Assessment of Registered Clinical Trial Designs: Comparison of L-Arginine and/or L-Citrulline Interventions for Hypertension.

BACKGROUND: L-Arginine (Arg) is an essential amino acid and a precursor for the synthesis of vascular nitric oxide, while L-Citrulline is a non-essential amino acid substrate for increasing L-arginine. Both L-arginine and L-Citrulline in translational studies may acutely lower the blood pressure. Current meta-analysis for L-arginine or L-Citrulline interventions in blood pressure have identified significant heterogeneity. Clinical trial evidence for L-arginine or L-Citrulline in chronic blood pressure reduction in the general population requires an examination of trial designs, as not all translational studies may have influenced vascular reactivity. Our aims are to explore whether L-arginine and L-citrulline intervention trials in chronic blood pressure consider standardized end points relevant to the general adult populations. METHODS: A step-wise search on clinicaltrials.gov, the U.S. Library of Medicine registry for clinical trials, was performed including the following keyword search parameters: "completed" "L-Citrulline" "L-arginine" trial", and "adults", involving "blood pressure" reduction as a primary end point in adult humans. RESULTS: Of the forty-four completed trials, only five were included for analysis. Following the careful evaluation of trial design, we observed heterogeneity across participant inclusion criteria (population sample size, age range, sex), interventional design (dosages, duration), and primary outcomes, measured with respect to changes in diastolic or systolic blood pressure. CONCLUSION: In conclusion, there is a lack of robust trial design evidence to suggest that L-arginine or L-Citrulline, based on current RCTs in the general population, have an overall positive effect on vascular endothelial reactivity and a beneficial chronic blood pressure-lowering effect. Indeed, conclusions drawn from human meta-analysis studies have been heterogenous between studies, which may be attributed to study design heterogeneity, including differences in sample population, age, and blood pressure at the time of entry. Inconsistencies in the study design poses a challenge for systematic reviews and meta-analysis to accurately assess the effect size and impact of L-arginine or L-citrulline on both systolic and diastolic blood pressure.

Global google trends for construction demonstrate low search volume index for stress, mental and suicide.

The comparison of Google internet searches for English words in construction for "construction stress", "construction mental" and "construction suicide" with reference to "construction worker" has not previously been undertaken. It is important to understand internet interest across these 3 terms as all are relevant to mental health and stress in construction. Suicide risk is significantly complex and multifactorial. Our aim is to investigate internet search interest across construction with a focus on mental, stress and suicide, and determine whether there is consistent interest across these search terms. METHODS: Using Google Trends, data on global search queries we compared "construction mental" or "construction stress" and "construction suicide". Two time periods were compared, the last 5 years and the last 24 months, both till December 8th, 2022. The relationship between web search interest, reflected by search volume index (SVI) for society and community versus the business and industrial category and health category were evaluated. RESULTS: Open category searches on Google trends for the key words "construction mental" or "construction stress" demonstrated moderate SVI peaks over a 5-year period. Sub-group analyses for the industrial and business category demonstrated consistent low interest in suicide compared to search terms related to stress or mental health. CONCLUSION: There is limited online interest in construction mental and stress and even less interest in suicide.

Analysis and comparison of web searches in Google Trends in the business and industrial category for the word's "resilience" and "wellbeing" during COVID-19.

OBJECTIVE: The comparison of Google internet searches for worker wellbeing and resilience during COVID has not previously been undertaken. It is important to understand interest in wellbeing and resilience as both constructs influence health and burnout. Our objective to investigate internet interest in both wellbeing and resilience during COVID. Using Google Trends, data on global search English word queries we compared "worker wellbeing" or "wellbeing" versus "resilience" or "psychological resilience". Two time periods were compared, the last 5 years and the last 12 months, both up until the end of April 2022. The relationship between web search interest, reflected by search volume index (SVI) for all categories versus the business and industrial category evaluated. RESULTS: Open category searches on Google trends for the key words "worker wellbeing" or "wellbeing" demonstrated increased SVI peaks for COVID periods. Sub-group analyses demonstrated the category business and industrial had less web search interest in wellbeing and an increase in search terms related to resilience but not psychological resilience. Online interest in wellbeing and resilience represents a complex search metric. There are differing search interests depending on whether the category business and industrial is chosen versus the general Google Trends category.

Prevalence and associated factors of hypertension among veterans of the Indian Gorkha regiments living in Pokhara Metropolitan City, Nepal.

BACKGROUND: Hypertension is a major preventable risk factor for cardiovascular disease. Occupational factors such as having served or serving in armed forces may be associated with hypertension. This study aimed to assess the prevalence and factors associated with hypertension among veterans of the Indian Gorkha army living in western Nepal. METHODS: A community-based cross-sectional study was conducted among the veterans living in the Pokhara metropolitan city. Data on blood pressure (BP), anthropometric measurements, and behavioral factors were collected by face-to-face interviews using the World Health Organization's non-communicable disease risk factor surveillance (STEPS) tool. Hypertension was defined as systolic blood pressure (BP) ≥ 140 mm Hg and/or diastolic BP of ≥ 90 mm Hg or currently on antihypertensive medication. RESULTS: The age-adjusted prevalence of hypertension was 66.2 % among the study participants (317). Mean systolic and diastolic blood pressure was 144.5 mmHg (± 18.3) and 89.3mmHg (± 16.0), respectively. Among the hypertensive participants, 67 % were aware of their disease, 90 % of them were under treatment, and 14 % of the individuals who received treatment had their hypertension under control. The proportion of smokers was 12.9 % and alcohol drinker was 86.1 %. One-fourth (25.9 %) of the participants had a family history of hypertension. Veterans aged 55-64 years had higher odds (AOR: 5.3; 95 % CI: 1.8-15.9; p = 0.003) of being associated with hypertension as compared to 35-44 years. Being a current alcohol drinker (AOR: 2.5; 95 % CI: 1.4-4.5; p = 0.003), overweight (AOR: 1.9; 95 % CI: 1.0-3.5; p = 0.04), obese (AOR: 3.1; 95 % CI: 1.1-8.3; p = 0.03) and family history of hypertension (AOR: 2.9; 95 % CI: 1.5-5.8; p = 0.002) were independently associated with hypertension. CONCLUSIONS: Hypertension was prevalent in retired Nepal veterans. Hypertension was associated with a number of modifiable lifestyle and behavioral factors. Our findings suggest the need for screening, education and management of Nepal veterans for hypertension.

Classifying Multi-Level Stress Responses From Brain Cortical EEG in Nurses and Non-Health Professionals Using Machine Learning Auto Encoder.

OBJECTIVE: Mental stress is a major problem in our society and has become an area of interest for many psychiatric researchers. One primary research focus area is the identification of bio-markers that not only identify stress but also predict the conditions (or tasks) that cause stress. Electroencephalograms (EEGs) have been used for a long time to study and identify bio-markers. While these bio-markers have successfully predicted stress in EEG studies for binary conditions, their performance is suboptimal for multiple conditions of stress. METHODS: To overcome this challenge, we propose using latent based representations of the bio-markers, which have been shown to significantly improve EEG performance compared to traditional bio-markers alone. We evaluated three commonly used EEG based bio-markers for stress, the brain load index (BLI), the spectral power values of EEG frequency bands (alpha, beta and theta), and the relative gamma (RG), with their respective latent representations using four commonly used classifiers. RESULTS: The results show that spectral power value based bio-markers had a high performance with an accuracy of 83%, while the respective latent representations had an accuracy of 91%.

Effects of a health worker-led 3-month yoga intervention on blood pressure of hypertensive patients: a randomised controlled multicentre trial in the primary care setting.

BACKGROUND: Hypertension control remains a major challenge globally. A recent systematic review suggested that yoga has beneficial effects on reducing blood pressure. However, the role of yoga in hypertension management in primary health care has received little attention, and no studies have evaluated the impact of a yoga program fully delivered by health care staff on hypertension. This study, therefore, assessed the effects of a health worker-led yoga intervention on blood pressure reduction among hypertensives patients in the primary care setting. METHODS: This was a multicentric, two-arm, randomised trial conducted among hypertensive patients in seven Ayurveda Health Centres in Nepal between March 2017 and June 2018. One hundred and twenty-one participants who were on or without medications were randomised to intervention (n = 61) and wait-list control (n = 60) groups using stratified block randomisation. Participants in the intervention arm received an intervention consisting of an initial five-day structured yoga training at the centres and then a further home-based practice of yoga for five days a week for the following 90 days. Both intervention and control groups also participated in a 2-h health education session. The primary outcome of this trial was systolic blood pressure at 90-day follow-up. Data were analysed on an intention-to-treat basis using linear mixed-effects regression models. RESULTS: We included all 121 study participants (intervention/control = 61/60) in the primary analysis (52.1% males; mean ± SD age = 47.8 ± 10.8 years). The difference in systolic blood pressure between the intervention group and the control group was - 7.66 mmHg (95% CI: - 10.4, - 4.93). For diastolic blood pressure, the difference was - 3.86 mmHg (95% CI: - 6.65, - 1.06). No adverse events were reported by the participants. CONCLUSIONS: A yoga program for hypertensive patients consisting of a five-day training in health centres and 90 days of practice at home is effective for reducing blood pressure. Significant benefits for hypertensive patients could be expected if such programmes would become a part of the standard treatment practice. TRIAL REGISTRATION: This trial was prospectively registered with the Clinical Trial Registry of India [ CTRI/2017/02/007822 ] on 10/02/2017.

The angiotensin-converting enzyme 2 (ACE2) receptor in the prevention and treatment of COVID-19 are distinctly different paradigms.

There is current debate concerning the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor blockers (ARBs), for hypertension management, during COVID-19 infection. Specifically, the suggestion has been made that ACE inhibitors or ARBs could theoretically contribute to infection via increasing ACE2 receptor expression and hence increase viral load. The ACE2 receptor is responsible for binding the SAR-CoV2 viral spike and causing COVID-19 infection. What makes the argument somewhat obtuse for ACE inhibitors or ARBs is that ACE2 receptor expression can be increased by compounds that activate or increase the expression of SIRT1. Henceforth common dietary interventions, vitamins and nutrients may directly or indirectly influence the cellular expression of the ACE2 receptor. There are many common compounds that can increase the expression of the ACE2 receptor including Vitamin C, Metformin, Resveratrol, Vitamin B3 and Vitamin D. It is important to acknowledge that down-regulation or blocking the cellular ACE2 receptor will likely be pro-inflammatory and may contribute to end organ pathology and mortality in COVID-19. In conclusion from the perspective of the ACE2 receptor, COVID-19 prevention and treatment are distinctly different. This letter reflects on this current debate and suggests angiotensin-converting enzyme inhibitors and ARBs are likely beneficial during COVID-19 infection for hypertensive and normotensive patients.

Correction: Awareness, prevalence, treatment, and control of type 2 diabetes in a semi-urban area of Nepal: Findings from a cross-sectional study conducted as a part of COBIN-D trial.

[This corrects the article DOI: 10.1371/journal.pone.0206491.].

Awareness, prevalence, treatment, and control of type 2 diabetes in a semi-urban area of Nepal: Findings from a cross-sectional study conducted as a part of COBIN-D trial.

BACKGROUND: Type 2 diabetes is an escalating public health problem in Nepal. The current study aims to assess the prevalence, associated factors, awareness, treatment, and control of type 2 diabetes in a semi-urban area of Nepal. METHODS: A population-based cross-sectional survey was conducted including 2,310 adults aged 25 years or above from a semi-urban area of Lekhnath Municipality of Nepal, during October 2016 to April 2017 using the World Health Organization (WHO) STEPS approach. Data on demographics, behavioral risk factors, blood pressure, anthropometric measurements (weight, height, waist and hip circumference), and fasting blood glucose were collected by face-to-face interviews during a door-to-door visit. Participants were considered to have type 2 diabetes if they had previously been diagnosed by a physician and/or were on antidiabetic medications and/or had fasting blood glucose ≥ 7.0 mmol/L. Participants were classified as being aware of their diabetes conditions if they had earlier been told that they had type 2 diabetes. Treatment of diabetes among those aware was if participants received any kind of medication treatment or counseling, and control of diabetes among those treated was defined as fasting blood glucose level was <7.0 mmol/L. Odds Ratio (OR) with 95% Confidence Interval (CI) was used to determine the strength of association. RESULTS: The prevalence of type 2 diabetes was 11.7% (95% CI: 10.5-13.1). Among type 2 diabetes participants, 65% were aware of their disease, 94% of those who were aware received treatment, and 21% of the treated subjects had their diabetes under control. Factors significantly associated with type 2 diabetes were older age (OR = 3.2 for age group 45-54 years, OR = 3.8 for age group 55-64 years), Janajati ethnicity (OR = 1.4), abdominal obesity (OR = 2.3), being overweight or obese (OR = 1.4), and hypertension (OR = 2.0), while protective factors included being a female (OR = 0.4), medium physical activity (OR = 0.3), high physical activity (OR = 0.2), and not having family history of diabetes (OR = 0.3). CONCLUSIONS: The study revealed a high prevalence of type 2 diabetes among adults. Older age, male gender, Janajati ethnicity, abdominal obesity, overweight or obesity, hypertension, low physical activity, and family history of diabetes were associated with type 2 diabetes. Immediate public health and individual measures are warranted to reduce further burden of type 2 diabetes.

Impact of a structured yoga program on blood pressure reduction among hypertensive patients: study protocol for a pragmatic randomized multicenter trial in primary health care settings in Nepal.

BACKGROUND: Hypertension control remains a major global challenge. The behavioral approaches recommended for blood pressure reduction are stress reduction, increased exercise and healthy dietary habits. Some study findings suggest that yoga has a beneficial effect in reducing blood pressure. However, the role of yoga on blood pressure has received little attention in existing health care practices in developing countries. This study will be conducted in primary health care facilities in Nepal to assess the effectiveness of a pragmatic yoga intervention to complement standard practice in further reducing blood pressure. METHODS: This will be multicentric, two arms, randomized, nonblinded, pragmatic trial. It will be conducted in seven District Ayurveda Health Centers (DAHCs) in Nepal between July 2017 and June 2018. The study participants will consist of hypertensive patients with or without antihypertensive medication attending to the outpatient department (OPD). One hundred and forty participants will be randomized to treatment or control groups by using a stratified block randomization. At the study site, the treatment arm participants will receive an intervention consisting of five days of structured yoga training and practice of the same package at home with a recommendation of five days a week for the following 90 days. Both the intervention and control groups will receive two hours of health education on lifestyle modifications. The primary outcome of this trial will be the change in systolic blood pressure and it will be assessed after 90 days of the intervention. DISCUSSION: This study will establish the extent to which a yoga intervention package can help reduce blood pressure in hypertensive patients. If proven effective, study findings may be used to recommend the governing bodies and other stakeholders for the integration of yoga in the national healthcare system for the treatment and control of hypertension. TRIAL REGISTRATION: Clinical Trial Registry- India (CTRI); CTRI Reg. No- CTRI/2017/02/007822 . Registered on 10/02/2017.

Is modern external beam radiotherapy with androgen deprivation therapy still a viable alternative for prostate cancer in an era of robotic surgery and brachytherapy: a comparison of Australian series.

INTRODUCTION: We compare the results of modern external-beam radiotherapy (EBRT), using combined androgen deprivation and dose-escalated intensity-modulated radiotherapy with MRI-CT fusion and daily image guidance with fiducial markers (DE-IG-IMRT), with recently published Australian series of brachytherapy and surgery. METHODS: Five-year actuarial biochemical disease-free survival (bDFS), metastasis-free survival (MFS) and prostate cancer-specific survival (PCaSS) were calculated for 675 patients treated with DE-IG-IMRT and androgen deprivation therapy (ADT). Patients had intermediate-risk (IR) and high-risk (HR) disease. A search was conducted identifying Australian reports from 2005 onwards of IR and HR patients treated with surgery or brachytherapy, reporting actuarial outcomes at 3 years or later. RESULTS: With a median follow-up of 59 months, our 5-year bDFS was 93.3% overall: 95.5% for IR and 91.3% for HR disease. MFS was 96.9% overall (99.0% IR, 94.9% HR), and PCaSS was 98.8% overall (100% IR, 97.7% HR). Prevalence of Grade 2 genitourinary and gastrointestinal toxicity at 5 years was 1.3% and 1.6%, with 0.3% Grade 3 genitourinary toxicity and no Grade 3 gastrointestinal toxicity. Eight reports of brachytherapy and surgery were identified. The HDR brachytherapy series' median 5-year bDFS was 82.5%, MFS 90.0% and PCaSS 97.9%. One surgical series reported 5-year bDFS of 65.5% for HR patients. One LDR series reported 5-year bDFS of 85% for IR patients. CONCLUSIONS: Modern EBRT is at least as effective as modern Australian surgical and brachytherapy techniques. All patients considering treatment for localised prostate cancer should be referred to a radiation oncologist to discuss EBRT as an equivalent option.

The absence of pathological myofibre disarray in the diabetic heart: is it a paradox?

Myofibre disarray in progressive hypertrophic cardiomyopathy (HCM) is a well established pathological cardiac tissue change and thereby represents a biomarker for that condition. On the other hand, in diabetic cardiomyopathy, myofibre disarray historically has been reported not to occur. This is surprising given that many of the pathological, remodelling and mechanical changes that present in the diabetic ventricle are also present in HCM, for example, myocardial stiffness, myocardial hypertrophy, apoptosis, cell slippage, extensive collagen expression and fibrosis. The question therefore begs is the absence of myocyte disarray in the diabetic heart a paradox or simply an oversight?

Chronic angiotensin-converting enzyme inhibition up-regulates mouse kidney growth arrest specific-6 protein and the AXL subfamily of receptor tyrosine kinases.

INTRODUCTION: Growth arrest specific-6 (GAS-6), a vitamin K-dependent protein, is a potential mediator in progressive and chronic renal disease, specifically as a mediator of abnormal mesangial cell proliferation. Nitric oxide and angiotensin II affect mesangial cell proliferation. However, an association between nitric oxide synthase or angiotensin II on GAS-6 expression in the kidney has not previously been examined. Thus, our aim was to examine the effects of antihypertensive angiotensin-converting enzyme inhibitors and chronic nitric oxide synthase inhibition on the kidney expression of GAS-6 and its receptors AXL, MER and RSE. METHODS: Four groups of adult male C57BL/6J mice were studied: group 1, untreated controls (tap water for six weeks); group 2, treated orally with a nitric oxide synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME, 0.325 mg/ml for six weeks); group 3, treated orally with captopril (0.6875 mg/ml for six weeks); group 4, co-treated orally with L-NAME and captopril (same doses for six weeks). At the end of the study, kidneys were placed in fixative and processed to paraffin for immunohistochemical staining. RESULTS: GAS-6 and its receptors were not present in control and L-NAME-treated mice. Positive GAS-6 staining was detectable only in those mice receiving some form of chronic dosing with captopril, whether they were treated with captopril only or with captopril and L-NAME. Immunohistochemical detection across cases for MER and RSE was rare, whereas AXL-positive staining in the kidney mirrored GAS-6 staining/expression. The staining of GAS6 and AXL was predominantly localised to the renal tubular cells. CONCLUSIONS: These findings suggest that GAS-6 may not be a final common pathway for nitric oxide synthase inhibition-induced renal disease. Renal tubular GAS-6 expression following captopril treatment was unexpected and could be beneficial in preventing tubular atrophy following the onset of persistent systemic hypertension.

Chronic phenobarbital-induced mitochondrial pleomorphism in the rat liver.

Posttreatment effects of phenobarbital (30 mg/kg I.P. per day for 5 days) on liver mitochondrial TEM ultra-structure in adult rats were studied. Liver mitochondria population samples in treated rats exhibited pleomorphic morphological dumbbell shapes (7%), U-type (crescent) shapes (4%) and O-type (ring-like) shapes (4%). This pathology was not observed in vehicle-treated animals. Phenobarbital is a drug that induces within the rat liver increased protein synthesis in the mitochondria and mitochondrial morphological shape changes.

Acute coronary ligation in the dog induces time-dependent transitional changes in mitochondrial crista in the non-ischaemic ventricular myocardium.

1. The aim of the present study was to examine, in the dog myocardium, the incidence of zig-zag mitochondrial cristae over time in the non-ischaemic posterior wall, following an acute anterior wall infarct. 2. Changes within the myocardial mitochondrial crista membrane in dogs were investigated following acute left anterior descending coronary artery ligation. Transmyocardial biopsy samples were taken serially from the posterior non-ischaemic wall in the same dog. Changes in heart mitochondrial cristae were examined by transmission electron microscopy prior to coronary ligation (control) and 40 min and 2, 4, 6 and 24 h postinfarction. 3. In control hearts, 90% of mitochondrial cristae had a lamelliform appearance. Following infarction, there were two transitional states with respect to mitochondrial cristae, the first characterized by undulating lamelliform cristae that are also found in 10% of control samples and a second transitional state that was zig-zag and reached a maximum between 6 and 24 h after infarction. 4. In conclusion, an undulating lamelliform crista pattern is present in the non-ischaemic wall of the acute infarcted dog and we hypothesize that this may be an intermediate from, between 'normal' lamelliform and 'abnormal' zig-zag cristae.

Homocysteine is positively associated with cytokine IL-18 plasma levels in coronary artery bypass surgery patients.

Homocysteine, cytokines (IL-18, IL-6, IL-8) are involved in vascular inflammation and coronary artery disease. Homocysteine influences endothelial IL-6 and IL-8 cytokine expression and release, however, an association between homocysteine and IL-18 has not been previously investigated in endothelial/smooth muscle cells and or in coronary artery disease. We report in 9 coronary artery bypass surgery (CABG) patients a positive correlation r = 0.86 between homocysteine and IL-18 plasma levels (p < 0.05). Plasma IL-18 levels are significantly higher in those patients with elevated homocysteine compared to those with normal levels (p < 0.02; 153 +/- 19 pg/ml versus 116 +/- 14 pg/ml respectively). Our in vitro cell culture studies suggest that the source of IL-18 in CABG patients with elevated homocysteine is not from vascular smooth muscle or endothelial cells.