The tidal remnant of an unusually metal-poor globular cluster.

Globular clusters are some of the oldest bound stellar structures observed in the Universe1. They are ubiquitous in large galaxies and are believed to trace intense star-formation events and the hierarchical build-up of structure2,3. Observations of globular clusters in the Milky Way, and a wide variety of other galaxies, have found evidence for a 'metallicity floor', whereby no globular clusters are found with chemical (metal) abundances below approximately 0.3 to 0.4 per cent of that of the Sun4-6. The existence of this metallicity floor may reflect a minimum mass and a maximum redshift for surviving globular clusters to form-both critical components for understanding the build-up of mass in the Universe7. Here we report measurements from the Southern Stellar Streams Spectroscopic Survey of the spatially thin, dynamically cold Phoenix stellar stream in the halo of the Milky Way. The properties of the Phoenix stream are consistent with it being the tidally disrupted remains of a globular cluster. However, its metal abundance ([Fe/H] = -2.7) is substantially below the empirical metallicity floor. The Phoenix stream thus represents the debris of the most metal-poor globular clusters discovered so far, and its progenitor is distinct from the present-day globular cluster population in the local Universe. Its existence implies that globular clusters below the metallicity floor have probably existed, but were destroyed during Galactic evolution.

Rivaroxaban in Rheumatic Heart Disease-Associated Atrial Fibrillation.

BACKGROUND: Testing of factor Xa inhibitors for the prevention of cardiovascular events in patients with rheumatic heart disease-associated atrial fibrillation has been limited. METHODS: We enrolled patients with atrial fibrillation and echocardiographically documented rheumatic heart disease who had any of the following: a CHA2DS2VASc score of at least 2 (on a scale from 0 to 9, with higher scores indicating a higher risk of stroke), a mitral-valve area of no more than 2 cm2, left atrial spontaneous echo contrast, or left atrial thrombus. Patients were randomly assigned to receive standard doses of rivaroxaban or dose-adjusted vitamin K antagonist. The primary efficacy outcome was a composite of stroke, systemic embolism, myocardial infarction, or death from vascular (cardiac or noncardiac) or unknown causes. We hypothesized that rivaroxaban therapy would be noninferior to vitamin K antagonist therapy. The primary safety outcome was major bleeding according to the International Society of Thrombosis and Hemostasis. RESULTS: Of 4565 enrolled patients, 4531 were included in the final analysis. The mean age of the patients was 50.5 years, and 72.3% were women. Permanent discontinuation of trial medication was more common with rivaroxaban than with vitamin K antagonist therapy at all visits. In the intention-to-treat analysis, 560 patients in the rivaroxaban group and 446 in the vitamin K antagonist group had a primary-outcome event. Survival curves were nonproportional. The restricted mean survival time was 1599 days in the rivaroxaban group and 1675 days in the vitamin K antagonist group (difference, -76 days; 95% confidence interval [CI], -121 to -31; P<0.001). A higher incidence of death occurred in the rivaroxaban group than in the vitamin K antagonist group (restricted mean survival time, 1608 days vs. 1680 days; difference, -72 days; 95% CI, -117 to -28). No significant between-group difference in the rate of major bleeding was noted. CONCLUSIONS: Among patients with rheumatic heart disease-associated atrial fibrillation, vitamin K antagonist therapy led to a lower rate of a composite of cardiovascular events or death than rivaroxaban therapy, without a higher rate of bleeding. (Funded by Bayer; INVICTUS ClinicalTrials.gov number, NCT02832544.).

Evaluation of hydroxychloroquine or chloroquine for the prevention of COVID-19 (COPCOV): A double-blind, randomised, placebo-controlled trial.

BACKGROUND: Hydroxychloroquine (HCQ) has proved ineffective in treating patients hospitalised with Coronavirus Disease 2019 (COVID-19), but uncertainty remains over its safety and efficacy in chemoprevention. Previous chemoprevention randomised controlled trials (RCTs) did not individually show benefit of HCQ against COVID-19 and, although meta-analysis did suggest clinical benefit, guidelines recommend against its use. METHODS AND FINDINGS: Healthy adult participants from the healthcare setting, and later from the community, were enrolled in 26 centres in 11 countries to a double-blind, placebo-controlled, randomised trial of COVID-19 chemoprevention. HCQ was evaluated in Europe and Africa, and chloroquine (CQ) was evaluated in Asia, (both base equivalent of 155 mg once daily). The primary endpoint was symptomatic COVID-19, confirmed by PCR or seroconversion during the 3-month follow-up period. The secondary and tertiary endpoints were: asymptomatic laboratory-confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection; severity of COVID-19 symptoms; all-cause PCR-confirmed symptomatic acute respiratory illness (including SARS-CoV-2 infection); participant reported number of workdays lost; genetic and baseline biochemical markers associated with symptomatic COVID-19, respiratory illness and disease severity (not reported here); and health economic analyses of HCQ and CQ prophylaxis on costs and quality of life measures (not reported here). The primary and safety analyses were conducted in the intention-to-treat (ITT) population. Recruitment of 40,000 (20,000 HCQ arm, 20,000 CQ arm) participants was planned but was not possible because of protracted delays resulting from controversies over efficacy and adverse events with HCQ use, vaccine rollout in some countries, and other factors. Between 29 April 2020 and 10 March 2022, 4,652 participants (46% females) were enrolled (HCQ/CQ n = 2,320; placebo n = 2,332). The median (IQR) age was 29 (23 to 39) years. SARS-CoV-2 infections (symptomatic and asymptomatic) occurred in 1,071 (23%) participants. For the primary endpoint the incidence of symptomatic COVID-19 was 240/2,320 in the HCQ/CQ versus 284/2,332 in the placebo arms (risk ratio (RR) 0.85 [95% confidence interval, 0.72 to 1.00; p = 0.05]). For the secondary and tertiary outcomes asymptomatic SARS-CoV-2 infections occurred in 11.5% of HCQ/CQ recipients and 12.0% of placebo recipients: RR: 0.96 (95% CI, 0.82 to 1.12; p = 0.6). There were no differences in the severity of symptoms between the groups and no severe illnesses. HCQ/CQ chemoprevention was associated with fewer PCR-confirmed all-cause respiratory infections (predominantly SARS-CoV-2): RR 0.61 (95% CI, 0.42 to 0.88; p = 0.009) and fewer days lost to work because of illness: 104 days per 1,000 participants over 90 days (95% CI, 12 to 199 days; p < 0.001). The prespecified meta-analysis of all published pre-exposure RCTs indicates that HCQ/CQ prophylaxis provided a moderate protective benefit against symptomatic COVID-19: RR 0.80 (95% CI, 0.71 to 0.91). Both drugs were well tolerated with no drug-related serious adverse events (SAEs). Study limitations include the smaller than planned study size, the relatively low number of PCR-confirmed infections, and the lower comparative accuracy of serology endpoints (in particular, the adapted dried blood spot method) compared to the PCR endpoint. The COPCOV trial was registered with ClinicalTrials.gov; number NCT04303507. INTERPRETATION: In this large placebo-controlled, double-blind randomised trial, HCQ and CQ were safe and well tolerated in COVID-19 chemoprevention, and there was evidence of moderate protective benefit in a meta-analysis including this trial and similar RCTs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04303507; ISRCTN Registry ISRCTN10207947.

Core outcome set for intervention research on snakebite envenomation in South Asia.

BACKGROUND: The 2019 WHO strategy to reduce snakebite burden emphasises the need for fostering research on snakebite treatments. A core outcome set (COS) is a consensus minimal list of outcomes that should be measured in research on a particular condition. We aimed to develop a COS for snakebite research in South Asia, the region with the highest burden. METHODS: We used data from a systematic review of outcomes to develop a long list of outcomes which were rated in two rounds of online Delphi survey with healthcare providers, patients and the public, and potential COS users to develop a COS for intervention research on snakebite treatments in South Asia for five intervention groups. Subsequently, meetings, consultations and workshops were organised to reach further consensus. We defined the consensus criteria a priori. RESULTS: Overall, 72 and 61 people, including patients and the public, participated in round I and round II of the Delphi, respectively. Consensus COSs (including definition and time points) were developed for interventions that prevent adverse reaction to snake antivenom (three outcomes), specifically manage neurotoxic manifestations (five outcomes), specifically manage haematological manifestations (five outcomes) and those that act against snake venom (seven) outcomes. A priori criteria for inclusion in COS were not met for COS on interventions for management of the bitten part. CONCLUSION: The COS contributes to improving research efficiency by standardising outcome measurement in South Asia. It also provides methodological insights for future development of COS, beyond snakebite.

Frailty and outcomes in heart failure patients from high-, middle-, and low-income countries.

BACKGROUND AND AIMS: There is little information on the incremental prognostic importance of frailty beyond conventional prognostic variables in heart failure (HF) populations from different country income levels. METHODS: A total of 3429 adults with HF (age 61 ± 14 years, 33% women) from 27 high-, middle- and low-income countries were prospectively studied. Baseline frailty was evaluated by the Fried index, incorporating handgrip strength, gait speed, physical activity, unintended weight loss, and self-reported exhaustion. Mean left ventricular ejection fraction was 39 ± 14% and 26% had New York Heart Association Class III/IV symptoms. Participants were followed for a median (25th to 75th percentile) of 3.1 (2.0-4.3) years. Cox proportional hazard models for death and HF hospitalization adjusted for country income level; age; sex; education; HF aetiology; left ventricular ejection fraction; diabetes; tobacco and alcohol use; New York Heart Association functional class; HF medication use; blood pressure; and haemoglobin, sodium, and creatinine concentrations were performed. The incremental discriminatory value of frailty over and above the MAGGIC risk score was evaluated by the area under the receiver-operating characteristic curve. RESULTS: At baseline, 18% of participants were robust, 61% pre-frail, and 21% frail. During follow-up, 565 (16%) participants died and 471 (14%) were hospitalized for HF. Respective adjusted hazard ratios (95% confidence interval) for death among the pre-frail and frail were 1.59 (1.12-2.26) and 2.92 (1.99-4.27). Respective adjusted hazard ratios (95% confidence interval) for HF hospitalization were 1.32 (0.93-1.87) and 1.97 (1.33-2.91). Findings were consistent among different country income levels and by most subgroups. Adding frailty to the MAGGIC risk score improved the discrimination of future death and HF hospitalization. CONCLUSIONS: Frailty confers substantial incremental prognostic information to prognostic variables for predicting death and HF hospitalization. The relationship between frailty and these outcomes is consistent across countries at all income levels.

Mortality and Morbidity in Adults With Rheumatic Heart Disease.

Importance: Rheumatic heart disease (RHD) remains a public health issue in low- and middle-income countries (LMICs). However, there are few large studies enrolling individuals from multiple endemic countries. Objective: To assess the risk and predictors of major patient-important clinical outcomes in patients with clinical RHD. Design, Setting, and Participants: Multicenter, hospital-based, prospective observational study including 138 sites in 24 RHD-endemic LMICs. Main Outcomes and Measures: The primary outcome was all-cause mortality. Secondary outcomes were cause-specific mortality, heart failure (HF) hospitalization, stroke, recurrent rheumatic fever, and infective endocarditis. This study analyzed event rates by World Bank country income groups and determined the predictors of mortality using multivariable Cox models. Results: Between August 2016 and May 2022, a total of 13 696 patients were enrolled. The mean age was 43.2 years and 72% were women. Data on vital status were available for 12 967 participants (94.7%) at the end of follow-up. Over a median duration of 3.2 years (41 478 patient-years), 1943 patients died (15% overall; 4.7% per patient-year). Most deaths were due to vascular causes (1312 [67.5%]), mainly HF or sudden cardiac death. The number of patients undergoing valve surgery (604 [4.4%]) and HF hospitalization (2% per year) was low. Strokes were infrequent (0.6% per year) and recurrent rheumatic fever was rare. Markers of severe valve disease, such as congestive HF (HR, 1.58 [95% CI, 1.50-1.87]; P < .001), pulmonary hypertension (HR, 1.52 [95% CI, 1.37-1.69]; P < .001), and atrial fibrillation (HR, 1.30 [95% CI, 1.15-1.46]; P < .001) were associated with increased mortality. Treatment with surgery (HR, 0.23 [95% CI, 0.12-0.44]; P < .001) or valvuloplasty (HR, 0.24 [95% CI, 0.06-0.95]; P = .042) were associated with lower mortality. Higher country income level was associated with lower mortality after adjustment for patient-level factors. Conclusions and Relevance: Mortality in RHD is high and is correlated with the severity of valve disease. Valve surgery and valvuloplasty were associated with substantially lower mortality. Study findings suggest a greater need to improve access to surgical and interventional care, in addition to the current approaches focused on antibiotic prophylaxis and anticoagulation.

Global Variations in Heart Failure Etiology, Management, and Outcomes.

Importance: Most epidemiological studies of heart failure (HF) have been conducted in high-income countries with limited comparable data from middle- or low-income countries. Objective: To examine differences in HF etiology, treatment, and outcomes between groups of countries at different levels of economic development. Design, Setting, and Participants: Multinational HF registry of 23 341 participants in 40 high-income, upper-middle-income, lower-middle-income, and low-income countries, followed up for a median period of 2.0 years. Main Outcomes and Measures: HF cause, HF medication use, hospitalization, and death. Results: Mean (SD) age of participants was 63.1 (14.9) years, and 9119 (39.1%) were female. The most common cause of HF was ischemic heart disease (38.1%) followed by hypertension (20.2%). The proportion of participants with HF with reduced ejection fraction taking the combination of a ß-blocker, renin-angiotensin system inhibitor, and mineralocorticoid receptor antagonist was highest in upper-middle-income (61.9%) and high-income countries (51.1%), and it was lowest in low-income (45.7%) and lower-middle-income countries (39.5%) (P < .001). The age- and sex- standardized mortality rate per 100 person-years was lowest in high-income countries (7.8 [95% CI, 7.5-8.2]), 9.3 (95% CI, 8.8-9.9) in upper-middle-income countries, 15.7 (95% CI, 15.0-16.4) in lower-middle-income countries, and it was highest in low-income countries (19.1 [95% CI, 17.6-20.7]). Hospitalization rates were more frequent than death rates in high-income countries (ratio = 3.8) and in upper-middle-income countries (ratio = 2.4), similar in lower-middle-income countries (ratio = 1.1), and less frequent in low-income countries (ratio = 0.6). The 30-day case-fatality rate after first hospital admission was lowest in high-income countries (6.7%), followed by upper-middle-income countries (9.7%), then lower-middle-income countries (21.1%), and highest in low-income countries (31.6%). The proportional risk of death within 30 days of a first hospital admission was 3- to 5-fold higher in lower-middle-income countries and low-income countries compared with high-income countries after adjusting for patient characteristics and use of long-term HF therapies. Conclusions and Relevance: This study of HF patients from 40 different countries and derived from 4 different economic levels demonstrated differences in HF etiologies, management, and outcomes. These data may be useful in planning approaches to improve HF prevention and treatment globally.

First report of black pepper (Piper nigrum L.) anthracnose caused by Colletotrichum siamense in north-east India.

Black pepper (Piper nigrum L.) has been commonly cultivated as a spice crop in northeast India. In August 2021, anthracnose leaf spot was observed on black pepper vines with 50 to 60% of disease incidence in Assam Agricultural University, Jorhat (26.7509° N, 94.2037° E), Assam, India. On average, 80% of the leaves per individual vine were affected by this disease. Foliar symptoms initially appeared as chlorotic circular spots, which then coalesced into larger irregular lesions. The centers of the spots were brown, papery in texture, and surrounded by a yellow halo. Numerous acervuli at the center of the spots were observed. Ten vines from the orchard were sampled to identify the causal agent. Symptomatic leaves along with some healthy portion were cut (3 to 4.5 mm2), surface-sterilized in 70% ethanol for 30 s, rinsed in sterile distilled water twice, dried on sterilized filter paper, aseptically plated on potato dextrose agar (PDA) amended with Streptomycin sulphate (30 mg/L), and then incubated at 25°C for four days. Two Colletotrichum isolates were recovered from infected tissues and purified by the hyphal tip method. Fungal colonies on PDA were cottony, dense, white to gray in color, and with salmon pink conidial masses. Conidia (n = 50) were 13.6 to 19.8 × 4.2 to 6.4 µm, cylindrical, hyaline, single-celled, smooth-walled, and with rounded ends. Conidiophores were aseptate, hyaline, short and branched. Based on morphological features, the isolates were identified in the Colletotrichum gloeosporioides species complex (Weir et al. 2012). For accurate identification of two isolates, the DNA was extracted from pure culture. The internal transcribed spacer (ITS) region, actin (ACT), ß-tubulin 2 (TUB2) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) genes were amplified by polymerase chain reaction (Weir et al. 2012) and sequenced. The sequences were deposited in the GenBank database (ITS: OP297054 and OP296876; ACT: OP327082 and OP327081; TUB2; OP327086 and OP327085; GAPDH: OP327084 and OP327083). A BLAST analysis of ITS, ACT, TUB2 and GAPDH sequences revealed 99.5-100%, 99.9-100%, 99.9-100% and 99.8-100% similarity respectively to C. siamense for both isolates in NCBI database. The pathogenicity tests were carried out on potted four months old vine cuttings of P. nigrum L., which were kept in a greenhouse. Ten healthy plants were sprayed with 50 µl of conidial suspension of each isolate (107 conidia ml-1, 10 ml/plant). Five control plants were sprayed with sterile distilled water. The plants were covered with sterilized plastic bags after inoculation to maintain humidity and kept in a greenhouse at day/night temperatures of 25 ± 2°C and 17 ± 2°C (Zhang et al., 2021). Within eight days, all the inoculated plants showed symptoms similar to those observed in the field, whereas control plants were asymptomatic. The pathogenicity test was repeated twice. C. siamense was consistently reisolated from the lesions and was confirmed by morphological characterization and molecular assays as described above in this note, whereas no fungus was isolated from control leaves. To our knowledge this is the first report of C. siamense causing black pepper anthracnose in northeast India. The pathogen has significant potential for causing high losses in black pepper production. These data will help researchers to develop effective management strategies for this disease.

Recognition and management of community-acquired acute kidney injury in low-resource settings in the ISN 0by25 trial: A multi-country feasibility study.

BACKGROUND: Acute kidney injury (AKI) is increasingly encountered in community settings and contributes to morbidity, mortality, and increased resource utilization worldwide. In low-resource settings, lack of awareness of and limited access to diagnostic and therapeutic interventions likely influence patient management. We evaluated the feasibility of the use of point-of-care (POC) serum creatinine and urine dipstick testing with an education and training program to optimize the identification and management of AKI in the community in 3 low-resource countries. METHODS AND FINDINGS: Patients presenting to healthcare centers (HCCs) from 1 October 2016 to 29 September 2017 in the cities Cochabamba, Bolivia; Dharan, Nepal; and Blantyre, Malawi, were assessed utilizing a symptom-based risk score to identify patients at moderate to high AKI risk. POC testing for serum creatinine and urine dipstick at enrollment were utilized to classify these patients as having chronic kidney disease (CKD), acute kidney disease (AKD), or no kidney disease (NKD). Patients were followed for a maximum of 6 months with repeat POC testing. AKI development was assessed at 7 days, kidney recovery at 1 month, and progression to CKD and mortality at 3 and 6 months. Following an observation phase to establish baseline data, care providers and physicians in the HCCs were trained with a standardized protocol utilizing POC tests to evaluate and manage patients, guided by physicians in referral hospitals connected via mobile digital technology. We evaluated 3,577 patients, and 2,101 were enrolled: 978 in the observation phase and 1,123 in the intervention phase. Due to the high number of patients attending the centers daily, it was not feasible to screen all patients to assess the actual incidence of AKI. Of enrolled patients, 1,825/2,101 (87%) were adults, 1,117/2,101 (53%) were females, 399/2,101 (19%) were from Bolivia, 813/2,101 (39%) were from Malawi, and 889/2,101 (42%) were from Nepal. The age of enrolled patients ranged from 1 month to 96 years, with a mean of 43 years (SD 21) and a median of 43 years (IQR 27-62). Hypertension was the most common comorbidity (418/2,101; 20%). At enrollment, 197/2,101 (9.4%) had CKD, and 1,199/2,101 (57%) had AKD. AKI developed in 30% within 7 days. By 1 month, 268/978 (27%) patients in the observation phase and 203/1,123 (18%) in the intervention phase were lost to follow-up. In the intervention phase, more patients received fluids (observation 714/978 [73%] versus intervention 874/1,123 [78%]; 95% CI 0.63, 0.94; p = 0.012), hospitalization was reduced (observation 578/978 [59%] versus intervention 548/1,123 [49%]; 95% CI 0.55, 0.79; p < 0.001), and admitted patients with severe AKI did not show a significantly lower mortality during follow-up (observation 27/135 [20%] versus intervention 21/178 [11.8%]; 95% CI 0.98, 3.52; p = 0.057). Of 504 patients with kidney function assessed during the 6-month follow-up, de novo CKD arose in 79/484 (16.3%), with no difference between the observation and intervention phase (95% CI 0.91, 2.47; p = 0.101). Overall mortality was 273/2,101 (13%) and was highest in those who had CKD (24/106; 23%), followed by those with AKD (128/760; 17%), AKI (85/628; 14%), and NKD (36/607; 6%). The main limitation of our study was the inability to determine the actual incidence of kidney dysfunction in the health centers as it was not feasible to screen all the patients due to the high numbers seen daily. CONCLUSIONS: This multicenter, non-randomized feasibility study in low-resource settings demonstrates that it is feasible to implement a comprehensive program utilizing POC testing and protocol-based management to improve the recognition and management of AKI and AKD in high-risk patients in primary care.

Microbiological and Clinicoepidemiological Profile of a Series of Patients with Infective Endocarditis at a Center in Eastern Nepal.

BACKGROUND: The microbiological and clinicoepidemiological profile of infective endocarditis (IE) has undergone significant change over time. The pattern of IE studied at local level provides broader vision in understanding the current scenario of this disease. This study aimed to depict the overall picture of IE and its changing profile by evaluating the microbiological and clinicoepidemiological features in the context of a tertiary care center of eastern Nepal. METHODS: The descriptive study was conducted from September 2017 to August 2018 among IE patients presenting to B. P. Koirala Institute of Health Sciences, Nepal. Detailed history and clinical manifestations of patients were noted. Microorganisms isolated from the blood culture were processed for identification by standard microbiological methods, and susceptibility testings were done. Each patient was assessed daily during hospital stay. RESULTS: Ten definite and 7 possible endocarditis cases were studied. The mean age was 41.4 ± 15.85 (17-70) years with predominance of male (4.7 : 1). Rheumatic heart disease (41.1%) was the most common underlying heart disease observed followed by injection drug user endocarditis (23.5%). All the cases had native valve endocarditis. Aortic valve was the most common valve involved (35.3%) followed by mitral, tricuspid, and pulmonary valves. Blood culture positivity was 53%. Staphylococcus aureus was the major causative agent responsible for 23.5% of the cases followed by Enterococcus faecium, Enterococcus faecalis, and Pseudomonas aeruginosa. Mortality of 2 cases (11.8%) was associated with S. aureus and P. aeruginosa. Majority of patients developed acute kidney injury (35.3%) and congestive cardiac failure (23.5%). CONCLUSION: IE patients in our center exhibited differences from the west in terms of age at presentation and predisposing factors but held similarity in terms of commonly isolated microorganisms. The changing patterns of IE, etiological agents, and their antimicrobial susceptibility observed in this study may be helpful for clinicians in formulating a new empirical antibiotic treatment protocol.

The INVICTUS rheumatic heart disease research program: Rationale, design and baseline characteristics of a randomized trial of rivaroxaban compared to vitamin K antagonists in rheumatic valvular disease and atrial fibrillation.

BACKGROUND: Rheumatic heart disease (RHD) is a neglected disease affecting 33 million people, mainly in low and middle income countries. Yet very few large trials or registries have been conducted in this population. The INVICTUS program of research in RHD consists of a randomized-controlled trial (RCT) of 4500 patients comparing rivaroxaban with vitamin K antagonists (VKA) in patients with RHD and atrial fibrillation (AF), a registry of 17,000 patients to document the contemporary clinical course of patients with RHD, including a focused sub-study on pregnant women with RHD within the registry. This paper describes the rationale, design, organization and baseline characteristics of the RCT and a summary of the design of the registry and its sub-study. Patients with RHD and AF are considered to be at high risk of embolic strokes, and oral anticoagulation with VKAs is recommended for stroke prevention. But the quality of anticoagulation with VKA is poor in developing countries. A drug which does not require monitoring, and which is safe and effective for preventing stroke in patients with valvular AF, would fulfill a major unmet need. METHODS: The INVestIgation of rheumatiC AF Treatment Using VKAs, rivaroxaban or aspirin Studies (INVICTUS-VKA) trial is an international, multicentre, randomized, open-label, parallel group trial, testing whether rivaroxaban 20 mg given once daily is non-inferior (or superior) to VKA in patients with RHD, AF, and an elevated risk of stroke (mitral stenosis with valve area ≤2 cm2, left atrial spontaneous echo-contrast or thrombus, or a CHA2DS2VASc score ≥2). The primary efficacy outcome is a composite of stroke or systemic embolism and the primary safety outcome is the occurrence of major bleeding. The trial has enrolled 4565 patients from 138 sites in 23 countries from Africa, Asia and South America. The Registry plans to enroll an additional 17,000 patients with RHD and document their treatments, and their clinical course for at least 2 years. The pregnancy sub-study will document the clinical course of pregnant women with RHD. CONCLUSION: INVICTUS is the largest program of clinical research focused on a neglected cardiovascular disease and will provide new information on the clinical course of patients with RHD, and approaches to anticoagulation in those with concomitant AF.

Dialysis Care and Dialysis Funding in Asia.

Asia is the largest and most populated continent in the world, with a high burden of kidney failure. In this Policy Forum article, we explore dialysis care and dialysis funding in 17 countries in Asia, describing conditions in both developed and developing nations across the region. In 13 of the 17 countries surveyed, diabetes is the most common cause of kidney failure. Due to great variation in gross domestic product per capita across Asian countries, disparities in the provision of kidney replacement therapy (KRT) exist both within and between countries. A number of Asian nations have satisfactory access to KRT and have comprehensive KRT registries to help inform practices, but some do not, particularly among low- and low-to-middle-income countries. Given these differences, we describe the economic status, burden of kidney failure, and cost of KRT across the different modalities to both governments and patients and how changes in health policy over time affect outcomes. Emerging trends suggest that more affluent nations and those with universal health care or access to insurance have much higher prevalent dialysis and transplantation rates, while in less affluent nations, dialysis access may be limited and when available, provided less frequently than optimal. These trends are also reflected by an association between nephrologist prevalence and individual nations' incomes and a disparity in the number of nephrologists per million population and per thousand KRT patients.

Prevalence of multimorbidity and its associated risk factors among population of Mechinagar municipality of Nepal.

Background: Multimorbidity is a group of conditions, it has significant impact on the population as a whole, resulting in lower quality of life, higher mortality, frequent use of medical services, and consequently higher healthcare costs. The objective of this study is to document the prevalence of common multimorbidity and its associated risk factors among population of Mechinagar Municipality. Methods: Community-based cross-sectional study was conducted where selected multimorbidity were assessed in selected areas of Mechinagar municipality of Jhapa District . Systematic random sampling technique was used to select 590 adult participants from three pre-defined pocket areas. Pre-designed semi-structured multimorbidity assessment questionnaire for primary care (MAQ-PC)was used to assess prevalence of multimorbidity. Multiple logistic regression was conducted to identify the strongest determinants of multimorbidity. Results: The prevalence of multimorbidity was 22.4%.Hypertension, Diabetes mellitus and COPD was seen in 39.2%, 7.8.% and 4.4% of the participants respectively . Participants with advancing age i. e. 40-49yrs were 12.62 times (AOR) more likely to have multimorbidity compared to their counterparts who were 20-29yrs old( p=<0.01,CI3.01-15.28) after adjusting for occupation, physical activity and family history of kidney disease. Working individuals, Physical inactivity and positive family history of kidney disease were the strongest determinates of multimorbidity. Conclusions: The study revealed that participants with increasing age, working individuals, physical inactivity and family history of kidney disease were more vulnerable of having multimorbidity. The findings of our study indicate need of intervention strategies and community-based health promotion programs in reducing burden of chronic disease among adult population.

Frailty and chronic diseases: A bi-directional relationship.

Frailty is a multidimensional syndrome associated with a decline in reserve capacity across multiple organ systems involving physical, psychological, and social aspects. Weakness is the earliest indicator of the frailty process. Multi-morbidity is the state of presence of two or more chronic diseases. Frailty and chronic diseases are interlinked as frail individuals are more prone to develop chronic diseases and multi-morbid individuals may present with frailty. They share common risk factors, pathogenesis, progression, and outcomes. Significant risk factors include obesity, smoking, aging, sedentary, and stressful lifestyle. Pathophysiological mechanisms involve high levels of circulating inflammatory cytokines as seen in individuals with frailty and chronic diseases such as hypertension, cardiovascular diseases, type 2 diabetes mellitus, chronic kidney disease, and anemia. Hence, frailty and chronic diseases go hand in hand and it is of utmost importance to identify them and intervene during early stages. Screening frailty and treating multi-morbidity incorporate both pharmacological and majorly non- pharmacological measures, such as physical activities, nutrition, pro-active care, minimizing polypharmacy and addressing reversible medical conditions. The purpose of this mini-review is to highlight the interrelation of frailty and chronic diseases through the discussion of their predictors and outcomes and how timely interventions are essential to prevent the progression of one to the other.

Posterior reversible encephalopathy syndrome due to nonadherence to antihypertensive treatment: A case report from Nepal.

Key Clinical Message: Posterior reversible encephalopathy syndrome may occur secondary to abrupt cessation of antihypertensive therapy. A gradual reduction in blood pressure and counseling regarding medication adherence are crucial to prevent adverse consequences. Abstract: Posterior reversible encephalopathy syndrome (PRES) is a reversible clinical radiographic syndrome with headache, hypertensive encephalopathy, seizures, and visual disturbances as common modes of presentation. PRES can be attributed to several risk factors. We reported the case of a 66-year-old Asian female with PRES following nonadherence to antihypertensive treatment. Initially, her computed tomography scan of the head was normal. After 48 h, we again ordered a head CT scan, which showed lesions suggestive of hypertensive encephalopathy. We immediately reduced 20%-25% of mean arterial pressure, followed by a gradual blood pressure lowering to avoid adverse consequences. We did a follow-up CT scan of the head at 2 weeks, showing the resolution of early lesions. Hence, we made a diagnosis of PRES. In these patients, it is crucial to ensure medication adherence to avoid complications.

Spatiotemporal characterization of heatwave exposure across historically vulnerable communities.

Heatwaves pose a serious threat and are projected to amplify with changing climate and social demographics. A comprehensive understanding of heatwave exposure to the communities is imperative for the development of effective strategies and mitigation plans. This study explores spatiotemporal characterization of heatwaves across the historically vulnerable communities in Mississippi, United States. We derive multiple heatwave metrics including frequency, duration, and magnitude based on temperature data for urban-specific daytime, nighttime, and day-night combined conditions. Our analysis depicts a rising heatwave trend across all counties, with the most extreme shifts observed in prolonged day-night events lacking overnight relief. We integrate physical heatwave hazards with a socioeconomic vulnerability index to develop an integrated urban heatwave risk index. Integrated metric identifies the counties in northwest Mississippi as heat-prone areas, exhibiting an urgent need to prioritize heat resilience and adaptive strategies in these regions. The compounding urban heatwave and vulnerability risks in these communities highlights an environmental justice imperative to implement equitable policies that protect disadvantaged populations. Although this study is focused on Mississippi, our framework is scalable and can be employed to urban regions globally. This study provides a solid foundation for developing timely heatwave preparedness and mitigation to avert preventable heat-related tragedies as extremes intensify with climate change.

Performance and usability of cardiometabolic point of care devices in Nepal: A prospective, quantitative, accuracy study.

Non-communicable diseases (NCDs), such as cardiovascular disease and diabetes, represent a serious global health concern. There is an urgent need for prompt diagnosis and effective monitoring at point of care, especially in low- and middle-income countries. Here we present the results of a study assessing the quantitative accuracy of two devices that may fit the target product profile for a cardiometabolic point-of-care device. This prospective, quantitative, accuracy study (NCT05257564) was conducted between March to May 2022, investigating the performance of the JanaCare Aina Blood Monitoring System (JCAina) and the Tascom SimplexTAS 101 device (TAS101) compared with local standard laboratory methods in rural Nepal. Using fingerstick capillary blood, cardiometabolic parameters were analysed using both devices. The quantitative accuracy was compared against a local laboratory reference assay. System usability was also assessed. For JCAina, the mean absolute biases (Bland-Altman analysis) for glucose, HbA1c and total cholesterol tests were -3.87 mg/dL (95% CI: -7.52--0.22), 1.34% (95% CI: 1.21-1.47), and -9.52 mg/dL (95% CI: -11.9--7.2), respectively, corresponding to mean percentage biases of 2.0%, 18.5%, and -6.4%. These indicate clinically small (<10% biases) differences from laboratory results for glucose and cholesterol, and a moderate (10-20%) positive bias for HbA1c. For TAS101, the mean absolute biases for glucose, HbA1c, total cholesterol and creatinine tests were 18.7 mg/dL (95% CI: 15.8-21.5), -0.2% (95% CI: -0.26--0.14), 29.8 mg/dL (95% CI: 27.0-32.6), and -0.02 mg/dL (95% CI: -0.05-0.01), respectively, corresponding to mean percentage biases of 12.1%, -2.6%, 15.8%, and -4.5%. These indicate clinically small differences for HbA1c and creatinine, and moderate positive biases for glucose and cholesterol. Both systems exhibited usability challenges. The JCAina and TAS101 point-of-care cardiometabolic devices were shown to have promising accuracy in environmental conditions such as in Nepal, though improvements are still needed for some parameters and for ease of use. Trial registration: NCT05257564 (ClinicalTrials.gov).

Decentralization and Integration of Advanced Cardiac Care for the World's Poorest Billion Through the PEN-Plus Strategy for Severe Chronic Non-Communicable Disease.

Rheumatic and congenital heart disease, cardiomyopathies, and hypertensive heart disease are major causes of suffering and death in low- and lower middle-income countries (LLMICs), where the world's poorest billion people reside. Advanced cardiac care in these counties is still predominantly provided by specialists at urban tertiary centers, and is largely inaccessible to the rural poor. This situation is due to critical shortages in diagnostics, medications, and trained healthcare workers. The Package of Essential NCD Interventions - Plus (PEN-Plus) is an integrated care model for severe chronic noncommunicable diseases (NCDs) that aims to decentralize services and increase access. PEN-Plus strategies are being initiated by a growing number of LLMICs. We describe how PEN-Plus addresses the need for advanced cardiac care and discuss how a global group of cardiac organizations are working through the PEN-Plus Cardiac expert group to promote a shared operational strategy for management of severe cardiac disease in high-poverty settings.

Correction: Decentralization and Integration of Advanced Cardiac Care for the World's Poorest Billion Through the PEN-Plus Strategy for Severe Chronic Non-Communicable Disease.

[This corrects the article DOI: 10.5334/gh.1313.].

Worm infestation as a cause of severe anemia in a frail older adult: a case report.

Introduction: Worm infestations are a common occurrence in low-income countries. Anemia due to iron deficiency can be brought on by human intestinal worms. The authors report a case of an 86-year-old frail older adult with upper gastrointestinal (GI) bleeding caused by a worm infestation most likely to be hookworm. Case presentation: An 86-year-old male, presented to the Emergency Department with complaints of bilateral lower limb swelling and shortness of breath for 4 days associated with melena for 2 months. The authors made a provisional diagnosis of heart failure precipitated by anemia. Upper GI endoscopy revealed multiple whitish exudates, which are resistant to water jets. Multiple worms were noted in the second part of the duodenum. Based on clinical evaluation and endoscopy, the diagnosis of oesophagial candidiasis and iron deficiency anemia secondary to upper GI bleeding due to Hookworm infestation was made. Clinical discussion: In low-income countries, especially those involving the tropical area, worm infestation should be considered as an important cause of obscure acute GI bleeding and severe anemia. Usually, malignancy is suspected in an older adult with severe anemia but hookworm infestation is a treatable disease with a good prognosis and complete recovery. The most commonly used drugs for treatment are mebendazole and albendazole. In a low-income country with a high burden of worm infestations, empirical treatment of iron deficiency anemia with single dose albendazole has been recommended. Conclusion: Usually, severe anemia in an older adult is mostly attributed to an underlying malignancy. Our case serves as a good example of how a treatable condition can improve the quality of life in a frail older adult. Normally, there is a tendency to defer UGI endoscopy in frail elderly due to ageism. However, the diagnosis of a treatable cause of upper GI bleeding can be made by a simple upper GI endoscopy. Severe anemia due to hookworm infestation is treated effectively and quickly with albendazole and iron therapy.