Drug resistance in Mycobacterium tuberculosis , the causative agent of tuberculosis disease, arises from genetic mutations in genes coding for drug-targets or drug-converting enzymes. SNPs linked to drug resistance have been extensively studied and form the basis of molecular diagnostics and sequencing-based resistance profiling. However, alternative forms of functional variation such as large deletions and other loss of function (LOF) mutations have received much less attention, but if incorporated into diagnostics they are likely to improve their predictive performance. Our work aimed to characterize the contribution of LOF mutations found in 42 established drug resistance genes linked to 19 anti-tuberculous drugs across 32689 sequenced clinical isolates. The analysed LOF mutations included large deletions (n=586), frameshifts (n=4764) and premature stop codons (n=826). We found LOF mutations in genes strongly linked to pyrazinamide (pncA), isoniazid (katG), capreomycin (tlyA), streptomycin (e.g. gid) and ethionamide (ethA, mshA) (P<10−5), but also in some loci linked to drugs where relatively less phenotypic data is available [e.g. cycloserine, delaminid, bedaquiline, para-aminosalicylic acid (PAS), and clofazimine]. This study reports that large deletions (median size 1115 bp) account for a significant portion of resistance variants found for PAS (+7.1% of phenotypic resistance percentage explained), pyrazinamide (+3.5%) and streptomycin (+2.6%) drugs, and can be used to improve the prediction of cryptic resistance. Overall, our work highlights the importance of including LOF mutations (e.g. large deletions) in predicting genotypic drug resistance, thereby informing tuberculosis infection control and clinical decision-making.

Recent studies have suggested that malaria may affect the cardiovascular system. The aim of this systematic review and meta-analysis was to determine the prevalence of cardiovascular complications in symptomatic malaria patients. We searched databases such as Pubmed, Embase, Cochrane, and Web of Science (January 1950–April 2020) for studies reporting on cardiovascular complications in adults and children with malaria. Cardiovascular complications were defined as abnormalities in electrocardiogram (ECG), cardiac biomarkers, and echocardiography on admission or during outpatient examination. Studies of patients with known heart disease or cardiovascular evaluation performed after the start of intravenous antimalarial medication were excluded. The study was registered in PROSPERO (No.: CRD42020167672). The literature search yielded 1,243 studies, and a total of 43 studies with symptomatic malaria patients were included. Clinical studies (n = 12 adults; n = 5 children) comprised 3,117 patients, of which a majority had Plasmodium falciparum (n = 15) and were diagnosed with severe malaria (n = 13). In random-effects models of adults, the pooled prevalence estimate for any cardiovascular complication was 7% (95% CI: 5–9). No meta-analysis was conducted in children, but the range of abnormal ECG was 0–8%, cardiac biomarkers 0–57%, and echocardiography 4–9%. We analyzed 33 cases (n = 10 postmortem), in which the most common cardiovascular pathologies were myocarditis and acute coronary syndrome. All histopathological studies found evidence of parasitized red blood cells in the myocardium. Cardiovascular complications are not uncommon in symptomatic adults and children with malaria. Additional studies investigating malaria and cardiovascular disease are encouraged.

Background Despite completion of the vaccine schedule for hepatitis B virus (HBV), children may display levels of HBV surface antibodies (anti-HBs) that are considered inadequate for sufficient protection (<10 IU/L). Aims Our aim was to investigate if age and gap time between HBV vaccine doses may negatively affect the levels of anti-HBs in children, and if these relationships are modified by sex. Methods In a high-endemic HBV region of the western Brazilian Amazon we enrolled children who had completed the HBV vaccine schedule. All children underwent analysis of anti-HBs and a clinical examination. Results We included 522 children (mean age 4.3 ± 0.8 years; 50% male). Median anti-HBs was 28.4 [interquartile range (IQR) 5.4 to 128.6] IU/L and 32% had anti-HBs <10 IU/L. The median gap time from last to preceding dose was 2.4 [IQR 2.1 to 3.3] months. Levels of anti-HBs decreased with higher age (-42% per year increase [95%CI -56% to -24%], p<0.001), but not with longer gap time (+23% per month increase [95%CI -16% to +62%], p = 0.249). After adjusting for relevant confounders, gap time became significant (p = 0.032) and age remained a significant predictor of anti-HBs (p<0.001). Conclusion One third of assessed children displayed anti-HBs <10 IU/L. Levels of anti-HBs decreased with higher age and increased with longer gap time between the last two doses.

Background Dengue virus can affect the cardiovascular system and men may be at higher risk of severe complications than women. We hypothesized that clinical dengue virus (DENV) infection could induce myocardial alterations of the left ventricle (LV) and that these changes could be detected by transthoracic echocardiography. Methodology/Principal findings We examined individuals from Acre in the Amazon Basin of Brazil in 2020 as part of the Malaria Heart Study. By questionnaires we collected information on self-reported prior dengue infection. All individuals underwent transthoracic echocardiography, analysis of left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS). We included 521 persons (mean age 40±15 years, 39% men, 50% urban areas) of which 253 (49%) had a history of dengue infection. In multivariable models adjusted for clinical and sociodemographic data, a history of self-reported dengue was significantly associated with lower LVEF (β = -2.37, P < 0.01) and lower GLS (β = 1.08, P < 0.01) in men, whereas no significant associations were found in women (P > 0.05). In line with these findings, men with a history of dengue had higher rates of LV systolic dysfunction (LVEF < 50% = 20%; GLS < 16% = 17%) than those without a history of dengue (LVEF < 50% = 7%; GLS < 16% = 8%; P < 0.01 and 0.06, respectively). Conclusions/Significance The findings of this study suggest that a clinical infection by dengue virus could induce myocardial alterations, mainly in men and in the LV, which could be detected by conventional transthoracic echocardiography. Hence, these results highlight a potential role of echocardiography for screening LV dysfunction in participants with a history of dengue infection. Further larger studies are warranted to validate the findings of this study.

ObjectivePrior studies have suggested that self-rated health may be a useful indicator of cardiovascular disease. Consequently, we aimed to assess the relationship between self-rated health, cardiovascular risk factors and subclinical cardiac disease in the Amazon Basin.DesignCross-sectional study.Setting, participants and interventionsIn participants from the Amazon Basin of Brazil we obtained self-rated health according to a Visual Analogue Scale, ranging from 0 (poor) to 100 (excellent). We performed questionnaires, physical examination and echocardiography. Logistic and linear regression models were applied to assess self-rated health, cardiac risk factors and cardiac disease by echocardiography. Multivariable models were mutually adjusted for other cardiovascular risk factors, clinical and socioeconomic data, and known cardiac disease.Outcome measuresCardiovascular risk factors and subclincial cardiac disease by echocardiography.ResultsA total of 574 participants (mean age 41 years, 61% female) provided information on self-rated health (mean 75±21 (IQR 60–90) points). Self-rated health (per 10-point increase) was negatively associated with hypertension (OR 0.87 (95% CI 0.78 to 0.97), p=0.01), hypercholesterolaemia (OR 0.89 (95%CI 0.80 to 0.99), p=0.04) and positively with healthy diet (OR 1.13 (95%CI 1.04 to 1.24), p=0.004). Sex modified these associations (p-interaction <0.05) such that higher self-rated health was associated with healthy diet and physical activity in men, and lower odds of hypertension and hypercholesterolaemia in women. No relationship was found with left ventricular ejection fraction <45% (OR 0.97 (95% CI 0.77 to 1.23), p=0.8), left ventricular hypertrophy (OR 0.97 (95% CI 0.76 to 1.24), p=0.81) or diastolic dysfunction (OR 1.09 (95% CI 0.85 to 1.40), p=0.51).ConclusionSelf-rated health was positively associated with health parameters in the Amazon Basin, but not with subclinical cardiac disease by echocardiography. Our findings are of hypothesis generating nature and future studies should aim to determine whether assessment of self-rated health may be useful for screening related to policy-making or lifestyle interventions.Trial registration numberClinicaltrials.gov: NCT04445103; Post-results