Polygenic risk score for schizophrenia was not associated with glycemic level (HbA1c) in patients with non-affective psychosis:Genetic Risk and Outcome of Psychosis (GROUP) cohort study

Introduction: Type 2 diabetes (T2D) is a common comorbidity in patients with schizophrenia (SCZ). The underlying pathophysiologic mechanisms are yet to be fully elucidated, although it can be argued that shared genes, environmental factors or their interaction effect are involved. This study investigated the association between polygenic risk score of SCZ (PRSSCZ) and glycated haemoglobin (HbA1c) while adjusting for polygenic risk score of T2D (PRST2D), and clinical and demographic covariables. Methods: Genotype, clinical and demographic data of 1129 patients with non-affective psychosis were extracted from Genetic Risk and Outcome of Psychosis (GROUP) cohort study. The glycated haemoglobin (HbA1c) was the outcome. PRS was calculated using standard methods. Univariable and multivariable linear regression analyses were applied to estimate associations. Additionally, sensitivity analysis based on multiple imputation was done. After correction for multiple testing, a two-sided p-value ≤.003 was considered to discover evidence for an association. Results: Of 1129 patients, 75.8% were male with median age of 29 years. The mean (standard deviation) HbA1c level was 35.1 (5.9) mmol/mol. There was no evidence for an association between high HbA1c level and increased PRSSCZ (adjusted regression coefficient (aβ) = 0.69, standard error (SE) = 0.77, p-value =.37). On the other hand, there was evidence for an association between high HbA1c level and increased PRST2D (aβ = 0.93, SE = 0.32, p-value =.004), body mass index (aβ = 0.20, SE = 0.08, p-value =.01), diastolic blood pressure (aβ = 0.08, SE = 0.04, p-value =.03), late age of first psychosis onset (aβ = 0.19, SE = 0.05, p-value =.0004) and male gender (aβ = 1.58, SE = 0.81, p-value =.05). After multiple testing correction, there was evidence for an association between high HbA1c level and late age of first psychosis onset. Evidence for interaction effect between PRSscz and antipsychotics was not observed. The multiple imputation-based sensitivity analysis provided consistent results with complete case analysis. Conclusions: Glycemic dysregulation in patients with SCZ was not associated with PRSSCZ. This suggests that the mechanisms of hyperglycemia or diabetes are at least partly independent from genetic predisposition to SCZ. Our findings show that the change in HbA1c level can be caused by at least in part due to PRST2D, late age of illness onset, male gender, and increased body mass index and diastolic blood pressure

Early or deferred initiation of efavirenz during rifampicin‐based TB therapy has no significant effect on CYP3A induction in TB‐HIV infected patients

Background and Purpose: In TB‐HIV co‐infection, prompt initiation of TB therapy is recommended but anti‐retroviral treatment (ART) is often delayed due to potential drug–drug interactions between rifampicin and efavirenz. In a longitudinal cohort study, we evaluated the effects of efavirenz/rifampicin co‐treatment and time of ART initiation on CYP3A induction. / Experimental Approach: Treatment‐naïve TB‐HIV co‐infected patients (n = 102) were randomized to efavirenz‐based‐ART after 4 (n = 69) or 8 weeks (n = 33) of commencing rifampicin‐based anti‐TB therapy. HIV patients without TB (n = 94) receiving efavirenz‐based‐ART only were enrolled as control. Plasma 4β‐hydroxycholesterol/cholesterol (4β‐OHC/Chol) ratio, an endogenous biomarker for CYP3A activity, was determined at baseline, at 4 and 16 weeks of ART. / Key Results: In patients treated with efavirenz only, median 4β‐OHC/Chol ratios increased from baseline by 269% and 275% after 4 and 16 weeks of ART, respectively. In TB‐HIV patients, rifampicin only therapy for 4 and 8 weeks increased median 4β‐OHC/Chol ratios from baseline by 378% and 576% respectively. After efavirenz/rifampicin co‐treatment, 4β‐OHC/Chol ratios increased by 560% of baseline (4 weeks) and 456% of baseline (16 weeks). Neither time of ART initiation, sex, genotype nor efavirenz plasma concentration were significant predictors of 4β‐OHC/Chol ratios after 4 weeks of efavirenz/rifampicin co‐treatment. / Conclusion and Implications: Rifampicin induced CYP3A more potently than efavirenz, with maximum induction occurring within the first 4 weeks of rifampicin therapy. We provide pharmacological evidence that early (4 weeks) or deferred (8 weeks) ART initiation during anti‐TB therapy has no significant effect on CYP3A induction

A systematic review and narrative synthesis of data-driven studies in schizophrenia symptoms and cognitive deficits

To tackle the phenotypic heterogeneity of schizophrenia, data-driven methods are often applied to identify subtypes of its symptoms and cognitive deficits. However, a systematic review on this topic is lacking. The objective of this review was to summarize the evidence obtained from longitudinal and cross-sectional data-driven studies in positive and negative symptoms and cognitive deficits in patients with schizophrenia spectrum disorders, their unaffected siblings and healthy controls or individuals from general population. Additionally, we aimed to highlight methodological gaps across studies and point out future directions to optimize the translatability of evidence from data-driven studies. A systematic review was performed through searching PsycINFO, PubMed, PsycTESTS, PsycARTICLES, SCOPUS, EMBASE and Web of Science electronic databases. Both longitudinal and cross-sectional studies published from 2008 to 2019, which reported at least two statistically derived clusters or trajectories were included. Two reviewers independently screened and extracted the data. In this review, 53 studies (19 longitudinal and 34 cross-sectional) that conducted among 17,822 patients, 8729 unaffected siblings and 5520 controls or general population were included. Most longitudinal studies found four trajectories that characterized by stability, progressive deterioration, relapsing and progressive amelioration of symptoms and cognitive function. Cross-sectional studies commonly identified three clusters with low, intermediate (mixed) and high psychotic symptoms and cognitive profiles. Moreover, identified subgroups were predicted by numerous genetic, sociodemographic and clinical factors. Our findings indicate that schizophrenia symptoms and cognitive deficits are heterogeneous, although methodological limitations across studies are observed. Identified clusters and trajectories along with their predictors may be used to base the implementation of personalized treatment and develop a risk prediction model for high-risk individuals with prodromal symptoms

Importance of Ethnicity, CYP2B6 and ABCB1 Genotype for Efavirenz Pharmacokinetics and Treatment Outcomes: A Parallel-group Prospective Cohort Study in two sub-Saharan Africa Populations.

We evaluated the importance of ethnicity and pharmacogenetic variations in determining efavirenz pharmacokinetics, auto-induction and immunological outcomes in two African populations. ART naïve HIV patients from Ethiopia (n = 285) and Tanzania (n = 209) were prospectively enrolled in parallel to start efavirenz based HAART. CD4+ cell counts were determined at baseline, 12, 24 and 48 weeks. Plasma and intracellular efavirenz and 8-hydroxyefvairenz concentrations were determined at week 4 and 16. Genotyping for common functional CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 variant alleles were done. Patient country, CYP2B6*6 and ABCB1 c.4036A>G (rs3842A>G) genotype were significant predictors of plasma and intracellular efavirenz concentration. CYP2B6*6 and ABCB1 c.4036A>G (rs3842) genotype were significantly associated with higher plasma efavirenz concentration and their allele frequencies were significantly higher in Tanzanians than Ethiopians. Tanzanians displayed significantly higher efavirenz plasma concentration at week 4 (p<0.0002) and week 16 (p = 0.006) compared to Ethiopians. Efavirenz plasma concentrations remained significantly higher in Tanzanians even after controlling for the effect of CYP2B6*6 and ABCB1 c.4036A>G genotype. Within country analyses indicated a significant decrease in the mean plasma efavirenz concentration by week 16 compared to week 4 in Tanzanians (p = 0.006), whereas no significant differences in plasma concentration over time was observed in Ethiopians (p = 0.84). Intracellular efavirenz concentration and patient country were significant predictors of CD4 gain during HAART. We report substantial differences in efavirenz pharmacokinetics, extent of auto-induction and immunologic recovery between Ethiopian and Tanzanian HIV patients, partly but not solely, due to pharmacogenetic variations. The observed inter-ethnic variations in efavirenz plasma exposure may possibly result in varying clinical treatment outcome or adverse event profiles between populations

The fitness of African malaria vectors in the presence and limitation of host behaviour

&lt;p&gt;Background Host responses are important sources of selection upon the host species range of ectoparasites and phytophagous insects. However little is known about the role of host responses in defining the host species range of malaria vectors. This study aimed to estimate the relative importance of host behaviour to the feeding success and fitness of African malaria vectors, and assess its ability to predict their known host species preferences in nature.&lt;/p&gt; &lt;p&gt;Methods Paired evaluations of the feeding success and fitness of African vectors Anopheles arabiensis and Anopheles gambiae s.s in the presence and limitation of host behaviour were conducted in a semi-field system (SFS) at Ifakara Health Institute, Tanzania. In one set of trials, mosquitoes were released within the SFS and allowed to forage overnight on a host that was free to exhibit natural behaviour in response to insect biting. In the other, mosquitoes were allowed to feed directly on from the skin surface of immobile hosts. The feeding success and subsequent fitness of vectors under these conditions were investigated on 6 host types (humans, calves, chickens, cows, dogs and goats) to assess whether physical movements of preferred host species (cattle for An. arabiensis, humans for An. gambiae s.s.) were less effective at preventing mosquito bites than those of common alternatives.&lt;/p&gt; &lt;p&gt;Results Anopheles arabiensis generally had greater feeding success when applied directly to host skin than when foraging on unrestricted hosts (in five of six host species). However, An. gambiae s.s obtained blood meals from free and restrained hosts with similar success from most host types (four out of six). Overall, the blood meal size, oviposition rate, fecundity and post-feeding survival of mosquito vectors were significantly higher after feeding on hosts free to exhibit behaviour, than those who were immobilized during feeding trials.&lt;/p&gt; &lt;p&gt;Conclusions Allowing hosts to move freely during exposure to mosquitoes was associated with moderate reductions in mosquito feeding success, but no detrimental impact to the subsequent fitness of mosquitoes that were able to feed upon them. This suggests that physical defensive behaviours exhibited by common host species including humans do not impose substantial fitness costs on African malaria vectors.&lt;/p&gt

A chromosomal reference genome sequence for the malaria mosquito Anopheles gambiae, Giles, 1902, Ifakara strain

We present a genome assembly from an individual female Anopheles gambiae (the malaria mosquito; Arthropoda; Insecta; Diptera; Culicidae), Ifakara strain. The genome sequence is 264 megabases in span. Most of the assembly is scaffolded into three chromosomal pseudomolecules with the X sex chromosome assembled. The complete mitochondrial genome was also assembled and is 15.4 kilobases in length

Polygenic risk score for schizophrenia was not associated with glycemic level (HbA1c) in patients with non-affective psychosis: Genetic Risk and Outcome of Psychosis (GROUP) cohort study

Introduction: Type 2 diabetes (T2D) is a common comorbidity in patients with schizophrenia (SCZ). The underlying pathophysiologic mechanisms are yet to be fully elucidated, although it can be argued that shared genes, environmental factors or their interaction effect are involved. This study investigated the association between polygenic risk score of SCZ (PRSSCZ) and glycated haemoglobin (HbA1c) while adjusting for polygenic risk score of T2D (PRST2D), and clinical and demographic covariables. Methods: Genotype, clinical and demographic data of 1129 patients with non-affective psychosis were extracted from Genetic Risk and Outcome of Psychosis (GROUP) cohort study. The glycated haemoglobin (HbA1c) was the outcome. PRS was calculated using standard methods. Univariable and multivariable linear regression analyses were applied to estimate associations. Additionally, sensitivity analysis based on multiple imputation was done. After correction for multiple testing, a two-sided p-value ≤.003 was considered to discover evidence for an association. Results: Of 1129 patients, 75.8% were male with median age of 29 years. The mean (standard deviation) HbA1c level was 35.1 (5.9) mmol/mol. There was no evidence for an association between high HbA1c level and increased PRSSCZ (adjusted regression coefficient (aβ) = 0.69, standard error (SE) = 0.77, p-value =.37). On the other hand, there was evidence for an association between high HbA1c level and increased PRST2D (aβ = 0.93, SE = 0.32, p-value =.004), body mass index (aβ = 0.20, SE = 0.08, p-value =.01), diastolic blood pressure (aβ = 0.08, SE = 0.04, p-value =.03), late age of first psychosis onset (aβ = 0.19, SE = 0.05, p-value =.0004) and male gender (aβ = 1.58, SE = 0.81, p-value =.05). After multiple testing correction, there was evidence for an association between high HbA1c level and late age of first psychosis onset. Evidence for interaction effect between PRSscz and antipsychotics was not observed. The multiple imputation-based sensitivity analysis provided consistent results with complete case analysis. Conclusions: Glycemic dysregulation in patients with SCZ was not associated with PRSSCZ. This suggests that the mechanisms of hyperglycemia or diabetes are at least partly independent from genetic predisposition to SCZ. Our findings show that the change in HbA1c level can be caused by at least in part due to PRST2D, late age of illness onset, male gender, and increased body mass index and diastolic blood pressure

Restricted Application of Insecticides: A Promising Tsetse Control Technique, but What Do the Farmers Think of It?

Restricted application of insecticides to cattle is a cheap and safe farmer-based method to control tsetse and the diseases they transmit, i.e. human and animal African trypanosomoses. The efficiency of this new control method has been demonstrated earlier but no data is available on its perception and adoption intensity by farmers. We studied these two features in Burkina Faso, where the method has diffused thanks to two development projects. The study allowed identifying three groups of farmers with various adoption intensities, of which one was modern and two traditional. The economic benefit and the farmers' knowledge of the epidemiological system appeared to have a low impact on the early adoption process whereas some modern practices, as well as social factors appeared critical. The quality of technical support provided to the farmers had also a great influence on the adoption rate. The study highlighted individual variations in risk perceptions and benefits, as well as the prominent role of the socio-technical network of cattle farmers. The results of the study are discussed to highlight the factors that should be taken into consideration, to move discoveries from bench to field for an improved control of trypanosomoses vectors