Trimethoprim+Sulfamethoxazole Reduces Rates of Melioidosis in High-Risk Hemodialysis Patients

Introduction Melioidosis causes sepsis and death in the Top End of Northern Australia during the monsoonal wet season. Dialysis-dependent adults suffer higher melioidosis rates compared to low rates among renal transplant patients who routinely receive trimethoprim+sulfamethoxazole prophylaxis. Methods We performed a prospective interventional study to determine the efficacy and safety of daily trimethoprim+sulfamethoxazole prophylaxis in hemodialysis patients during the wet season, from 1 November 2014 to 30 April 2015. Hemodialysis (for ≥ 3 months) patients ≥ 18 years of age were offered treatment. A total of 269 patients on hemodialysis were eligible. Eight of the 269 patients (3%) were excluded from the analysis for being on melioidosis treatment. In all, 169 of 261 patients (64.8%) received the prophylaxis, and 92 of 261 patients (35.2%) did not, because of allergy history (n = 10), remoteness and logistical reasons (n = 60), poor dialysis attendance (n = 11), and refusal (n = 11). We monitored for clinical side effects 3 times weekly and neutropenia, thrombocytopenia, and liver function monthly throughout treatment and for 2 months posttreatment. Results In all, 169 of 261 patients (64.8%) received the prophylaxis. There was no age (years) difference by group (prophylaxis vs. nonprophylaxis, 54.7 [11.3] vs. 54.3 [11.2] [P = 0.751]). Sixteen of 261 patients (6%) had melioidosis. The event frequency was 0% (0/169, prophylaxis, vs. 17.4% [16/92, nonprophylaxis], P < 0.001). Higher thrombocytopenia and neutropenia rates were noted in the prophylaxis group. These did not warrant treatment stoppage. There was no difference in liver function. Three patients (1.8%) withdrew from the treatment because of side effects. Conclusion Daily dosing was effective and safe. Posthemodialysis dosing in the subsequent seasons was effective and safer. We recommend this approach in melioidosis-prevalent regions

Examining pathways between genetic liability for schizophrenia and patterns of tobacco and cannabis use in adolescence

Background It is not clear to what extent associations between schizophrenia, cannabis use and cigarette use are due to a shared genetic etiology. We, therefore, examined whether schizophrenia genetic risk associates with longitudinal patterns of cigarette and cannabis use in adolescence and mediating pathways for any association to inform potential reduction strategies. Methods Associations between schizophrenia polygenic scores and longitudinal latent classes of cigarette and cannabis use from ages 14 to 19 years were investigated in up to 3925 individuals in the Avon Longitudinal Study of Parents and Children. Mediation models were estimated to assess the potential mediating effects of a range of cognitive, emotional, and behavioral phenotypes. Results The schizophrenia polygenic score, based on single nucleotide polymorphisms meeting a training-set p threshold of 0.05, was associated with late-onset cannabis use (OR = 1.23; 95% CI = 1.08,1.41), but not with cigarette or early-onset cannabis use classes. This association was not mediated through lower IQ, victimization, emotional difficulties, antisocial behavior, impulsivity, or poorer social relationships during childhood. Sensitivity analyses adjusting for genetic liability to cannabis or cigarette use, using polygenic scores excluding the CHRNA5-A3-B4 gene cluster, or basing scores on a 0.5 training-set p threshold, provided results consistent with our main analyses. Conclusions Our study provides evidence that genetic risk for schizophrenia is associated with patterns of cannabis use during adolescence. Investigation of pathways other than the cognitive, emotional, and behavioral phenotypes examined here is required to identify modifiable targets to reduce the public health burden of cannabis use in the population

Examining pathways between genetic liability for schizophrenia and patterns of tobacco and cannabis use in adolescence

Background It is not clear to what extent associations between schizophrenia, cannabis use and cigarette use are due to a shared genetic etiology. We, therefore, examined whether schizophrenia genetic risk associates with longitudinal patterns of cigarette and cannabis use in adolescence and mediating pathways for any association to inform potential reduction strategies. Methods Associations between schizophrenia polygenic scores and longitudinal latent classes of cigarette and cannabis use from ages 14 to 19 years were investigated in up to 3925 individuals in the Avon Longitudinal Study of Parents and Children. Mediation models were estimated to assess the potential mediating effects of a range of cognitive, emotional, and behavioral phenotypes. Results The schizophrenia polygenic score, based on single nucleotide polymorphisms meeting a training-set p threshold of 0.05, was associated with late-onset cannabis use (OR = 1.23; 95% CI = 1.08,1.41), but not with cigarette or early-onset cannabis use classes. This association was not mediated through lower IQ, victimization, emotional difficulties, antisocial behavior, impulsivity, or poorer social relationships during childhood. Sensitivity analyses adjusting for genetic liability to cannabis or cigarette use, using polygenic scores excluding the CHRNA5-A3-B4 gene cluster, or basing scores on a 0.5 training-set p threshold, provided results consistent with our main analyses. Conclusions Our study provides evidence that genetic risk for schizophrenia is associated with patterns of cannabis use during adolescence. Investigation of pathways other than the cognitive, emotional, and behavioral phenotypes examined here is required to identify modifiable targets to reduce the public health burden of cannabis use in the population

Individual common variants exert weak effects on the risk for autism spectrum disorders.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm&lt; 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest