The Cardioprotective Effects of Semaglutide Exceed Those of Dietary Weight Loss in Mice With HFpEF.

Obesity-related heart failure with preserved ejection fraction (HFpEF) has become a well-recognized HFpEF subphenotype. Targeting the unfavorable cardiometabolic profile may represent a rational treatment strategy. This study investigated semaglutide, a glucagon-like peptide-1 receptor agonist that induces significant weight loss in patients with obesity and/or type 2 diabetes mellitus and has been associated with improved cardiovascular outcomes. In a mouse model of HFpEF that was caused by advanced aging, female sex, obesity, and type 2 diabetes mellitus, semaglutide, compared with weight loss induced by pair feeding, improved the cardiometabolic profile, cardiac structure, and cardiac function. Mechanistically, transcriptomic, and proteomic analyses revealed that semaglutide improved left ventricular cytoskeleton function and endothelial function and restores protective immune responses in visceral adipose tissue. Strikingly, treatment with semaglutide induced a wide array of favorable cardiometabolic effects beyond the effect of weight loss by pair feeding. Glucagon-like peptide-1 receptor agonists may therefore represent an important novel therapeutic option for treatment of HFpEF, especially when obesity-related.

Author Correction: The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unresponsive to standard heart failure therapy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unreponsive to standard heart failure therapy.

Phospholamban (PLN) plays a role in cardiomyocyte calcium handling as primary inhibitor of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). The p.(Arg14del) pathogenic variant in the PLN gene results in a high risk of developing dilated or arrhythmogenic cardiomyopathy with heart failure. There is no established treatment other than standard heart failure therapy or heart transplantation. In this study, we generated a novel mouse model with the PLN-R14del pathogenic variant, performed detailed phenotyping, and tested the efficacy of established heart failure therapies eplerenone or metoprolol. Heterozygous PLN-R14del mice demonstrated increased susceptibility to ex vivo induced arrhythmias, and cardiomyopathy at 18 months of age, which was not accelerated by isoproterenol infusion. Homozygous PLN-R14del mice exhibited an accelerated phenotype including cardiac dilatation, contractile dysfunction, decreased ECG potentials, high susceptibility to ex vivo induced arrhythmias, myocardial fibrosis, PLN protein aggregation, and early mortality. Neither eplerenone nor metoprolol administration improved cardiac function or survival. In conclusion, our novel PLN-R14del mouse model exhibits most features of human disease. Administration of standard heart failure therapy did not rescue the phenotype, underscoring the need for better understanding of the pathophysiology of PLN-R14del-associated cardiomyopathy. This model provides a great opportunity to study the pathophysiology, and to screen for potential therapeutic treatments.

Plasma levels of heart failure biomarkers are primarily a reflection of extracardiac production.

Plasma heart failure (HF) biomarkers, like natriuretic peptides, are important in diagnosis, prognosis and HF treatment. Several novel HF biomarkers have been identified, including Gal-3, GDF-15 and TIMP-1, but their clinical potential remains vague. Here we investigated plasma biomarker levels in relation to tissue expression and structural and functional cardiac changes. Methods: Cardiac remodeling, cardiac function, and plasma and tissue biomarker levels were investigated in mice after myocardial infarction induced by temporal and permanent LAD ligation (tLAD and pLAD). In addition, a pressure overload model induced by transverse aortic constriction (TAC) and an obese/hypertensive HFpEF-like mouse model were investigated. Results: Plasma levels of ANP and its cardiac expression were strictly associated with cardiac remodeling and function. Gal-3, GDF-15 and TIMP-1 cardiac expressions were also related to cardiac remodeling and function, but not their plasma levels. Only directly after myocardial infarction could elevated plasma levels of Gal-3 and TIMP-1 be detected. Eight weeks after infarction, plasma levels were not elevated despite enhanced cardiac expression and low EF (18.3±3.3%, pLAD). Plasma levels of TIMP-1 and GDF-15 were elevated after TAC, but this also correlated with increased lung expression and congestion. In obese-hypertensive mice, elevated plasma levels of Gal-3, GDF-15 and TIMP1 were associated with increased adipose tissue expression and not with cardiac function. Conclusions: The Gal-3, GDF-15 and TIMP-1 plasma pool levels are hardly influenced by dynamic changes in cardiac expression. These biomarkers are not specific for indices of cardiac remodeling, but predominantly reflect stress in other affected tissues and hence provide health information beyond the heart.

Prevention of mother-to-child transmission of HIV: a cross-sectional study in Malawi.

OBJECTIVE: To estimate the use and outcomes of the Malawian programme for the prevention of mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV). METHODS: In a cross-sectional analysis of 33 744 mother-infant pairs, we estimated the weighted proportions of mothers who had received antenatal HIV testing and/or maternal antiretroviral therapy and infants who had received nevirapine prophylaxis and/or HIV testing. We calculated the ratios of MTCT at 4-26 weeks postpartum for subgroups that had missed none or at least one of these four steps. FINDINGS: The estimated uptake of antenatal testing was 97.8%; while maternal antiretroviral therapy was 96.3%; infant prophylaxis was 92.3%; and infant HIV testing was 53.2%. Estimated ratios of MTCT were 4.7% overall and 7.7% for the pairs that had missed maternal antiretroviral therapy, 10.7% for missing both maternal antiretroviral therapy and infant prophylaxis and 11.4% for missing maternal antiretroviral therapy, infant prophylaxis and infant testing. Women younger than 19 years were more likely to have missed HIV testing (adjusted odds ratio, aOR: 4.9; 95% confidence interval, CI: 2.3-10.6) and infant prophylaxis (aOR: 6.9; 95% CI: 1.2-38.9) than older women. Women who had never started maternal antiretroviral therapy were more likely to have missed infant prophylaxis (aOR: 15.4; 95% CI: 7.2-32.9) and infant testing (aOR: 13.7; 95% CI: 4.2-83.3) than women who had. CONCLUSION: Most women used the Malawian programme for the prevention of MTCT. The risk of MTCT increased if any of the main steps in the programme were missed.

Registration and management of community patients with tuberculosis in north-west China.

OBJECTIVES: To describe the registration, management and characteristics of patients with tuberculosis (TB) in north-west China, and investigate whether patients with TB were diagnosed and treated in a timely manner. STUDY DESIGN: Health-facility-based retrospective data were collected from district patient registers and case reports for all patients with TB registered from January 2009 to December 2011 in Xinjiang Uygur Autonomous Region, north-west China. METHODS: Patient characteristics and clinical data were collected from the national TB epidemic reporting system using standardized case reporting forms for diagnosis, treatment and outcome. Data were collected and entered by trained health staff in the regional TB clinics. RESULTS: In total, data for 20,396 patients with TB were collected; of these, 78.5% were farmers. The age peaks were 20-44 years and 60-74 years. Average health-seeking and diagnostic delays were 32 days and two days, respectively. More than half (54.7%) of the patients with smear-negative TB were diagnosed by chest x-ray. Moreover, 94.3% of patients with TB were treated successfully. From 2009 to 2011, the health-seeking delay decreased significantly (P < 0.05), and the diagnostic delay increased significantly (P < 0.05). A significant decreasing trend in smear-positive TB was observed (P < 0.05), along with an increasing trend in treatment success (P < 0.05). CONCLUSIONS: In north-west China, there is a need to focus on key high-risk populations for prevention and control of TB, such as those aged 20-44 years and 60-74 years, males and farmers. Delays in diagnosis and treatment have a negative effect on cure rates and make it more difficult to control the propagation of TB.

Survival and associated mortality risk factors among post-treatment pulmonary tubercolosis patients in the northwest of China.

OBJECTIVE: The tuberculosis (TB) program was carried out in the Changji zone in northwest of China. Directly Observed Treatment, Short-Course (DOTS) is a modern control strategy against tuberculosis recommended by World Health Organization. The purpose of this work is to describe the survival of post-treatment TB (PTB) patients and to identify the risk factors associated with mortality and treatment outcomes, so that effective measures and interventions could be used to decrease the mortality rate. PATIENTS AND METHODS: Registry of 4501 TB patients at Center for Disease Control and Prevention (CDC) treated from 2007 to 2014 were collected. Mortality was used as an outcome measure and calculated per 100 person years of observation (PYO) from the date of completion of the treatment to the date of interview if the patients were alive or to the date of death. Kaplan-Meier and Cox regression methods were used to determine the survival and hazard ratios. An indirect method of standardization was used to calculate the standard mortality ratio (SMR). RESULTS: The average PYO was 5.0 and the total was 21851. Mortality per 100 PYO was 1.9/100 PYO [223/11871] for smear-positive, 3.4/100 PYO [305/9048] for smear-negative and 2.4/100 PYO [22/932] for EPTB cases. Univariate and Cox regression analysis showed that age (p < 0.01), education (p < 0.01), occupation (p < 0.01) and economic status (p < 0.01) were associated with increased mortality. DISCUSSION: Since the mortality rate was higher in Post-treatment TB patients than the general population these patients need special health care. An integrated survival and associated mortality risk factors and information system is necessary for TB surveillance, personal health status and treatment management. Further studies are required to identify the causes of death in these patients.

Large inter-individual variation in isoflavone plasma concentration limits use of isoflavone intake data for risk assessment.

BACKGROUND/OBJECTIVES: Isoflavones are present in soy foods and soy-based supplements. Despite low plasma isoflavone concentrations in the general Western population, concentrations in supplement users exceed those suggested to be beneficial for health in Asian populations, raising concerns for adverse effects. To aid risk assessment, quantification of the relation between isoflavone intake and plasma concentrations is essential. SUBJECTS/METHODS: Plasma samples were collected from postmenopausal women in three placebo-controlled crossover studies with 8-week periods for supplements (two studies, ~100 mg isoflavones/day, n=88) or 4-week periods for soy foods (one study, ~48 mg isoflavones/day, n=15). Plasma isoflavone concentrations (daidzein, equol, genistein and glycitein) were quantified using high-performance liquid chromatography and electrochemical detection. The association between plasma concentrations and isoflavone intake, equol producer status, intake-producer interaction and background dietary intake was assessed based on the assumption of a log-linear relation. RESULTS: Median plasma total isoflavone concentrations after the soy food and supplement interventions were respectively 2.16 and 3.47 µmol/l for equol producers and 1.30 and 2.39 µmol/l for non-producers. Regression analysis showed that doubling isoflavone intake increased plasma concentrations by 55-62% (±s.e. 1-2%, R(2)>0.87) for daidzein, genistein, equol (only for producers) and total isoflavones; for glycitein the association was weaker (15±1%, R(2)=0.48). Adjustments for energy, carbohydrate and fat intake did not affect these estimates. Inter-individual variation, estimated based on repeated measures in one of the studies, was 30-96%. CONCLUSIONS: Although the relation between isoflavone intake and plasma concentrations was adequately quantified, the use of isoflavone intake data for risk assessment needs caution due to large inter-individual variation in plasma concentrations.

Antioxidant micronutrients improve intrinsic and UV-induced apoptosis of human lymphocytes particularly in elderly people.

OBJECTIVE: Aging and oxidative stress may lead to enhanced cellular damage and programmed cell death. To study the association of intrinsic apoptosis with age and the effect of antioxidant supplementation on intrinsic and UV-induced apoptosis in children, young and elderly people. METHODS: The study was a 2 months, double-blind, randomized trial. Three age groups were studied: children, young adults and elderly people. A total of 274 healthy subjects were allocated to a group supplemented with moderate amounts of retinol, ß-carotene, α-tocopherol, ascorbic acid and selenium or placebo. Plasma oxidative stress parameters were detected and apoptosis of lymphocytes was evaluated with TUNEL staining. RESULTS: At baseline, percentages of intrinsic apoptosis were 13.8% and 11.1% in elderly and young people, respectively, both significantly higher than children (6.3%). A decrease of 1.7% and 2.3% in intrinsic apoptosis of lymphocytes was found in the supplemented groups of young and elderly people compared with their control groups (all p values <0.001), but no significant decrease in children. Moreover, percentages UV-induced apoptosis significantly decreased by 1.4%, 1.9% and 3.1% in children, young and elderly people, respectively, compared with control groups after the trial. There were considerable increments in concentrations of plasma ß-carotene, retinol, tocopherol, ascorbic acid and selenium in all three treated groups after the supplementation. CONCLUSIONS: Young and elderly people have a higher intrinsic apoptosis than children, which was improved by antioxidant supplementation. UV-induced damage was attenuated by the supplementation in all three age groups.

Retention and attrition during the preparation phase and after start of antiretroviral treatment in Thyolo, Malawi, and Kibera, Kenya: implications for programmes?

Among adults eligible for antiretroviral therapy (ART) in Thyolo (rural Malawi) and Kibera (Nairobi, Kenya), this study (a) reports on retention and attrition during the preparation phase and after starting ART and (b) identifies risk factors associated with attrition. 'Retention' implies being alive and on follow-up, whilst 'attrition' implies loss to follow-up, death or stopping treatment (if on ART). There were 11,309 ART-eligible patients from Malawi and 3633 from Kenya, of whom 8421 (74%) and 2792 (77%), respectively, went through the preparation phase and started ART. In Malawi, 2649 patients (23%) were lost to attrition in the preparation phase and 2189 (26%) after starting ART. Similarly, in Kenya 546 patients (15%) were lost to attrition in the ART preparation phase and 647 (23%) while on ART. Overall programme attrition was 43% (4838/11,309) for Malawi and 33% (1193/3633) for Kenya. Restricting cohort evaluation to 'on ART' (as is usually done) underestimates overall programme attrition by 38% in Malawi and 36% in Kenya. Risk factors associated with attrition in the preparation phase included male sex, age <35 years, advanced HIV/AIDS disease and increasing malnutrition. Considerable attrition occurs during the preparation phase of ART, and programme evaluations confined to on-treatment analysis significantly underestimate attrition. This has important operational implications, which are discussed here.

Viewpoint: Why do we need a point-of-care CD4 test for low-income countries?

In this paper, we discuss the reasons why we urgently need a point-of-care (POC) CD4 test, elaborate the problems we have experienced with the current technology which hampers CD4-count coverage and highlight the ideal characteristics of a universal CD4 POC test. It is high-time that CD4 technology is simplified and adapted for wider use in low-income countries to change the current paradigm of restricted access once and for all.

Anemia prevalence among pregnant women and birth weight in five areas in China.

OBJECTIVES: To investigate the current prevalence of anemia among pregnant women in different areas of China and the association with birth weight and educational level. METHODS: A total of 6,413 women aged 24-37 in the third trimester of pregnancy from five areas were randomly selected from all gravidas who gave birth in the hospitals from 1999 to 2003. Blood hemoglobin concentration (Hb) was measured by the cyanomethemoglobin method; Hb <110 g/l was considered as anemia. RESULTS: The overall prevalence of anemia was 58.6%, ranging from 48.1 to 70.5% in the five areas. There was a significant difference in the prevalence of anemia between women who have mental jobs and those who have physical jobs (52.3 vs. 61.1%, p < 0.01). The prevalence of anemia depended on the level of education: with 52.9, 62.4 and 66.5%, for college, secondary school and primary education, respectively, and the difference was statistically significant (p = 0.005). Results showed that higher birth weight was associated with Hb concentrations ranging from 90 to 140 g/l, whereas lower birth weight occurred below 80 g/l and above 140 g/l Hb. CONCLUSIONS: The prevalence of anemia in Chinese pregnant women was high both in rural areas and towns. Area of residence, education level and type of job influenced the prevalence of anemia. Low maternal Hb concentrations influenced birth weight.

Outcomes in HIV-infected patients who develop tuberculosis after starting antiretroviral treatment in Malawi.

A retrospective review was conducted of patients starting antiretroviral treatment (ART) at Mzuzu Central Hospital, Malawi, to identify those who developed tuberculosis (TB) within 6 months of commencing ART and document their treatment outcomes. Of 2933 patients, 22 (0.75%) developed active TB, 17 (77%) of whom had commenced ART as a result of unexplained weight loss and/or fever. Of those who developed TB, 41% successfully completed anti-tuberculosis treatment, with lower survival probabilities than patients who did not develop TB. Easier methods are needed to diagnose TB in human immunodeficiency virus-infected patients and to prevent patients from developing TB while on ART.

Reasons for loss to follow-up among mothers registered in a prevention-of-mother-to-child transmission program in rural Malawi.

This study was conducted to identify reasons for a high and progressive loss to follow-up among HIV-positive mothers within a prevention-of-mother-to-child HIV transmission (PMTCT) program in a rural district hospital in Malawi. Three focus group discussions were conducted among a total of 25 antenatal and post-natal mothers as well as nurse midwives (median age 39 years, range 22-55 years). The main reasons for loss to follow-up included: (1) not being prepared for HIV testing and its implications before the antenatal clinic (ANC) visit; (2) fear of stigma, discrimination, household conflict and even divorce on disclosure of HIV status; (3) lack of support from husbands who do not want to undergo HIV testing; (4) the feeling that one is obliged to rely on artificial feeding, which is associated with social and cultural taboos; (5) long waiting times at the ANC; and (6) inability to afford transport costs related to the long distances to the hospital. This study reveals a number of community- and provider-related operational and cultural barriers hindering the overall acceptability of PMTCT that need to be addressed urgently. Mothers attending antenatal services need to be better informed and supported, at both community and health-provider level.

Outcomes of HIV-infected children with tuberculosis who are started on antiretroviral therapy in Malawi.

SETTING: Mzuzu Central Hospital, in the northern region of Malawi, which provides free antiretroviral therapy (ART) to human immunodeficiency virus (HIV) infected adults and children, including those with tuberculosis (TB). OBJECTIVES: To compare outcomes in HIV-infected children who have been started on ART because of 1) active TB, 2) a past history of TB in the last 2 years and 3) a non-TB diagnosis. DESIGN: Retrospective data collection using ART patient master cards and ART patient registers. RESULTS: Between July 2004 and September 2006, 439 (11%) children of a total 3908 patients were started on ART. There were 29 with active TB, 56 with a past history of TB in the last 2 years and 354 with a non-TB diagnosis. The three groups were similar in nutritional indices and CD4-lymphocyte percentages. The 6-month probability of survival was 0.86 in the active TB group, 0.94 in the past history of TB group and 0.89 in the non-TB group. 12-month survival probability for the same groups was 0.86, 0.86 and 0.88, respectively. CONCLUSION: HIV-infected children with active and previous TB who are started on ART have good outcomes that are similar to those of children started on ART due to a non-TB diagnosis.

Outcomes of tuberculosis patients who start antiretroviral therapy under routine programme conditions in Malawi.

SETTING: Public sector facilities in Malawi providing antiretroviral therapy (ART) to human immunodeficiency virus (HIV) positive patients, including those with tuberculosis (TB). OBJECTIVES: To compare 6-month and 12-month cohort treatment outcomes of HIV-positive TB patients and HIV-positive non-TB patients treated with ART. DESIGN: Retrospective data collection using ART patient master cards and ART patient registers. RESULTS: Between July and September 2005, 7905 patients started ART, 6967 with a non-TB diagnosis and 938 with a diagnosis of active TB. 6-month cohort outcomes of non-TB and TB patients censored on 31 March 2006 showed significantly more TB patients alive and on ART (77%) compared with non-TB patients (71%) (P < 0.001). Between January and March 2005, 4580 patients started ART, 4179 with a non-TB diagnosis and 401 with a diagnosis of active TB. 12-month cohort outcomes of non-TB and TB patients censored on 31 March 2006 showed significantly more TB patients alive and on ART (74%) compared with non-TB patients (66%) (P < 0.001). Other outcomes of default and transfer out were also significantly less frequent in TB compared with non-TB patients. CONCLUSION: HIV-positive TB patients on ART in Malawi have generally good treatment outcomes, and more patients need to access this HIV treatment.

Alcohol, smoking, and physical activity related to respiratory infections in elderly people.

OBJECTIVE: Elderly people show an increased risk of acute respiratory infections and their complications. This increased susceptibility may be the result of immunosenescence. If lifestyle factors could influence the risk of the infections, this could result in great public health relevance. We investigated the relation between alcohol consumption, smoking, and physical activity with acute respiratory infections. DESIGN: Prospective observational analysis. SETTING: The study took place between September 1998 - June 2000, in the Wageningen area of The Netherlands. PARTICIPANTS: In total 652 relatively healthy elderly people participated. Participants were noninstitutionalized and 60 years and older. MEASUREMENTS: The lifestyle factors were assessed at baseline by means of standardized and validated questionnaires in the participants. Self-reported respiratory infections were assessed from 1998-2000 by nurse telephone contact, and home visits, and were evaluated by microbiological tests in a subset. RESULTS: We detected 1024 acute respiratory infections among 443 participants, the overall incidence rate (IR) was 1.6 infections per person per year. IR ratio (95% confidence interval) of the infections was 1.31 (1.01, 1.70) for occasional (superior 0 glasses/day < 1), 1.22 (0.92, 1.64) for light (1 < glasses/day < 3 (men) and 1< glasses/day < 2 (women)), and 1.33 (1.04, 1.83) at moderate/heavy (superior 3 (men) or superior 2 (women) glasses/day) alcohol consumption after adjustment for age and sex. Alcohol intake was not related to illness severity. Smoking and physical activity were not related to the incidence and severity of the infections. All results remained unaltered after adjustment for lifestyle factors and for other potential risk factors for respiratory infections. CONCLUSION: Our findings suggest that only alcohol intake may be unfavorably associated with the frequency of acute respiratory infections in apparently healthy elderly people. Until our results are confirmed in trials, it is not warranted to recommend elderly people to change their habits of life, such as alcohol consumption, smoking and physical activity in order to reduce the risk of acute respiratory infections.

Determinants of childhood overweight and obesity in China.

In order to investigate the determinants of childhood overweight and obesity in China, the prevalence of overweight (including obesity) was compared according to different dietary and physical activity patterns and parental body weight status. A total of 6826 children aged 7-17 years from the 2002 China National Nutrition and Health Survey were included in the study. Information for dietary intake was collected using three consecutive 24-h recalls by trained interviewers. The amounts of cooking oil and condiments consumed were weighed. An interview-administered 1-year physical activity questionnaire was used to collect physical activity information. The results showed that the heavier the parental bodyweight, the higher the overweight prevalence in children. The prevalence ratio increased if parent(s) were overweight and/or obese, up to 12.2 if both parents were obese. Overweight children consumed significantly more dietary energy, protein and fat, but less carbohydrate than their normal weight counterparts. On average, overweight children spent 0.5 h less on moderate/vigorous activities and 2.3 h more on low intensity activities per week. The following prevalence ratios were statistically significant: walking to and from school (0.6); moderate/vigorous activities > or =45 min/d (0.8); low intensity physical activities >2 h/d (1.3); the consumption of > or =25 g/d cooking oil (1.4); > or =200 g/d meat and meat products consumption (1.5); > or =100g/d dairy products (1.8). After adjustment for parental body weight status and socioeconomic status, only cooking oil consumption and walking to and from school remained significantly related to child overweight. In conclusion, parental weight status is an import-ant determinant. Fat intake, low intensity activities and active transport to/from school may be suitable entry points for overweight prevention among Chinese school children.