Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Impacts of altered precipitation regimes on soil communities and biogeochemistry in arid and semi-arid ecosystems

Altered precipitation patterns resulting from climate change will have particularly significant consequences in water-limited ecosystems, such as arid to semi-arid ecosystems, where discontinuous inputs of water control biological processes. Given that these ecosystems cover more than a third of Earth's terrestrial surface, it is important to understand how they respond to such alterations. Altered water availability may impact both aboveground and belowground communities and the interactions between these, with potential impacts on ecosystem functioning; however, most studies to date have focused exclusively on vegetation responses to altered precipitation regimes. To synthesize our understanding of potential climate change impacts on dryland ecosystems, we present here a review of current literature that reports the effects of precipitation events and altered precipitation regimes on belowground biota and biogeochemical cycling. Increased precipitation generally increases microbial biomass and fungal:bacterial ratio. Few studies report responses to reduced precipitation but the effects likely counter those of increased precipitation. Altered precipitation regimes have also been found to alter microbial community composition but broader generalizations are difficult to make. Changes in event size and frequency influences invertebrate activity and density with cascading impacts on the soil food web, which will likely impact carbon and nutrient pools. The long-term implications for biogeochemical cycling are inconclusive but several studies suggest that increased aridity may cause decoupling of carbon and nutrient cycling. We propose a new conceptual framework that incorporates hierarchical biotic responses to individual precipitation events more explicitly, including moderation of microbial activity and biomass by invertebrate grazing, and use this framework to make some predictions on impacts of altered precipitation regimes in terms of event size and frequency as well as mean annual precipitation. While our understanding of dryland ecosystems is improving, there is still a great need for longer term in situ manipulations of precipitation regime to test our model

Environmental harshness mediates the relationship between aboveground and belowground communities in Antarctica

Linkages between aboveground and belowground communities are a key but globally under-researched component of responses to environmental change. Given the logistical complications to studying these relationships, much of our knowledge derives from laboratory experiments and localized field studies which have so far yielded inconsistent results. Because environmental factors may alter relationships between above- and belowground communities, there is a need for broad-scale field studies testing these interactions. The Antarctic Peninsula provides an ideal test setting, given the relatively simple communities both above- and belowground. The Peninsula is also experiencing rapid environmental changes, including alterations in species diversity and distribution both above- and belowground. Thus, an improved understanding of the broad-scale consequences of altered environments and vegetation communities for the soil microbiome is of high priority. To determine the nature and strength of the relationship between in situ plant and soil communities across a broad spatial scale and range of environmental conditions, we sampled soil communities at 9 locations (spanning 60–72°S along the Scotia Arc and Antarctic Peninsula) beneath the major aboveground habitats (moss, grass, lichen, algae and bare soil). We measured a comprehensive suite of soil physicochemical properties, microbial (bacterial and fungal) diversity and composition, and invertebrate abundance and community composition to determine the relationships between plant and soil communities. Our results suggest that, with increased environmental severity, plant cover types become more important for influencing the physicochemical soil environment, and therefore the soil microbial communities. Although we found site-specific relationships, broad-scale patterns reveal significant differences among bare soils and vegetated soils, particularly soils beneath grass and moss. This suggests that expansion of vegetation communities under current climate warming projections will be accompanied by shifts in the soil microbiome, with important implications for the ecosystem functioning with which they are associated

The ecology of pulse events : insights from an extreme climatic event in a polar desert ecosystem

Climate change is occurring globally, with wide ranging impacts on organisms and ecosystems alike. While most studies focus on increases in mean temperatures and changes in precipitation, there is growing evidence that an increase in extreme events may be particularly important to altering ecosystem structure and function. During extreme events organisms encounter environmental conditions well beyond the range normally experienced. Such conditions may cause rapid changes in community composition and ecosystem states. We present the impact of an extreme pulse event (a flood) on soil communities in an Antarctic polar desert. Taylor Valley, McMurdo Dry Valleys, is dominated by large expanses of dry, saline soils. During the austral summer, melting of glaciers, snow patches and subsurface ice supplies water to ephemeral streams and wetlands. We show how the activation of a non-annual ephemeral stream, Wormherder Creek, and the associated wetland during an exceptional high-flow event alters soil properties and communities. The flow of water increased soil water availability and decreased salinity within the wetted zone compared with the surrounding dry soils. We propose that periodic leaching of salts from flooding reduces soil osmotic stress to levels that are more favorable for soil organisms, improving the habitat suitability, which has a strong positive effect on soil animal abundance and diversity. Moreover, we found that communities differentiated along a soil moisture gradient and that overland water flow created greater connectivity within the landscape, and is expected to promote soil faunal dispersal. Thus, floods can ‘precondition' soils to support belowground communities by creating conditions below or above key environmental thresholds. We conclude that pulse events can have significant long-term impacts on soil habitat suitability, and knowledge of pulse events is essential for understanding the present distribution and functioning of communities in soil ecosystems

The hydroecology of an ephemeral wetland in the McMurdo Dry Valleys, Antarctica

The McMurdo Dry Valleys is a polar desert on the coast of East Antarctica where ephemeral wetlands become hydrologically active during warm and sunny summers when subsurface flows are generated from melting snowfields. To understand the structure and function of polar wetland ecosystems, we investigated the hydroecology of one such wetland, the Wormherder Creek wetland, during the warm and sunny summer of 2008 – 2009, when the wetland was hydrologically reactivated. Conservative tracer (LiCl) was injected for a 2-hr period into a stream above the wetland to determine flow path orientations and hydrologic residence times. Tracer results indicated that surface water is rapidly exchanged with wetland groundwater and wetland residence times may exceed two austral summers. Major ion concentrations were uniform in samples from surface water and shallow groundwater throughout the wetland. Microbial mats in the wetland had high autotrophic index values (the ratios of chlorophyll a [Chl-a]/ash-free dry mass), ranging from 9 to 38 μg Chl-a/mg ash-free dry mass, indicative of actively photosynthesizing mat communities. The diatom communities in the mats were relatively uniform compared to those in mats from regularly flowing McMurdo Dry Valleys streams, with four endemic and one widespread diatom taxa of the genus Luticola accounting for an average of 86% of the community. These results indicate that the hydrologic characteristics of the wetland contribute to uniform geochemical conditions. In turn, uniform geochemical conditions may explain the high autotrophic index values of the microbial mats and relatively low spatial variation of the diatom community

Perioperative Topical Antisepsis and Surgical Site Infection in Patients Undergoing Upper Aerodigestive Tract Reconstruction

Importance: Surgical site infections (SSIs) after vascularized reconstruction of the upper aerodigestive tract (UADT) are associated with considerable morbidity. The association between perioperative prophylaxis practices, particularly topical antisepsis, and SSIs remains uncertain. Objective: To assess the association between perioperative topical antisepsis and SSIs in patients undergoing vascularized reconstruction of the UADT. Design, setting, and participants: This cohort study included patients from 12 academic tertiary care centers over an 11-month period, from July 1, 2020, to June 1, 2021. Patients undergoing open surgical procedures requiring a communication between the UADT and cervical skin with a planned regional pedicled flap, free flap, or both were included. Patients with an active infection at the time of surgical procedure were excluded. Main outcomes and measures: The primary outcome measure was an SSI within 30 days of surgery. The association of demographic characteristics, perioperative antibiotic prophylaxis, surgical technique, and postoperative care with SSIs was assessed using univariable and multivariable analyses. The relative risk ratio and 95% CIs for developing SSI were calculated for each of the variables based on predetermined categories. Variables for which the relative risk 95% CI did not include the value of zero effect (relative risk = 1.00) were included in the multivariable model. Results: A total of 554 patients (median age, 64 years; range, 21-95 years; 367 men [66.2%]) were included. Cancer ablation was the most frequent reason for surgery (n = 480 [86.6%]). Overall, the SSI rate was 20.9% (n = 116), with most infections involving the head and neck surgical site only (91 [78.4%]). The median time to SSI diagnosis was 11 days (range, 1-28 days). Topical antisepsis mucosal preparation was performed preoperatively in 35.2% (195) and postoperatively in 52.2% (289) of cases. Ampicillin and sulbactam was the most common systemic antibiotic prophylaxis agent used (n = 367 [66.2%]), with 24 hours being the most common duration (n = 363 [65.5%]). On multivariable analysis, preoperative topical antisepsis mucosal preparation (odds ratio [OR], 0.49; 95% CI, 0.30-0.77) and systemic prophylaxis with piperacillin and tazobactam (OR, 0.42; 95% CI, 0.21-0.84) were associated with a decreased risk of a postoperative SSI. The use of an osseous vascularized flap was associated with an increased risk of postoperative SSI (OR, 1.76; 95% CI, 1.13-2.75). Conclusions and relevance: Findings of this study suggest that preoperative topical antisepsis mucosal preparation was independently associated with a decreased risk of SSIs in a 12-center multi-institutional cohort. Further investigation of the association between individual perioperative practices and the incidence of postoperative SSIs is necessary to develop evidence-based protocols to reduce SSIs after UADT reconstruction