Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants with Treatment Resistance in Schizophrenia

Importance: About 20% to 30% of people with schizophrenia have psychotic symptoms that do not respond adequately to first-line antipsychotic treatment. This clinical presentation, chronic and highly disabling, is known as treatment-resistant schizophrenia (TRS). The causes of treatment resistance and their relationships with causes underlying schizophrenia are largely unknown. Adequately powered genetic studies of TRS are scarce because of the difficulty in collecting data from well-characterized TRS cohorts. Objective: To examine the genetic architecture of TRS through the reassessment of genetic data from schizophrenia studies and its validation in carefully ascertained clinical samples. Design, Setting, and Participants: Two case-control genome-wide association studies (GWASs) of schizophrenia were performed in which the case samples were defined as individuals with TRS (n = 10501) and individuals with non-TRS (n = 20325). The differences in effect sizes for allelic associations were then determined between both studies, the reasoning being such differences reflect treatment resistance instead of schizophrenia. Genotype data were retrieved from the CLOZUK and Psychiatric Genomics Consortium (PGC) schizophrenia studies. The output was validated using polygenic risk score (PRS) profiling of 2 independent schizophrenia cohorts with TRS and non-TRS: a prevalence sample with 817 individuals (Cardiff Cognition in Schizophrenia [CardiffCOGS]) and an incidence sample with 563 individuals (Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances [STRATA-G]). Main Outcomes and Measures: GWAS of treatment resistance in schizophrenia. The results of the GWAS were compared with complex polygenic traits through a genetic correlation approach and were used for PRS analysis on the independent validation cohorts using the same TRS definition. Results: The study included a total of 85490 participants (48635 [56.9%] male) in its GWAS stage and 1380 participants (859 [62.2%] male) in its PRS validation stage. Treatment resistance in schizophrenia emerged as a polygenic trait with detectable heritability (1% to 4%), and several traits related to intelligence and cognition were found to be genetically correlated with it (genetic correlation, 0.41-0.69). PRS analysis in the CardiffCOGS prevalence sample showed a positive association between TRS and a history of taking clozapine (r2 = 2.03%; P =.001), which was replicated in the STRATA-G incidence sample (r2 = 1.09%; P =.04). Conclusions and Relevance: In this GWAS, common genetic variants were differentially associated with TRS, and these associations may have been obscured through the amalgamation of large GWAS samples in previous studies of broadly defined schizophrenia. Findings of this study suggest the validity of meta-analytic approaches for studies on patient outcomes, including treatment resistance

The Pre-Aksumite Period: indigenous origins and development in the Horn of Africa

The Pre-Aksumite Period (mid-second to late first millennia BC) witnessed the rise of complex societies in the Horn of Africa. Archaeological survey and excavations in the Gulo Makeda region of Eastern Tigrai by the Eastern Tigrai Archaeological Project (ETAP) have produced new data and insights into this critical juncture in the cultural history of the region. Based on data from Mezber and other archaeological sites, we present a new Pre-Aksumite chronology and discuss the material culture, settlement, political organisation, economy, agricultural history and regional interactions of this period. We recommend the use of the term ‘Pre-Aksumite Period’ to encompass this time when the earliest polities developed in the region. Mezber provides us with a glimpse into the lifeways of indigenous peoples inhabiting the northern Horn of Africa who encountered South Arabian visitors to the region during the early first millennium BC. Data from Mezber shift our focus from external influences to considering the culture and development of autochthonous peoples of the Ethiopian/Eritrean highlands who had an active role in negotiating cultural contacts. This perspective constitutes a missing piece of the puzzle needed to better understand the broader socio-economic, political and cultural dynamics of the Pre-Aksumite Period.ETAP investigations at Mezber were financially supported by three grants from the Social Sciences and Humanities Research Council of Canada (SSHRC), including Standard Research Grants 410-2007-2472, 410-2011-1646 and Insight Grant 435-2014-01. Further support was obtained by grants from Simon Fraser University, including four SSHRC/SFU Institutional Grants and a VP Research SSHRC 4A grant. Field and laboratory microbotanical work completed by AR-G and CL was developed within the framework of the RAINDROPS project, funded by the European Research Council (ERC-Stg 759800) and both are part of CaSEs, a recognised research group of the Generalitat De Catalunya (AGAUR SGR-e-2017-212)

Pygmy Rice Rat as Potential Host of Castelo dos Sonhos Hantavirus

To study the dynamics of wild rodent populations and identify potential hosts for hantavirus, we conducted an eco-epidemiologic study in Campo Novo do Parecis, Mato Grosso State, Brazil. We detected and genetically characterized Castelo dos Sonhos virus found in a species of pygmy rice rat (Oligoryzomys utiaritensis)

Futility in acute care surgery: first do no harm

The consequences of the delivery of futile or potentially ineffective medical care and interventions are devastating on the healthcare system, our patients and their families, and healthcare providers. In emergency situations in particular, determining if escalating invasive interventions will benefit a frail and/or severely critically ill patient can be exceedingly difficult. In this review, our objective is to define the problem of potentially ineffective care within the specialty of acute care surgery and describe strategies for improving the care of our patients in these difficult situations