Relationship between lta4h promotor polymorphism and tuberculosis-associated immune reconstitution inflammatory syndrome and its prevention with prednisone

The development of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) and its prevention using prednisone may potentially be mediated by the LTA4H genotype. We assessed this hypothesis in a clinical trial evaluating prednisone to prevent TB-IRIS. We did not find an association between LTA4H genotype and TB-IRIS incidence or prednisone efficacy

Using biomarkers to predict TB treatment duration (Predict TB): a prospective, randomized, noninferiority, treatment shortening clinical trial

Background : By the early 1980s, tuberculosis treatment was shortened from 24 to 6 months, maintaining relapse rates of 1-2%. Subsequent trials attempting shorter durations have failed, with 4-month arms consistently having relapse rates of 15-20%. One trial shortened treatment only among those without baseline cavity on chest x-ray and whose month 2 sputum culture converted to negative. The 4-month arm relapse rate decreased to 7% but was still significantly worse than the 6-month arm (1.6%, P<0.01).  We hypothesize that PET/CT characteristics at baseline, PET/CT changes at one month, and markers of residual bacterial load will identify patients with tuberculosis who can be cured with 4 months (16 weeks) of standard treatment.Methods: This is a prospective, multicenter, randomized, phase 2b, noninferiority clinical trial of pulmonary tuberculosis participants. Those eligible start standard of care treatment. PET/CT scans are done at weeks 0, 4, and 16 or 24. Participants who do not meet early treatment completion criteria (baseline radiologic severity, radiologic response at one month, and GeneXpert-detectable bacilli at four months) are placed in Arm A (24 weeks of standard therapy). Those who meet the early treatment completion criteria are randomized at week 16 to continue treatment to week 24 (Arm B) or complete treatment at week 16 (Arm C). The primary endpoint compares the treatment success rate at 18 months between Arms B and C.Discussion: Multiple biomarkers have been assessed to predict TB treatment outcomes. This study uses PET/CT scans and GeneXpert (Xpert) cycle threshold to risk stratify participants. PET/CT scans are not applicable to global public health but could be used in clinical trials to stratify participants and possibly become a surrogate endpoint. If the Predict TB trial is successful, other immunological biomarkers or transcriptional signatures that correlate with treatment outcome may be identified. TRIAL REGISTRATION: NCT02821832

Lower levels of high-density lipoprotein cholesterol in urban Africans presenting with communicable versus non-communicable forms of heart disease: the 'Heart of Soweto' hospital registry study

Objectives: To investigate if urban Africans displayed lower levels of atheroprotective high-density lipoprotein cholesterol (HDLC) when presenting with communicable versus non-communicable forms of heart disease (HD) as both acute infection and chronic inflammation reduce HDLC levels. Design: Hospital registry of 5328 de novo cases of HD over a 3-year period. Setting: Cardiology Unit, Baragwanath Hospital in Soweto, South Africa. Participants: A total of 1199 patients of African descent (59% women; 57.0±13.4 years) had fasting blood lipid levels (total cholesterol (TC), triglyceride, HDLC and low-density lipoprotein cholesterol (LDLC)) documented on admission. Serum inflammatory marker C reactive protein (CRP) was measured in a subset of 367 patients (31% of cases). Main Outcome Measures: Lipid profiles were compared according to prespecified classification of non-communicable (eg, hypertensive HD) versus communicable (eg, rheumatic HD) HD. Low HDLC was defined as <1.0 mmol/L for men and <1.2 mmol/L for women, according to applicable South African Clinical Guidelines. Results: Overall 694 (58%) of those presenting with HD had low HDLC levels; 344 of 678 (51%) and 350 of 521 (67%) for non-communicable and communicable, respectively (p<0.001). Comparatively, overall prevalence of high TC was 32% and high LDLC was 37%. On an adjusted basis, those with non-communicable HD were more likely to record a low HDLC relative to non-communicable presentations (odds ratio (OR) 1.91, 95% CI 1.42 to 2.57; p<0.001). There was a strong relationship between low HDLC and higher levels of CRP, but only in women. Conclusions: Despite largely favourable lipid profiles, there are clear differences according to aetiology of underlying HD in urban Africans, with younger patients with communicable HD having particularly low levels of HDLC. Appropriate prospective evidence is needed to determine if persistent low levels of HDLC expose patients to increased, long-term risk of atherosclerotic forms of HD. The women-only inverse association between HDLC and CRP warrants further investigation.Jasmine G Lyons, Karen Sliwa, Melinda J Carrington, Frederick Raal, Sandra Pretorius, Friedrich Thienemann, Simon Stewar

Aquatic community response to volcanic eruptions on the Ecuadorian Andean flank: evidence from the palaeoecological record

Aquatic ecosystems in the tropical Andes are under increasing pressure from human modification of the landscape (deforestation and dams) and climatic change (increase of extreme events and 1.5 °C on average temperatures are projected for AD 2100). However, the resilience of these ecosystems to perturbations is poorly understood. Here we use a multi-proxy palaeoecological approach to assess the response of aquatic ecosystems to a major mechanism for natural disturbance, volcanic ash deposition. Specifically, we present data from two Neotropical lakes located on the eastern Andean flank of Ecuador. Laguna Pindo (1°27.132′S–78°04.847′W) is a tectonically formed closed basin surrounded by a dense mid-elevation forest, whereas Laguna Baños (0°19.328′S–78°09.175′W) is a glacially formed lake with an inflow and outflow in high Andean Páramo grasslands. In each lake we examined the dynamics of chironomids and other aquatic and semi-aquatic organisms to explore the effect of thick (> 5 cm) volcanic deposits on the aquatic communities in these two systems with different catchment features. In both lakes past volcanic ash deposition was evident from four large tephras dated to c.850 cal year BP (Pindo), and 4600, 3600 and 1500 cal year BP (Baños). Examination of the chironomid and aquatic assemblages before and after the ash depositions revealed no shift in composition at Pindo, but a major change at Baños occurred after the last event around 1500 cal year BP. Chironomids at Baños changed from an assemblage dominated by Pseudochironomus and Polypedilum nubifer-type to Cricotopus/Paratrichocladius type-II, and such a dominance lasted for approximately 380 years. We suggest that, despite potential changes in the water chemistry, the major effect on the chironomid community resulted from the thickness of the tephra being deposited, which acted to shallow the water body beyond a depth threshold. Changes in the aquatic flora and fauna at the base of the trophic chain can promote cascade effects that may deteriorate the ecosystem, especially when already influenced by human activities, such as deforestation and dams, which is frequent in the high Andes

Final analysis of a trial of M72/AS01E vaccine to prevent tuberculosis

Background Results of an earlier analysis of a trial of the M72/AS01E candidate vaccine against Mycobacterium tuberculosis showed that in infected adults, the vaccine provided 54.0% protection against active pulmonary tuberculosis disease, without evident safety concerns. We now report the results of the 3-year final analysis of efficacy, safety, and immunogenicity. Methods From August 2014 through November 2015, we enrolled adults 18 to 50 years of age with M. tuberculosis infection (defined by positive results on interferon-γ release assay) without evidence of active tuberculosis disease at centers in Kenya, South Africa, and Zambia. Participants were randomly assigned in a 1:1 ratio to receive two doses of either M72/AS01E or placebo, administered 1 month apart. The primary objective was to evaluate the efficacy of M72/AS01E to prevent active pulmonary tuberculosis disease according to the first case definition (bacteriologically confirmed pulmonary tuberculosis not associated with human immunodeficiency virus infection). Participants were followed for 3 years after the second dose. Participants with clinical suspicion of tuberculosis provided sputum samples for polymerase-chain-reaction assay, mycobacterial culture, or both. Humoral and cell-mediated immune responses were evaluated until month 36 in a subgroup of 300 participants. Safety was assessed in all participants who received at least one dose of M72/AS01E or placebo. Results A total of 3575 participants underwent randomization, of whom 3573 received at least one dose of M72/AS01E or placebo, and 3330 received both planned doses. Among the 3289 participants in the according-to-protocol efficacy cohort, 13 of the 1626 participants in the M72/AS01E group, as compared with 26 of the 1663 participants in the placebo group, had cases of tuberculosis that met the first case definition (incidence, 0.3 vs. 0.6 cases per 100 person-years). The vaccine efficacy at month 36 was 49.7% (90% confidence interval [CI], 12.1 to 71.2; 95% CI, 2.1 to 74.2). Among participants in the M72/AS01E group, the concentrations of M72-specific antibodies and the frequencies of M72-specific CD4+ T cells increased after the first dose and were sustained throughout the follow-up period. Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two groups. Conclusions Among adults infected with M. tuberculosis, vaccination with M72/AS01E elicited an immune response and provided protection against progression to pulmonary tuberculosis disease for at least 3 years. (Funded by GlaxoSmithKline Biologicals and Aeras; ClinicalTrials.gov number, NCT01755598. opens in new tab.

Electrocardiographic findings and prognostic values in patients hospitalised with COVID-19 in the World Heart Federation Global Study

BACKGROUND COVID-19 affects the cardiovascular system and ECG abnormalities may be associated with worse prognosis. We evaluated the prognostic value of ECG abnormalities in individuals with COVID-19. METHODS Multicentre cohort study with adults hospitalised with COVID-19 from 40 hospitals across 23 countries. Patients were followed-up from admission until 30 days. ECG were obtained at each participating site and coded according to the Minnesota coding criteria. The primary outcome was defined as death from any cause. Secondary outcomes were admission to the intensive care unit (ICU) and major adverse cardiovascular events (MACE). Multiple logistic regression was used to evaluate the association of ECG abnormalities with the outcomes. RESULTS Among 5313 participants, 2451 had at least one ECG and were included in this analysis. The mean age (SD) was 58.0 (16.1) years, 60.7% were male and 61.1% from lower-income to middle-income countries. The prevalence of major ECG abnormalities was 21.3% (n=521), 447 (18.2%) patients died, 196 (8.0%) had MACE and 1115 (45.5%) were admitted to an ICU. After adjustment, the presence of any major ECG abnormality was associated with a higher risk of death (OR 1.39; 95% CI 1.09 to 1.78) and cardiovascular events (OR 1.81; 95% CI 1.30 to 2.51). Sinus tachycardia (>120 bpm) with an increased risk of death (OR 3.86; 95% CI 1.97 to 7.48), MACE (OR 2.68; 95% CI 1.10 to 5.85) and ICU admission OR 1.99; 95% CI 1.03 to 4.00). Atrial fibrillation, bundle branch block, ischaemic abnormalities and prolonged QT interval did not relate to the outcomes. CONCLUSION Major ECG abnormalities and a heart rate >120 bpm were prognostic markers in adults hospitalised with COVID-19

Porewater methane transport within the gas vesicles of diurnally migrating Chaoborus spp.: An energetic advantage

We show that diurnally migrating Chaoborus sp. (phantom midge larvae), which can be highly abundant in eutrophic lakes with anoxic bottom, utilises sediment methane to inflate their tracheal sacs, which provides positive buoyancy to aid vertical migration. This process also effectively transports sediment methane bypassing oxidation to the upper water column, adding to the total methane outflux to the atmosphere

Gender disparities in pulmonary hypertension at a tertiary centre in Cameroon

Background. Pulmonary hypertension (PH) is a potent cause of heart failure and has been little investigated in the African setting.Objective. To investigate the effects of gender on the clinical presentation, echocardiographic features and outcomes of patients with PH in Douala, Cameroon.Methods. A prospective cohort study was conducted from March 2012 to December 2013 as part of the Pan African Pulmonary Hypertension Cohort study. PH was diagnosed by echocardiography and defined as a right ventricular systolic pressure &gt;35 mmHg in the absence of acute right heart failure. Patients were followed up for a maximum of 12 months for primary endpoint mortality.Results. In total, 130 patients with PH were recruited; 71 (54.6%) were women. The median age was 59.2 years for men and 58.3 years for women (p=0.76). Active smoking and alcohol use were more frequent in men than women (both p&lt;0.001), but women had greater exposure to indoor cooking fumes than men (p&lt;0.001). Previous tuberculosis infection (11.3% v. 1.7%) and S3 gallop rhythm (30.9% v. 11.9%) were more common in women (both p&lt;0.03). Women had a significantly higher mean systolic blood pressure (134 mmHg v. 125 mmHg; p=0.04) and pulse pressure (53.8 mmHg v. 44.9 mmHg; p=0.01) and a lower mean haemoglobin concentration (10.4 g/dL v. 12.4 g/dL; p&lt;0.05) compared with men. Echocardiographic left ventricular (LV) systolic dysfunction was more frequent in men: mean LV ejection fraction 42.6% v. 51.5% (p=0.01) and mean fractional shortening 21.4% v. 28.6% (p=0.01). The overall mortality rate was 20.3%, and rates were similar in the two groups (Kaplan-Meier log rank 1.1; p=0.30).Conclusions. Despite differences in baseline characteristics including cardiovascular risk factors, mortality rates on follow-up were similar in men and women in this study. However, these different baseline characteristics probably suggest differences in the pathogenesis of PH in men and women in our setting that need further investigation.

Activation During Observed Parent–Child Interactions with Anxious Youths: A Pilot Study

Parent–child interaction paradigms are often used to observe dysfunctional family processes; however, the influence of such tasks on a participant’s level of activation remain unclear. The aim of this pilot project is to explore the stimulus value of interaction paradigms that have been commonly used in child anxiety research. Twenty-nine parent–child dyads with clinically anxious (n = 16) and non-anxious (n = 13) youths engaged in a series of tasks (threat and non-threat) used in previous studies of parenting and youth anxiety. Heart rate (HR) data, as an indicator of physiological activation, were collected across tasks, and participants rated the perceived representativeness of their interactions in the laboratory to their usual behavior at home. Significant HR changes were observed for both parent and child. Change in child HR from baseline to non-threat task was smaller than change in HR from baseline to threat tasks. Change in parent HR from baseline to ambiguous situations tasks was smaller than changes from baseline to other threat tasks. Differences in HR change between anxious and non-anxious children were explored. Participants rated laboratory interactions as similar to those experienced in the home. Results suggest that presumably emotionally-charged discussion tasks may produce increased activation compared to tasks that were designed to be more neutral. Implications for future research and limitations are discussed