Incidence and risk factors of serious adverse events during antituberculous treatment in Rwanda: a prospective cohort study

Background

Tuberculosis (TB) and TB-human immunodeficiency virus infection (HIV) coinfection is a major public health concern in resource-limited settings. Although TB treatment is challenging in HIV-infected patients because of treatment interactions, immunopathological reactions, and concurrent infections, few prospective studies have addressed this in sub-Saharan Africa.In this study we aimed to determine incidence, causes of, and risk factors for serious adverse events among patients on first-line antituberculous treatment, as well as its impact on antituberculous treatment outcome.

Methods and findings

Prospective observational cohort study of adults treated for TB at the Internal Medicine department of the Kigali University Hospital from May 2008 through August 2009.Of 263 patients enrolled, 253 were retained for analysis: median age 35 (Interquartile range, IQR 28–40), 55% male, 66% HIV-positive with a median CD4 count 104 cells/mm³ (IQR 44–248 cells/mm³). Forty percent had pulmonary TB, 43% extrapulmonary TB and 17% a mixed form. Sixty-four (26%) developed a serious adverse event; 58/167 (35%) HIV-infected vs. 6/86 (7%) HIV-uninfected individuals. Commonest events were concurrent infection (n = 32), drug-induced hepatitis (n = 24) and paradoxical reactions/TB-IRIS (n = 23).HIV-infection (adjusted Hazard Ratio, aHR 3.4, 95% Confidence Interval, CI 1.4–8.7) and extrapulmonary TB (aHR 2, 95%CI 1.1–3.7) were associated with an increased risk of serious adverse events. For TB/HIV co-infected patients, extrapulmonary TB (aHR 2.0, 95%CI 1.1–3.9) and CD4 count <100 cells/mm3 at TB diagnosis (aHR 1.7, 95%CI 1.0–2.9) were independent predictors. Adverse events were associated with an almost two-fold higher risk of unsuccessful treatment outcome at 6 months (HR 1.89, 95%CI 1.3–3.0).

Conclusion

Adverse events frequently complicate the course of antituberculous treatment and worsen treatment outcome, particularly in patients with extrapulmonary TB and advanced immunodeficiency. Concurrent infection accounts for most events. Our data suggest that deterioration in a patient already receiving antituberculous treatment should prompt an aggressive search for additional infections.     

High-content assays for evaluating cellular and hepatic diacylglycerol acyltransferase activity

Acyl-CoA:diacylglycerol acyltransferase (DGAT) catalyzes the terminal step in triglyceride (TG) synthesis using diacylglycerol (DAG) and fatty acyl-CoA as substrates. In the liver, the production of VLDL permits the delivery of hydrophobic TG from the liver to peripheral tissues for energy metabolism. We describe here a novel high-content, high-throughput LC/MS/MS-based cellular assay for determining DGAT activity. We treated endogenous DGAT-expressing cells with stable isotope-labeled [¹³C₁₈]oleic acid. The [¹³C₁₈]oleoyl-incorporated TG and DAG lipid species were profiled. The TG synthesis pathway assay was optimized to a one-step extraction, followed by LC/MS/MS quantification. Further, we report a novel LC/MS/MS method for tracing hepatic TG synthesis and VLDL-TG secretion in vivo by administering [¹³C₁₈]oleic acid to rats. The [¹³C₁₈]oleic acid-incorporated VLDL-TG was detected after one-step extraction without conventional separation of TG and recovery by derivatizing [¹³C₁₈]oleic acid for detection. Using potent and selective DGAT1 inhibitors as pharmacological tools, we measured changes in [¹³C₁₈]oleoyl-incorporated TG and DAG and demonstrated that DGAT1 inhibition significantly reduced [¹³C₁₈]oleoyl-incorporated VLDL-TG. This DGAT1-selective assay will enable researchers to discern differences between the roles of DGAT1 and DGAT2 in TG synthesis in vitro and in vivo.     

Elasticity–density and viscoelasticity–density relationships at the tibia mid-diaphysis assessed from resonant ultrasound spectroscopy measurements

Cortical bone tissue is an anisotropic material characterized by typically five independent elastic coefficients (for transverse isotropy) governing shear and longitudinal deformations in the different anatomical directions. It is well established that the Young’s modulus in the direction of the bone axis of long bones has a strong relationship with mass density. It is not clear, however, whether relationships of similar strength exist for the other elastic coefficients, for they have seldom been investigated, and the results available in the literature are contradictory. The objectives of the present work were to document the anisotropic elastic properties of cortical bone at the tibia mid-diaphysis and to elucidate their relationships with mass density. Resonant ultrasound spectroscopy (RUS) was used to measure the transverse isotropic stiffness tensor of 55 specimens from 19 donors. Except for Poisson’s ratios and the non-diagonal stiffness coefficient, strong linear correlations between the different elastic coefficients \((0.7 < {r^{2}} < 0.99)\) and between these coefficients and density \((0.79 < {r^{2}} < 0.89)\) were found. Comparison with previously published data from femur specimens suggested that the strong correlations evidenced in this study may not only be valid for the mid-tibia. RUS also measures the viscous part of the stiffness tensor. An anisotropy ratio close to two was found for damping coefficients. Damping increased as the mass density decreased. The data suggest that a relatively accurate estimation of all the mid-tibia elastic coefficients can be derived from mass density. This is of particular interest (1) to design organ-scale bone models in which elastic coefficients are mapped according to Hounsfield values from computed tomography scans as a surrogate for mass density and (2) to model ultrasound propagation at the mid-tibia, which is an important site for the in vivo assessment of bone status with axial transmission techniques.     

“Pandemic Public Health Paradox”: Time Series Analysis of the 2009/10 Influenza A / H1N1 Epidemiology,Media Attention,Risk Perception and Public Reactions in 5 European Countries

In 2009, influenza A H₁N₁ caused the first pandemic of the 21^st century. Although a vaccine against this influenza subtype was offered before or at the onset of the second epidemic wave that caused most of the fatal cases in Europe, vaccination rates for that season were lower than expected. We propose that the contradiction between high risk of infection and low use of available prevention measures represents a pandemic public health paradox. This research aims for a better understanding of this paradox by exploring the time-dependent interplay among changing influenza epidemiology, media attention, pandemic control measures, risk perception and public health behavior among five European countries (Czech Republic, Denmark, Germany, Spain and the UK). Findings suggest that asynchronicity between media curves and epidemiological curves may potentially explain the pandemic public health paradox; media attention for influenza A H₁N₁ in Europe declined long before the epidemic reached its peak, and public risk perceptions and behaviors may have followed media logic, rather than epidemiological logic.     

Measuring endemicity and burden of leprosy across countries and regions: A systematic review and Delphi survey

BackgroundLeprosy is a chronic infectious disease caused by Mycobacterium leprae, the annual new case detection in 2019 was 202,189 globally. Measuring endemicity levels and burden in leprosy lacks a uniform approach. As a result, the assessment of leprosy endemicity or burden are not comparable over time and across countries and regions. This can make program planning and evaluation difficult. This study aims to identify relevant metrics and methods for measuring and classifying leprosy endemicity and burden at (sub)national level.MethodsWe used a mixed-method approach combining findings from a systematic literature review and a Delphi survey. The literature search was conducted in seven databases, searching for endemicity, burden and leprosy. We reviewed the available evidence on the usage of indicators, classification levels, and scoring methods to measure and classify endemicity and burden. A two round Delphi survey was conducted to ask experts to rank and weigh indicators, classification levels, and scoring methods.ResultsThe literature review showed variation of indicators, levels, and cut-off values to measure leprosy endemicity and/or burden. The most used indicators for endemicity include new case detection rate (NCDR), new cases among children and new cases with grade 2 disability. For burden these include NCDR, MB cases, and prevalence. The classification levels ‘high’ and ‘low’ were most important. It was considered most relevant to use separate scoring methods for endemicity and burden. The scores would be derived by use of multiple indicators.ConclusionThere is great variation in the existing method for measuring endemicity and burden across countries and regions. Our findings contribute to establishing a standardized uniform approach to measure and classify leprosy endemicity and burden at (sub)national level, which would allow effective communication and planning of intervention strategies.     

GPR30 does not mediate estrogenic responses in reproductive organs in mice

The G protein-coupled receptor Gpr30 (Gper) was recently claimed to bind to estradiol and to activate cytoplasmic signal transduction pathways in response to estradiol. However, there are conflicting data regarding the role of Gpr30 as an estrogen receptor (ER): several laboratories were unable to demonstrate estradiol binding to GPR30 or estradiol-activated signal transduction in Gpr30-expressing cells. To clarify the potential role of Gpr30 as an ER, we generated Gpr30-deficient mice. Although Gpr30 was expressed in all reproductive organs, histopathological analysis did not reveal any abnormalities in these organs in Gpr30-deficient mice. Mutant male and female mice were as fertile as their wild-type littermates, indicating normal function of the hypothalamic-pituitary-gonadal axis. Moreover, we analyzed estrogenic responses in two major estradiol target organs, the uterus and the mammary gland. For that purpose, we examined different readout paradigms such as morphological measures, cellular proliferation, and target gene expression. Our data demonstrate that in vivo Gpr30 is dispensable for the mediation of estradiol effects in reproductive organs. These results are in clear contrast to the phenotype of mice lacking the classic ER alpha (Esr1) or aromatase (Cyp19a1). We conclude that the perception of Gpr30 (based on homology related to peptide receptors) as an ER might be premature and has to be reconsidered.     

The genus Nelcyndana Stål (Hemiptera, Cicadidae, Taphurini) with description of three new species from Borneo

The type species of Nelcyndana, Nelcyndana tener (Stål, 1870) from the Philippines, is redescribed and illustrated. The taxonomic position of the genus Nelcyndana in the tribe Taphurini is discussed. Three new species from Borneo are described and illustrated: Nelcyndana borneensis sp. n., Nelcyndana vantoli sp. n., and Nelcyndana mulu sp. n. Distributions maps for the three Borneo species are presented and a key for the identification of the four Asian species of the genus is provided.     

Lack of peripheral memory B cell responses in recovered patients with severe acute respiratory syndrome: a six-year follow-up study

Six years have passed since the outbreak of severe acute respiratory syndrome (SARS). Previous studies indicated that specific Abs to SARS-related coronavirus (SARS-CoV) waned over time in recovered SARS patients. It is critical to find out whether a potential anamnestic response, as seen with other viral infections, exists to protect a person from reinfection in case of another SARS outbreak. Recovered SARS patients were followed up to 6 y to estimate the longevity of specific Ab. The specific memory B cell and T cell responses to SARS-CoV Ags were measured by means of ELISPOT assay. Factors in relation to humoral and cellular immunity were investigated. Six years postinfection, specific IgG Ab to SARS-CoV became undetectable in 21 of the 23 former patients. No SARS-CoV Ag-specific memory B cell response was detected in either 23 former SARS patients or 22 close contacts of SARS patients. Memory T cell responses to a pool of SARS-CoV S peptides were identified in 14 of 23 (60.9%) recovered SARS patients, whereas there was no such specific response in either close contacts or healthy controls. Patients with more severe clinical manifestations seemed to present a higher level of Ag-specific memory T cell response. SARS-specific IgG Ab may eventually vanish and peripheral memory B cell responses are undetectable in recovered SARS patients. In contrast, specific T cell anamnestic responses can be maintained for at least 6 y. These findings have applications in preparation for the possible reemergence of SARS.     

Genetically engineered maize plants reveal distinct costs and benefits of constitutive volatile emissions in the field

Genetic manipulation of plant volatile emissions is a promising tool to enhance plant defences against herbivores. However, the potential costs associated with the manipulation of specific volatile synthase genes are unknown. Therefore, we investigated the physiological and ecological effects of transforming a maize line with a terpene synthase gene in field and laboratory assays, both above‐ and below ground. The transformation, which resulted in the constitutive emission of (E)‐β‐caryophyllene and α‐humulene, was found to compromise seed germination, plant growth and yield. These physiological costs provide a possible explanation for the inducibility of an (E)‐β‐caryophyllene‐synthase gene in wild and cultivated maize. The overexpression of the terpene synthase gene did not impair plant resistance nor volatile emission. However, constitutive terpenoid emission increased plant apparency to herbivores, including adults and larvae of the above ground pest Spodoptera frugiperda, resulting in an increase in leaf damage. Although terpenoid overproducing lines were also attractive to the specialist root herbivore Diabrotica virgifera virgifera below ground, they did not suffer more root damage in the field, possibly because of the enhanced attraction of entomopathogenic nematodes. Furthermore, fewer adults of the root herbivore Diabrotica undecimpunctata howardii were found to emerge near plants that emitted (E)‐β‐caryophyllene and α‐humulene. Yet, overall, under the given field conditions, the costs of constitutive volatile production overshadowed its benefits. This study highlights the need for a thorough assessment of the physiological and ecological consequences of genetically engineering plant signals in the field to determine the potential of this approach for sustainable pest management strategies.