≥ 100.8 and < 126.0 mg/dL, P-interaction = 0.486). CONCLUSIONS: In this sample of hypertensive patients, we found a significant positive association between baseline baPWV and the risk of new-onset diabetes. Clinical trial registration Trial registration: NCT00794885 (clinicaltrials.gov). Retrospectively registered November 20, 2008.

Serum Trimethylamine N-Oxide Concentration Is Positively Associated With First Stroke in Hypertensive Patients.

Background and Purpose- Trimethylamine N-oxide (TMAO)-a gut derived metabolite-has been shown to be atherogenic. It remains unknown whether TMAO is associated with the risk of first stroke. We aimed to determine the association between serum TMAO levels and first stroke in hypertensive patients without major cardiovascular diseases and examine any possible effect modifiers. Methods- We used a nested case-control design, using data from the CSPPT (China Stroke Primary Prevention Trial), including 622 patients with first stroke and 622 matched controls. The study was conducted from May 2008 to August 2013. The primary outcome was a first stroke. Results- After adjusting for choline, L-carnitine, and other important covariates, including baseline systolic blood pressure and time-averaged systolic blood pressure, during the treatment period, the risk of first stroke increased with each increment of TMAO level (per natural log [TMAO] increment: odds ratio, 1.22; 95% CI, 1.02-1.46). Consistently, compared with participants in the lowest tertile (<1.79 µmol/L) of serum TMAO levels, a significantly higher risk of first stroke was found in those in higher TMAO tertiles (≥1.79 µmol/L; odds ratio, 1.34; 95% CI, 1.00-1.81) or in TMAO tertile 3 (≥3.19 µmol/L; odds ratio, 1.43; 95% CI, 1.02-2.01). In the exploratory analysis, we observed an interaction between TMAO and folate levels (≥7.7 [median] versus <7.7 ng/mL) on first stroke ( P for interaction, 0.030). Conclusions- Higher TMAO levels were associated with increased risk of first stroke in hypertensive patients. Our finding, if further confirmed, calls for a carefully designed clinical trial to further evaluate the role of higher TMAO levels on outcomes in hypertensive patients. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT00794885.

Effect of Smoking and Folate Levels on the Efficacy of Folic Acid Therapy in Prevention of Stroke in Hypertensive Men.

BACKGROUND AND PURPOSE: We aimed to examine whether the efficacy of folic acid therapy in the primary prevention of stroke is jointly affected by smoking status and baseline folate levels in a male population in a post hoc analysis of the CSPPT (China Stroke Primary Prevention Trial). METHODS: Eligible participants of the CSPPT were randomly assigned to a double-blind daily treatment of a combined enalapril 10-mg and folic acid 0.8-mg tablet or an enalapril 10-mg tablet alone. In total, 8384 male participants of the CSPPT were included in the current analyses. The primary outcome was first stroke. RESULTS: The median treatment duration was 4.5 years. In the enalapril-alone group, the first stroke risk varied by baseline folate levels and smoking status (never versus ever). Specifically, there was an inverse association between folate levels and first stroke in never smokers (P for linear trend=0.043). However, no such association was found in ever smokers. A test for interaction between baseline folate levels and smoking status on first stroke was significant (P=0.045). In the total sample, folic acid therapy significantly reduced the risk of first stroke in never smokers with folate deficiency (hazard risk, 0.36; 95% confidence interval, 0.16-0.83) and in ever smokers with normal folate levels (hazard risk, 0.69; 95% confidence interval, 0.48-0.99). CONCLUSIONS: Baseline folate levels and smoking status can interactively affect the risk of first stroke. Our data suggest that compared with never smokers, ever smokers may require a higher dosage of folic acid to achieve a greater beneficial effect on stroke. Our findings need to be confirmed by future randomized trials. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00794885.

Impact of achieved blood pressure on renal function decline and first stroke in hypertensive patients with chronic kidney disease.

Background: The effect of achieved blood pressure (BP) on first stroke and renal function decline among hypertensive patients with mild to moderate chronic kidney disease (CKD) is still uncertain. Methods: In total, 3230 hypertensive patients with estimated glomerular filtration rate 30-60 mL/min/1.73 m2 and/or proteinuria were included in the present analyses. Eligible participants were randomly assigned to a daily treatment of a combined enalapril 10 mg and folic acid 0.8 mg tablet or an enalapril 10 mg tablet alone. Participants were followed up every 3 months. The study outcomes included first stroke and the progression of CKD. Results: The median antihypertensive treatment duration was 4.7 years. Compared with participants with a time-averaged on-treatment systolic blood pressure (SBP) of 135 to ≤140 mmHg, the incidence of total first stroke [1.7% versus 3.3%; hazard ratio (HR), 0.51; 95% confidence interval (CI): 0.26-0.99] and ischemic stroke (1.3% versus 2.8%; HR, 0.46; 95% CI: 0.22-0.98) decreased significantly in those with a time-averaged SBP of ≤135 mmHg. Furthermore, a time-averaged diastolic blood pressure (DBP) of ≤80 mmHg, compared with a time-averaged DBP level of 80 to ≤90 mmHg, was significantly related to a decreased risk of hemorrhagic stroke (0.2% versus 0.9%; HR, 0.18; 95% CI: 0.04-0.80). However, compared with participants with a time-averaged SBP of 135 to ≤140 mmHg, a lower but non-significant trend of CKD progression was found in those with a time-averaged SBP of ≤130 mmHg. Conclusions: A BP treatment level of ≤135/80 mmHg, compared with a BP treatment level of 135-140/80-90 mmHg, could lead to a decreased risk of first stroke in hypertensive patients with mild-to-moderate CKD.

Elevated Homocysteine Concentrations Decrease the Antihypertensive Effect of Angiotensin-Converting Enzyme Inhibitors in Hypertensive Patients.

OBJECTIVE: We aimed to examine whether baseline homocysteine (Hcy) concentrations affect antihypertensive responses to enalapril treatment among previously untreated hypertensive patients (n=10 783) in the CSPPT (China Stroke Primary Prevention Trial). APPROACH AND RESULTS: After a 3-week run-in treatment with a daily dose of 10 mg enalapril, eligible hypertensive patients were randomly assigned to a double-blind daily treatment of a tablet of either enalapril (10 mg) and folic acid (0.8 mg) or enalapril (10 mg) alone for a median of 4.5 years. After the 3-week treatment period with enalapril alone, the systolic blood pressure-lowering effect was significantly reduced by 1.39 (95% confidence interval 0.40-2.37) and 3.25 (95% confidence interval 1.98-4.52) mm Hg, respectively, in those with baseline Hcy concentrations of 10 to 15 and ≥15 µmol/L (P for trend <0.001) as compared with those with Hcy concentration of <10 µmol/L. Similar results were observed after a 15-week treatment period with enalapril alone. After a median 4.5-year enalapril-based antihypertensive treatment period, compared with those with Hcy concentration of <10 µmol/L, the systolic blood pressure-lowering effect was still significantly reduced by 0.77 (95% confidence interval 0.01-1.53) and 1.70 (95% confidence interval 0.72-2.68) mm Hg, respectively, in those with Hcy concentrations of 10 to 15 and ≥15 µmol/L (P for trend <0.001). In addition, participants with higher baseline Hcy concentrations had persistently higher systolic blood pressure levels across the entire study treatment period. Similarly, baseline Hcy concentrations were inversely associated with diastolic blood pressure reduction during the short-term enalapril alone treatment. However, the inverse association between baseline Hcy and diastolic blood pressure reduction was attenuated and became insignificant after the long-term enalapril-based treatment period. CONCLUSIONS: Elevated Hcy concentrations significantly decreased the antihypertensive effect of the short-term and long-term enalapril-based antihypertensive treatment in previously untreated hypertensive patients.

Effect of long-term low-dose folic acid supplementation on degree of total homocysteine-lowering: major effect modifiers.

We sought to examine the potential modifiers in the association between long-term low-dose folic acid supplementation and the reduction of serum total homocysteine (tHcy) among hypertensive patients, using data from the China Stroke Primary Prevention Trial (CSPPT). This analysis included 16 867 participants who had complete data on tHcy measurements at both the baseline and exit visit. After a median treatment period of 4·5 years, folic acid treatment significantly reduced the tHcy levels by 1·6 µmol/l (95 % CI 1·4, 1·8). More importantly, after adjustment for baseline tHcy and other important covariates, a greater degree of tHcy reduction was observed in certain subgroups: males, the methylenetetrahydrofolate reductase (MTHFR) 677TT genotype, higher baseline tHcy levels (≥12·5 (median) v. <12·5 µmol/l), lower folate levels (<8·0 (median) v. ≥8·0 ng/ml), estimated glomerular filtration rate (eGFR) <60 ml/min per 1·73 m2 (v. 60-<90 and ≥90 ml/min per 1·73 m2), ever smokers and concomitant use of diuretics (P for all interactions <0·05). The degree of tHcy reduction associated with long-term folic acid supplementation can be significantly affected by sex, MTHFR C677T genotypes, baseline folate, tHcy, eGFR levels and smoking status.

Effect of folic acid supplementation on cancer risk among adults with hypertension in China: A randomized clinical trial.

The relationship of folic acid supplementation with the risk of cancer remains inconclusive. We aimed to evaluate the effects of folic acid supplementation on cancer incidence among adults with hypertension without history of stroke or myocardial infarction (MI) in the China Stroke Primary Prevention Trial (CSPPT). A total of 20,702 hypertensive adults without history of stroke or MI, stratified by MTHFR C677T genotypes(CC, CT and TT), were randomly assigned to receive double-blind daily treatment with a single pill containing 10 mg enalapril and 0.8 mg folic acid(n = 10,348) or a pill containing 10 mg enalapril alone(n = 10,354). During a median treatment duration of 4.5 years, cancer occurred in 116 participants(1.12%) in the enalapril-folic acid group versus 116 participants(1.12%) in the enalapril group (HR, 1.00; 95%CI, 0.77-1.29). There was also no significant difference in the HRs for specific types of cancer(esophageal, gastric, breast, lung, colorectal, head and neck, liver and gynecologic cancer or lymphoma) or cancer mortality(HR, 1.05; 95%CI, 0.69-1.58). For participants not receiving folic acid treatment (enalapril only group), MTHFR 677 TT genotype was an independent predictor of total cancer risk compared to CC genotype (HR, 1.86; 95%CI, 1.07-3.22). Consistently, a beneficial effect was observed in participants with MTHFR TT genotype and low folate levels (<9.0 ng/mL; HR, 0.47; 95%CI, 0.24-0.94). There is no evidence that 0.8 mg daily folic acid supplementation can increase the risk of cancer incidence among adults with hypertension without history of stroke or MI in China. Our data suggest a protective effect in participants with MTHFR TT genotype and low folate levels.