Cardiovascular Risk Assessment in Developing World

Many international and national authorities recommend that cardiovascular risk assessment using multivariate risk scores be used to identify individuals at high risk of cardiovascular disease (CVD). This approach is likely to assure that resources in developing countries are allocated to those who need it most. However, not many developing countries have implemented this approach and different countries have varying progresses in adopting the concept. While many developing countries solely described estimated cardiovascular risk by applying existing CVD risk scores to their population’s cross-sectional data, a number of countries have validated and recalibrated existing risk scores and only a few have developed new risk scores specific to their populations. To enhance the adoption of such a policy in developing countries, new CVD risk prediction charts for low- and medium-resource settings were developed and endorsed by the WHO and International Society of Hypertension. However, a number of issues need to be addressed, including development of population-specific risk scores, recalibration of available risk scores and uncertainty over cost-effectiveness of CVD risk assessment in developing countries. Although this high risk approach might represent an effective and practical strategy for developing countries, a complementary population-based approach is also needed to maximize benefits for CVD prevention

Diabetes and risk of hospitalization due to infection in northeastern Thailand:Retrospective cohort study using population-based healthcare service data

Background: Population-based studies describing the association between diabetes and increased risk of infection have largely been based in high-income countries. There is limited information describing the burden of infectious disease attributable to diabetes in low and middle-income countries. This study aimed to describe the burden and risk of infectious disease hospitalisation in people with diabetes compared to those without diabetes in northeastern Thailand. Methods: In a retrospective cohort study using electronic health record data for 2012–2018 for 3.8 million people aged ≥20 years in northeastern Thailand, hospitalisation rates for any infectious diseases (ICD-10 codes A00-B99) were estimated and negative binomial regression used to estimate rate ratios (RR) for the association between diabetes and infectious disease hospitalisation adjusted for age, sex and area of residence. Results: In this study, 164,177 people had a diagnosis of diabetes mellitus at any point over the study period. Infectious disease hospitalisation rates per 1000 person-years (95%CI) were 71.8 (70.9, 72.8), 27.7 (27.1, 28.3) and 7.5 (7.5, 7.5) for people with prevalent diabetes, incident diabetes and those without diabetes respectively. Diabetes was associated with a 4.6-fold higher risk of infectious disease hospitalisation (RR (95% CI) 4.59 (4.52, 4.66)). RRs for infectious disease hospitalisation were 3.38 (3.29, 3.47) for people with diabetes managed by lifestyle alone and 5.29 (5.20, 5.39) for people receiving prescriptions for diabetes drugs. Conclusions: In this Thai population, diabetes was associated with substantially increased risk of hospitalisation due to infectious diseases and people with diabetes who were on pharmacological treatment had a higher risk than those receiving lifestyle modification advice alone.</p

Diabetes mellitus is associated with a shared hyper-inflammatory immune response in melioidosis and tuberculosis patients: an observational case-control study

Background Melioidosis is a serious infection caused by the bacterium Burkholderia pseudomallei with a case fatality rate of up to 40% in Northeast Thailand. Diabetes increases the risk of developing melioidosis by 12-fold. A similar, but less marked, relationship with diabetes is seen in tuberculosis (TB) patients, with a 3-fold increased risk of developing TB in people with diabetes. However, the mechanisms underlying increased susceptibility are not fully understood. Methods 81 acute melioidosis patients from Northeast Thailand and 151 TB patients from South Africa, Indonesia, Romania and Peru alongside uninfected control cohorts were studied by whole blood RNA sequencing. Both supervised and unsupervised data analysis approaches were performed including differential gene expression (DGE) analysis, pathway analyses, and weighted gene co-expression network analysis (WGCNA). Results Diabetes status was associated with a hyper-inflammatory response to both melioidosis and TB, with increased neutrophil and platelet degranulation, and exaggerated activation of coagulation and scavenger activation pathways, alongside decreased phosphoinositide-3-kinase protein kinase B (P13K-Akt) signalling. In melioidosis, changes with diabetes were subtle but also included increased tumour necrosis factor (TNF) signalling via nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and enhancement of endoplasmic reticulum stress and unfolded protein responses. Diabetes-related changes were more distinct in TB, with marked reduction of interferon signalling responses. Conclusion Diabetes is associated with enhanced non-specific inflammatory responses in both melioidosis and TB and an impaired interferon-mediated response to TB, with implications for future host-directed therapies. Summary Diabetes status is associated with a hyper-inflammatory response to both melioidosis and TB, with increased neutrophil and platelet degranulation, and exaggerated activation of coagulation and scavenger activation pathways. The impact is more subtle in melioidosis but pronounced in tuberculosis with stunted interferon responses

Dysregulated immunologic landscape of early host response in melioidosis

Melioidosis, a neglected tropical infection caused by Burkholderia pseudomallei, commonly presents as pneumonia or sepsis with mortality rates up to 50% despite appropriate treatment. A better understanding of the early host immune response to melioidosis may lead to new therapeutic interventions and prognostication strategies to reduce disease burden. Whole blood transcriptomic signatures in 164 melioidosis patients and 70 patients with other infections hospitalized in northeastern Thailand enrolled within 24 hours following hospital admission were studied. Key findings were validated in an independent melioidosis cohort. Melioidosis was characterized by upregulation of interferon signaling responses compared to other infections. Mortality in melioidosis was associated with excessive inflammation, up-regulated type 2 immune responses and a dramatic decrease in T cell-mediated immunity compared to survivors. We identified and independently confirmed a five-gene predictive set classifying fatal melioidosis (validation cohort: an area under the receiver operating characteristic curve 0.83, 95% CI: 0.67-0.99). In conclusion, this study highlights the intricate balance between innate and adaptive immunity during fatal melioidosis and can inform future precision medicine strategies for targeted therapies and prognostication in this severe infection

Benchmarking CRISPR-BP34 for point-of-care melioidosis detection in low-income and middle-income countries: a molecular diagnostics study

Background: Melioidosis is a neglected but often fatal tropical disease. The disease has broad clinical manifestations, which makes diagnosis challenging and time consuming. To improve diagnosis, we aimed to evaluate the performance of the CRISPR-Cas12a system (CRISPR-BP34) to detect Burkholderia pseudomallei DNA across clinical specimens from patients suspected to have melioidosis. Methods: We conducted a prospective, observational cohort study of adult patients (aged ≥18 years) with melioidosis at Sunpasitthiprasong Hospital, a tertiary care hospital in Thailand. Participants were eligible for inclusion if they had culture-confirmed B pseudomallei infection from any clinical samples. Data were collected from patient clinical records and follow-up telephone calls. Routine clinical samples (blood, urine, respiratory secretion, pus, and other body fluids) were collected for culture. We documented time taken for diagnosis, and mortality at day 28 of follow-up. We also performed CRISPR-BP34 detection on clinical specimens collected from 330 patients with suspected melioidosis and compared its performance with the current gold-standard culture-based method. Discordant results were validated by three independent qualitative PCR tests. This study is registered with the Thai Clinical Trial Registry, TCTR20190322003. Findings: Between Oct 1, 2019, and Dec 31, 2022, 876 patients with culture-confirmed melioidosis were admitted or referred to Sunpasitthiprasong Hospital, 433 of whom were alive at diagnosis and were enrolled in this study. Median time from sample collection to diagnosis by culture was 4·0 days (IQR 3·0–5·0) among all patients with known survival status at day 28, which resulted in delayed treatment. 199 (23%) of 876 patients died before diagnosis and 114 (26%) of 433 patients in follow-up were treated, but died within 28 days of admission. To test the CRISPR-BP34 assay, we enrolled and collected clinical samples from 114 patients with melioidosis and 216 patients without melioidosis between May 26 and Dec 31, 2022. Application of CRISPR-BP34 reduced the median sample-to-diagnosis time to 1·1 days (IQR 0·7–1·5) for blood samples, 2·3 h (IQR 2·3–2·4) for urine, and 3·3 h (3·1–3·4) for respiratory secretion, pus, and other body fluids. The overall sensitivity of CRISPR-BP34 was 93·0% (106 of 114 samples [95% CI 86·6–96·9]) compared with 66·7% (76 of 114 samples [57·2–75·2]) for culture. The overall specificity of CRISPR-BP34 was 96·8% (209 of 216 samples [95% CI 93·4–98·7]), compared with 100% (216 of 216 samples [98·3–100·0]) for culture. Interpretation: The sensitivity, specificity, speed, and window of clinical intervention offered by CRISPR-BP34 support its prospective use as a point-of-care diagnostic tool for melioidosis. Future development should be focused on scalability and cost reduction

Derivation and external validation of community-acquired pneumonia subphenotypes in Southeast Asia: a secondary analysis of prospective cohort studies

BackgroundIdentifying pneumonia subphenotypes in understudied populations can advance equitable personalized medicine for pneumonia care. We aimed to derive and validate subphenotypes of patients presenting with community-acquired pneumonia (CAP) in Southeast Asia.MethodsThis secondary analysis included three prospective cohorts conducted between March 2013 and April 2020. First, we performed latent class analysis to identify subphenotypes using clinical and laboratory variables in a prospective cohort of adults hospitalized with CAP in northeastern Thailand. Next, we compared clinical and biological features between the subphenotypes and then developed a parsimonious classifier model (PCM) for accurate subphenotype assignment. We then validated the accuracy of PCM subphenotype assignment in an external, multinational prospective cohort of patients hospitalized with CAP in Southeast Asia. Finally, in an exploratory analysis, we used the PCM to assign pneumonia subphenotypes in a prospective cohort of patients hospitalized with COVID-19 in the United States of America and evaluated a heterogeneity of treatment effect with corticosteroids.FindingsAmong 953 CAP patients in the Thai derivation cohort, we identified two subphenotypes: CAP1 (141, 15%) and CAP2 (812, 85%). We observed greater respiratory failure, 28-day mortality, inflammatory cytokines and metabolic derangements among CAP1 patients. A four-variable PCM discriminated subphenotype assignment in bootstrap internal validation (optimism-corrected C-statistic 0.97). In the Southeast Asian external validation cohort, CAP1 and CAP2 subphenotypes assigned by the PCM shared similar differential clinical features and outcomes with the Thai derivation cohort. In the cohort of patients with COVID-19, CAP1 and CAP2 subphenotypes assigned by the PCM differed by key clinical characteristics and revealed an interaction between corticosteroid treatment and mortality (P = 0.002).InterpretationIn Southeast Asia, CAP subphenotypes are associated with distinct outcomes, inflammatory profiles, and metabolomic signatures. These subphenotypes may represent unique targets for future CAP interventional trials.FundingSupported by US NIH awards T32HL007287, F32HL168809, K08HL157562, U01AI115520, R01AI137111, R01GM114029, R21AI173435, R01HL113382, the Wellcome Trust grants 090219/Z/09/Z, 101103/Z/13/Z, 106680/B/14/Z, and 106698/B/14/Z, the US National Cancer Institute, National Institutes of Health HHSN261200800001E, and Firland Foundation award 20220012. For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission

Frequency and mortality rate following antimicrobial-resistant bloodstream infections in tertiary-care hospitals compared with secondary-care hospitals

There are few studies comparing proportion, frequency, mortality and mortality rate following antimicrobial-resistant (AMR) infections between tertiary-care hospitals (TCHs) and secondary-care hospitals (SCHs) in low and middle-income countries (LMICs) to inform intervention strategies. The aim of this study is to demonstrate the utility of an offline tool to generate AMR reports and data for a secondary data analysis. We conducted a secondary-data analysis on a retrospective, multicentre data of hospitalised patients in Thailand. Routinely collected microbiology and hospital admission data of 2012 to 2015, from 15 TCHs and 34 SCHs were analysed using the AMASS v2.0 (www.amass.website). We then compared the burden of AMR bloodstream infections (BSI) between those TCHs and SCHs. Of 19,665 patients with AMR BSI caused by pathogens under evaluation, 10,858 (55.2%) and 8,807 (44.8%) were classified as community-origin and hospital-origin BSI, respectively. The burden of AMR BSI was considerably different between TCHs and SCHs, particularly of hospital-origin AMR BSI. The frequencies of hospital-origin AMR BSI per 100,000 patient-days at risk in TCHs were about twice that in SCHs for most pathogens under evaluation (for carbapenem-resistant Acinetobacter baumannii [CRAB]: 18.6 vs. 7.0, incidence rate ratio 2.77; 95%CI 1.72–4.43, p0.20). Due to the higher frequencies, all-cause in-hospital mortality rates following hospital-origin AMR BSI per 100,000 patient-days at risk were considerably higher in TCHs for most pathogens (for CRAB: 10.2 vs. 3.6,mortality rate ratio 2.77; 95%CI 1.71 to 4.48, p<0.001; CRPA: 1.6 vs. 0.8; p = 0.020; 3GCREC: 4.0 vs. 2.4, p = 0.009; 3GCRKP, 4.0 vs. 1.8, p<0.001; CRKP: 0.8 vs. 0.3, p = 0.042; and MRSA: 2.3 vs. 1.1, p = 0.023). In conclusion, the burden of AMR infections in some LMICs might differ by hospital type and size. In those countries, activities and resources for antimicrobial stewardship and infection control programs might need to be tailored based on hospital setting. The frequency and in-hospital mortality rate of hospital-origin AMR BSI are important indicators and should be routinely measured to monitor the burden of AMR in every hospital with microbiology laboratories in LMICs

Barriers and enablers to blood culture sampling in Indonesia, Thailand and Viet Nam: a Theoretical Domains Framework-based survey

Objective Blood culture (BC) sampling is recommended for all suspected sepsis patients prior to antibiotic administration. We examine barriers and enablers to BC sampling in three Southeast Asian countries. Design A Theoretical Domains Framework (TDF)-based survey, comprising a case scenario of a patient presenting with community-acquired sepsis and all 14 TDF domains of barriers/enablers to BC sampling. Setting Hospitals in Indonesia, Thailand and Viet Nam, December 2021 to 30 April 2022. Participants 1070 medical doctors and 238 final-year medical students were participated in this study. Half of the respondents were women (n=680, 52%) and most worked in governmental hospitals (n=980, 75.4%). Outcome measures Barriers and enablers to BC sampling. Results The proportion of respondents who answered that they would definitely take BC in the case scenario was highest at 89.8% (273/304) in Thailand, followed by 50.5% (252/499) in Viet Nam and 31.3% (157/501) in Indonesia (p<0.001). Barriers/enablers in nine TDF domains were considered key in influencing BC sampling, including ‘priority of BC (TDF-goals)’, ‘perception about their role to order or initiate an order for BC (TDF-social professional role and identity)’, ‘perception that BC is helpful (TDF-beliefs about consequences)’, ‘intention to follow guidelines (TDF-intention)’, ‘awareness of guidelines (TDF-knowledge)’, ‘norms of BC sampling (TDF-social influence)’, ‘consequences that discourage BC sampling (TDF-reinforcement)’, ‘perceived cost-effectiveness of BC (TDF-environmental context and resources)’ and ‘regulation on cost reimbursement (TDF-behavioural regulation)’. There was substantial heterogeneity between the countries. In most domains, the lower (higher) proportion of Thai respondents experienced the barriers (enablers) compared with that of Indonesian and Vietnamese respondents. A range of suggested intervention types and policy options was identified. Conclusions Barriers and enablers to BC sampling are varied and heterogenous. Cost-related barriers are more common in more resource-limited countries, while many barriers are not directly related to cost. Context-specific multifaceted interventions at both hospital and policy levels are required to improve diagnostic stewardship practices