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Common genetic risk variants for type 2 diabetes (T2D) have primarily been identified in populations of European and Asian ancestry. We tested whether the direction of association with 20 T2D risk variants generalizes across six major racial/ethnic groups in the U.S. as part of the Population Architecture using Genomics and Epidemiology Consortium (16,235 diabetes case and 46,122 control subjects of European American, African American, Hispanic, East Asian, American Indian, and Native Hawaiian ancestry). The percentage of positive (odds ratio [OR] >1 for putative risk allele) associations ranged from 69% in American Indians to 100% in European Americans. Of the nine variants where we observed significant heterogeneity of effect by racial/ethnic group (P(heterogeneity) < 0.05), eight were positively associated with risk (OR >1) in at least five groups. The marked directional consistency of association observed for most genetic variants across populations implies a shared functional common variant in each region. Fine-mapping of all loci will be required to reveal markers of risk that are important within and across populations. [ABSTRACT FROM AUTHOR]

Dapagliflozin has been associated with euglycemic ketoacidosis in adults with diabetes contributing to poor outcomes when continued prior to surgery. It is unknown if preoperative use of dapagliflozin may lead to adverse events (AE) in nondiabetic children with advanced heart failure (HF) undergoing heart transplantation (HTx). We performed a single-center, matched case-control analysis of nondiabetic primary pediatric HTx recipients < 21 years-old who underwent HTx and followed through postoperative day (POD) 3. Cases who received dapagliflozin leading up to HTx (n = 22) were matched by age and cardiac diagnosis to two historical controls who did not receive dapagliflozin (n = 44). Median age at HTx was 13.8 years (range 0.36-20.7) and 48% were female. Cardiac diagnoses included cardiomyopathy (45%), Fontan failure (41%), and single ventricle status post stage I palliation (14%). Cases received median dapagliflozin dose of 0.17 mg/kg once daily; therapy was stopped one day prior to HTx. There were no significant differences in blood glucose nadirs, arterial blood gas indices including nadirs of pH, bicarbonate, or peaks of arterial blood lactic acid POD0-3. Vasopressor, inotrope, and insulin infusion usage were not different. No patients were treated for severe hypoglycemia, euglycemic ketoacidosis, or urinary tract infections. There were no deaths. Length of stay in ICU and time from HTx to hospital discharge did not differ between cohorts. Use of dapagliflozin in children with advanced HF until HTx is not associated with AE in the immediate postoperative period nor increased length of hospitalization post-HTx. Potential cardiovascular benefits of dapagliflozin in patients awaiting HTx should be prioritized., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The prevalence of iron deficiency and anemia in the setting of modern-day maintenance immunosuppression in pediatric heart transplant (HTx) recipients is unclear. The primary aim was to determine the prevalence of iron deficiency (serum ferritin < 30 ng/mL ± transferrin saturation < 20%) and anemia per World Health Organization diagnostic criteria and associated risk factors., Methods: Single-center, cross-sectional analysis of 200 consecutive pediatric HTx recipients (<21 years old) from 2005 to 2021. Data were collected at 1-year post-HTx at the time of annual protocol biopsy., Results: Median age at transplant was 3 years (IQR .5-12.2). The median ferritin level was 32 ng/mL with 46% having ferritin < 30 ng/mL. Median transferrin saturation (TSAT) was 22% with 47% having TSAT < 20%. Median hemoglobin was 11 g/dL with 54% having anemia. Multivariable analysis revealed lower absolute lymphocyte count, TSAT < 20%, and estimated glomerular filtration rate <75 mL/min/1.73 m 2 were independently associated with anemia. Ferritin < 30 ng/mL in isolation was not associated with anemia. Ferritin < 30 ng/mL may aid in detecting absolute iron deficiency while TSAT < 20% may be useful in identifying patients with functional iron deficiency ± anemia in pediatric HTx recipients., Conclusion: Iron deficiency and anemia are highly prevalent in pediatric HTx recipients. Future studies are needed to assess the impact of iron deficiency, whether with or without anemia, on clinical outcomes in pediatric HTx recipients., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Doctors (and sociologists) have a long history of struggling to understand why patients seek medical help yet resist treatment recommendations. Explanations for resistance have pointed to macrostructural changes, such as the rise of the engaged patient or decline of physician authority. Rather than assuming that concepts such as resistance, authority, or engagement are exogenous phenomena transmitted via conversational conduits, we examine how they are dynamically co-constituted interactionally. Using conversation analysis to analyze a videotaped interaction of an oncology patient resisting the treatment recommendation even though she might die without treatment, we show how sustained resistance manifests in and through her doctor's actions. This paradox, in which the doctor can both recommend life-prolonging care and condition resistance to it, has broad relevance beyond cancer treatment; it also can help us to understand other doctor-patient decisional conflicts, for instance, medication nonadherence, delaying emergent care, and vaccine refusal.

Uncontrolled fires place considerable burdens on forest ecosystems, compromising our ability to meet conservation and restoration goals. A poor understanding of the impacts of fire on ecosystems and their biodiversity exacerbates this challenge, particularly in tropical regions where few studies have applied consistent analytical techniques to examine a broad range of ecological impacts over multiyear time frames. We compiled 16 y of data on ecosystem properties (17 variables) and biodiversity (21 variables) from a tropical peatland in Indonesia to assess fire impacts and infer the potential for recovery. Burned forest experienced altered structural and microclimatic conditions, resulting in a proliferation of nonforest vegetation and erosion of forest ecosystem properties and biodiversity. Compared to unburned forest, habitat structure, tree density, and canopy cover deteriorated by 58 to 98%, while declines in species diversity and abundance were most pronounced for trees, damselflies, and butterflies, particularly for forest specialist species. Tracking ecosystem property and biodiversity datasets over time revealed most to be sensitive to recurrent high-intensity fires within the wider landscape. These megafires immediately compromised water quality and tree reproductive phenology, crashing commercially valuable fish populations within 3 mo and driving a gradual decline in threatened vertebrates over 9 mo. Burned forest remained structurally compromised long after a burn event, but vegetation showed some signs of recovery over a 12-y period. Our findings demonstrate that, if left uncontrolled, fire may be a pervasive threat to the ecological functioning of tropical forests, underscoring the importance of fire prevention and long-term restoration efforts, as exemplified in Indonesia., Competing Interests: Competing interests statement:The authors declare no competing interest.

Aspirin (ASA) remains the most common antiplatelet agent used in children. VerifyNow Aspirin Test® (VN) assesses platelet response to ASA, with therapeutic effect defined by the manufacturer as ≤ 549 aspirin reaction units (ARU). Single-center, observational, analysis of 195 children (< 18 years-old) who underwent first VN between 2015 and 2020. Primary outcome was proportion of patients with ASA biochemical resistance (> 549 ARU). Secondary outcomes included incidence of new clinical thrombotic and bleeding events during ≤ 6 months from VN in those who received ASA monotherapy (n = 113). Median age was 1.8 years. Common indications for ASA included cardiac anomalies or dysfunction (74.8%) and ischemic stroke (22.6%). Median ASA dose before VN was 4.6 mg/kg/day. Mean VN was 471 ARU. ASA biochemical resistance was detected in 14.4% (n = 28). Of 113 patients receiving ASA monotherapy, 14 (12.4%) had a thrombotic event and 2 (1.8%) had a bleeding event. Mean VN was significantly higher at initial testing in patients experiencing thrombotic event compared to those without thrombosis (516 vs 465 ARU, [95% CI: 9.8, 92.2], p = 0.02). Multivariable analysis identified initial VN ASA result ≥ 500 ARU at initial testing as the only significant independent risk factor for thrombosis (p < 0.01). VN testing identifies ASA biochemical resistance in 14.4% of children. VN ASA ≥ 500 ARU rather than ≥ 550 ARU at initial testing was independently associated with increased odds of thrombosis. Designated cut-off of 550 ARU for detecting platelet dysfunction by ASA may need reconsideration in children., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Kidney disease is common after pediatric heart transplantation. Serum creatinine-based glomerular filtration rate is the most frequently reported measure of kidney function. Albuminuria is an additional marker of kidney dysfunction and is not well described in this population. In this study, we evaluate the prevalence and degree of albuminuria and describe clinical factors associated with albuminuria in a cohort of pediatric heart transplant recipients., Methods: This was a cross-sectional study of pediatric heart transplant recipients. Albuminuria was assessed using spot urine albumin-to-creatinine ratio collected at the most recent annual screening cardiac catheterization through August 2019., Results: In 115 patients at a median duration of 10.2 years post-transplant, 39% had albuminuria. Stage 3 or greater chronic kidney disease was present in 6%. The immunosuppressive regimen at the time of measurement contained a calcineurin inhibitor (CNI) in 88% and a proliferation signal inhibitor (PSI) in 62%. In multivariable modeling, lower eGFR, PSI use, and younger age at transplant were associated with higher levels of albuminuria, whereas CNI use was associated with lower levels of albuminuria., Conclusion: Albuminuria is a prevalent finding in medium-term follow up of pediatric heart transplant recipients, reflecting kidney injury, and is associated with other markers of kidney dysfunction, such as low eGFR. Younger age at transplant, lower eGFR, and PSI use were among the associations with albuminuria., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: This discussion paper outlines challenges and proposes solutions for successfully implementing prediction models that incorporate patient-reported outcomes (PROs) in cancer practice., Methods: We organized a full-day multidisciplinary meeting of people with expertise in cancer care delivery, PRO collection, PRO use in prediction modeling, computing, implementation, and decision science. The discussions presented here focused on identifying challenges to the development, implementation and use of prediction models incorporating PROs, and suggesting possible solutions., Results: Specific challenges and solutions were identified across three broad areas. (1) Understanding decision making and implementation: necessitating multidisciplinary collaboration in the early stages and throughout; early stakeholder engagement to define the decision problem and ensure acceptability of PROs in prediction; understanding patient/clinician interpretation of PRO predictions and uncertainty to optimize prediction impact; striving for model integration into existing electronic health records; and early regulatory alignment. (2) Recognizing the limitations to PRO collection and their impact on prediction: incorporating validated, clinically important PROs to maximize model generalizability and clinical engagement; and minimizing missing PRO data (resulting from both structural digital exclusion and time-varying factors) to avoid exacerbating existing inequalities. (3) Statistical and modeling challenges: incorporating statistical methods to address missing data; ensuring predictive modeling recognizes complex causal relationships; and considering temporal and geographic recalibration so that model predictions reflect the relevant population., Conclusion: Developing and implementing PRO-based prediction models in cancer care requires extensive multidisciplinary working from the earliest stages, recognition of implementation challenges because of PRO collection and model presentation, and robust statistical methods to manage missing data, causality, and calibration. Prediction models incorporating PROs should be viewed as complex interventions, with their development and impact assessment carried out to reflect this.

Background: Literature is limited comparing adverse effects (AEs) of the proliferation signal inhibitors (PSIs) sirolimus (SRL) and everolimus (EVL) in pediatric heart transplant (HTx) recipients., Methods: Single-center, observational cohort analysis assessing first use of SRL or EVL in pediatric HTx recipients <21 years of age with up to 2 years follow-up between 2009 and 2020., Results: Eighty-seven patients were included, with 52 (59.8%) receiving EVL and 35 (40.2%) receiving SRL. Tacrolimus with PSI was the most common regimen. Intergroup comparison revealed lower baseline estimated glomerular filtration rate (eGFR) and greater increase in eGFR from baseline to 6 months and latest follow-up in SRL cohort compared to EVL cohort. There was greater increase in HDL cholesterol in SRL cohort compared to EVL cohort. Intragroup analysis revealed eGFR and HDL cholesterol increased significantly within SRL cohort, triglycerides and glycosylated hemoglobin increased in EVL cohort, and LDL cholesterol and total cholesterol increased in both cohorts (all p < .05). There were no differences in hematological indices or rates of aphthous ulcers, effusions, or infections between cohorts. Incidence of proteinuria was not significantly different among those screened within cohorts. Of those included in our analysis, one patient in SRL cohort (2.9%) and two in EVL cohort (3.8%) had PSI withdrawn due to AE., Conclusion: Low-dose PSIs in calcineurin inhibitor minimization regimens appear well-tolerated with low withdrawal rate secondary to AE in pediatric HTx recipients. While incidence of most AE was similar between PSI, our results suggest EVL may be associated with less favorable metabolic impact than SRL in this population., (© 2023 Wiley Periodicals LLC.)

Indonesia is embarking on an ambitious relocation of its capital city to Kalimantan, Borneo, bringing with it major urban and road infrastructure. Yet, despite being one of the world's most biologically diverse regions, the potential implications of this development for wildlife have yet to be fully assessed. We explored the potential impacts of the capital relocation, and road expansion and upgrades to critical habitat for medium-large mammals (>1 kg) using camera trap data from 11 forested landscapes. We applied Bayesian multi-species occupancy models to predict community and species-level responses to anthropogenic and environmental factors. We extrapolated spatial patterns of occupancy and species diversity across the forests of Kalimantan and identified "critical habitats" as the top 20 th percentile of occupancy and species richness values. We subsequently overlapped these critical habitat layers with infrastructure impact zones to estimate the area that could potentially be affected by direct or secondary impacts. At both the community and species-level, distance to primary roads had the strongest negative influence on habitat-use. Occupancy was also influenced by forest quality and multidimensional poverty conditions in adjacent villages, demonstrating the sensitivity of biodiversity to socio-ecological pressures. Less than 1 % of the critical habitat for the threatened mammal community lay within the direct impact zone (30 km radius) of the capital relocation. However, approximately 16 % was located within 200 km and could potentially be affected by uncontrolled secondary impacts such as urban sprawl and associated regional development. The often-overlooked secondary implications of upgrading existing roads could also intersect a large amount of critical habitat for lowland species. Mitigating far-reaching secondary impacts of infrastructure development should be fully incorporated into environmental impact assessments. This will provide Indonesia with an opportunity to set an example of sustainable infrastructure development in the tropics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Flocculated suspended sediments (flocs) are found in a variety of environments globally, and their transport and behavior bear substantial importance to several industries including fisheries, aquaculture, and shipping. Additionally, the modelling of their behavior is important for estuarine and coastal flood prediction and defence, and the process of flocculation occurs in other unrelated industries such as paper and chemical production. Floc porosity is conventionally assessed using inferential indirect or proxy data approaches. These methods underestimate floc porosity % by c. 30% and cannot measure the micro-scale complexity of these pore spaces and networks, rendering inputs to models sub-optimal. This study introduces a novel 3D porosity and pore space quantification protocol, that produces directly quantified porosity % and pore space data.•3D floc data from micro-CT scanning is segmented volumetrically•This segmented volume is quantified to extract porosity and several pore space parameters from the floc structure., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Natural sediment flocs are fragile and highly heterogeneous aggregates of biogenic and minerogenic material typically with high porosity and low density. In aquatic environments dominated by fine, cohesive or mixed sediments they can dominate suspended sediment flux. Consequently, monitoring and modelling the behaviour, transport and distribution of flocs is very important for many aquatic industries, maintenance of waterways and conservation and management of aquatic waterbodies. Mathematical models that predict the behaviour of flocs rely on the accurate assessments of the size, shape, density, porosity and fractal dimension of flocs. These inherently 3-dimensional (3D) characteristics are typically derived from 2-dimensional (2D) data, largely due to the challenges associated with sampling, capturing, imaging and quantifying these fragile aggregates. We have developed new volumetric microscopy techniques which can quantify 3D internal and external structures and characteristics of sediment flocs. Here, these techniques were applied to quantify the 3D size (volume), shape and fractal dimension of natural and artificial sediment flocs and compare them to standard 2D approaches. Our study demonstrates that 2D approaches are under-estimating shape complexity and over-estimating the size and mass settling flux of flocs by up to two orders of magnitude, and the discrepancy between 2D and 3D is most marked for natural, organic rich macroflocs. Our study has significant implications for estimations of sediment flux at local to global scales within in aquatic environments. These new data and approaches offer the potential to improve the current parameterisation of sediment transport models and to improve the accuracy of current field-monitoring techniques., (Copyright © 2022. Published by Elsevier Ltd.)

Flocculation is a key process for controlling the fate and transport of suspended particulate matter (SPM) in water environments and has received considerable attention in the field of water science (e.g., oceanography, limnology, and hydrology), remaining an active area of research. The research on flocculation has been conducted to elucidate the SPM dynamics and to diagnose various environmental issues. The flocculation, sedimentation, and transportation of SPM are closely linked to the compositional and structural properties of flocs. In fact, flocs are highly heterogeneous in terms of composition. However, the lack of comprehensive research on floc composition and structure has led to misconceptions regarding the temporal and spatial dynamics of SPM. This review summarizes the current understanding of the heterogeneous composition of flocs (e.g., minerals, organic matter, metals, microplastic, engineered nanoparticles) and its effect on their structure and on their fate and transport within aquatic environments. Furthermore, the effects of human activities (e.g., pollutant discharge, construction) on floc composition are discussed., (Copyright © 2022. Published by Elsevier Ltd.)

Despite changes in specific features of the US health-care system and policy environment in the past 50 years, professional dominance of medicine remains consistent. Extant social science research has considered how the cultural authority of medicine manifests and persists, sometimes emphasizing institutional structural influences and other times focusing on how individuals' agentic behaviour shapes their decisions and strategies regarding the consumption of health-care. We build on and extend these literatures using qualitative in-depth interview data to explore a typology of ways palliative care patients and their caregivers experience medical treatment imperatives across a range of social contexts. Rather than viewing or validating these lived experiences through a medical lens, we foreground the accounts of patients and caregivers as they describe their experiences of where, when, and how they perceive pressure to engage in medical treatment in late life. We adopt a Foucauldian lens to examine how this biopower is both an internal and external experience in our modern biomedicalized society. Our work reveals how treatment imperatives are generated within clinical medical encounters, but also coproduced through multiple and overlapping forces that compel individuals to pursue medical solutions to bodily problems., (© 2022 Foundation for the Sociology of Health & Illness.)

Sociologists have made fundamental contributions to the study of race and health in the United States. They have disrupted biological assumptions of race, uncovered individual and structural factors that drive racial health disparities and explored the effects of racism on health. In recent years, however, with broader shifts towards big data, the work to understand the dynamics between race and health has been increasingly pursued from a quantitative perspective. Often, such analyses isolate intermediary mechanisms to further explain race as a cause of disease. While important, these approaches potentially limit our investigations of underlying assumptions about race and the complexity of this critical social construct. We argue that the resulting dearth of qualitative research on race and health substantially limits the knowledge being produced. After providing an overview of the overwhelming shift towards quantitative methods in the study of race and health, we present three areas of study that would benefit from greater qualitative inquiry as follows: (1) Healthy Immigrant Effect, (2) Maternal Health and (3) End-of-Life Care. We conclude with a call to the discipline to embrace the critical role of qualitative research in exploring the dynamics of race and health in the United States., (© 2021 Foundation for Sociology of Health & Illness.)

Natural sediment flocs are fragile, highly irregular, loosely bound aggregates comprising minerogenic and organic material. They contribute a major component of suspended sediment load and are critical for the fate and flux of sediment, carbon and pollutants in aquatic environments. Understanding their behaviour is essential to the sustainable management of waterways, fisheries and marine industries. For several decades, modelling approaches have utilised fractal mathematics and observations of two dimensional (2D) floc size distributions to infer levels of aggregation and predict their behaviour. Whilst this is a computationally simple solution, it is highly unlikely to reflect the complexity of natural sediment flocs and current models predicting fine sediment hydrodynamics are not efficient. Here, we show how new observations of fragile floc structures in three dimensions (3D) demonstrate unequivocally that natural flocs are non-fractal. We propose that floc hierarchy is based on observations of 3D structure and function rather than 2D size distribution. In contrast to fractal theory, our data indicate that flocs possess characteristics of emergent systems including non-linearity and scale-dependent feedbacks. These concepts and new data to quantify floc structures offer the opportunity to explore new emergence-based floc frameworks which better represent natural floc behaviour and could advance our predictive capacity.

Historical mining activities cause widespread, long-term trace metal contamination of freshwater ecosystems. However, measuring trace metal bioavailability has proven difficult, because it depends on many factors, not least concentrations in water, sediment and habitat. Simple tools are needed to assess bioavailabilities. The use of biomonitors has been widely advocated to provide a realistic measure. To date there have been few attempts to identify ubiquitous patterns of trace metal accumulation within and between freshwater biomonitors at geographical scales relevant to trace metal contamination. Here we address this through a nationwide collection of freshwater biomonitors (species of Gammarus, Leuctra, Baetis, Rhyacophila, Hydropsyche) from 99 English and Welsh stream sites spanning a gradient of high to low trace metal loading. The study tested for inter-biomonitor variation in trace metal body burden, and for congruence amongst accumulations of trace metals within taxa and between taxa across the gradient. In general, significant differences in trace metal body burden occurred between taxa: Gammarus sp. was the most different compared with insect biomonitors. Bivariate relationships between trace metals within biomonitors reflected trace metal profiles in the environment. Strong correlations between some trace metals suggested accumulation was also influenced by physiological pathways. Bivariate relationships between insect biomonitors for body burdens of As, Cu, Mn and Pb were highly consistent. Our data show that irrespective of taxonomic or ecological differences, there is a commonality of response amongst insect taxa, indicating one or more could provide consistent measures of trace metal bioavailability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Despite growing interest in the environmental impact of microplastics, a standardized characterization method is not available. We carried out a systematic analysis of reliable global data detailing the relative abundance of polymers in freshwaters and estuaries. The polymers were identified according to seven main categories: polyethylene terephthalate, polyethylene, polyvinyl chloride, polypropylene, polystyrene, polyurethane and a final category of miscellaneous plastic. The results show that microplastics comprised of polyvinyl chloride and polyurethane are significantly less abundant than would be expected based on global production, possibly due to their use. This has implications for models of microplastic release into the environment based on production and fate. When analysed by matrix (water, sediment or biota) distinct profiles were obtained for each category. Polyethylene, polypropylene and polystyrene were more abundant in sediment than in biota, while miscellaneous plastics was more frequent in biota. The data suggest that environmental sorting of microplastic particles, influenced by physical, chemical and biological processes, may play a key role in environmental impact, although partitioning among matrices based on density was not realized. The distinct profile of microplastics in biota raises an important question regarding potential selectivity in uptake by organisms, highlighting the priority for more and better-informed laboratory exposure studies.

Background: Facilitating patient conversion to hospice at end of life is a prominent clinical concern. Enrollment in outpatient palliative care services is often assumed to encourage seamless transition to hospice care, but this has not been demonstrated. Moreover, decisions to convert from palliative care to hospice are generally treated as dichotomous, thus hampering our ability to understand decision processes., Objective: To examine medical decision-making among patients who are prospectively evaluating whether to convert from palliative care to hospice., Design: Qualitative case study, using in-depth interviews and constant comparative method., Setting/patients: Terminally ill patients currently enrolled in outpatient palliative care services (N = 26) and their caregivers (N = 16), selected purposely for maximum variation in condition and personal background., Measurements: Themes identified in qualitative in-depth interviews., Results: Patients rarely refused hospice outright but more often postponed using a "soft no," in which they neither accepted nor overtly refused hospice. Justifications patients and caregivers offered for why hospice was not needed (yet) appeared in these themes: (1) not seeing the value added of hospice, (2) assuming the timing is premature, and (3) relying on extensive health-related support networks that justify or endorse continuation of active care., Conclusions: Despite assumptions to the contrary, benefits associated with utilization of outpatient palliative care services have the potential to incentivize the delay of hospice in some cases. Clinical interactions with outpatient palliative care patients should consider the influence of these broad social support systems when discussing hospice options.

Historically, solid wastes were commonly landfilled in the coastal zone in sites with limited engineering to isolate waste from adjacent coastal environments. Climate change is increasing the likelihood that these historic coastal landfills will be inundated or eroded resulting in the release of soluble contaminants to the coastal zone. Previously research has focussed on the environmental impacts of leaching from landfills in freshwater environments with little or no consideration being given to saline environments. This research investigated the magnitude, variability and potential environmental consequences of soluble metal release from solid wastes when historic coastal landfills are inundated, or wastes are eroded and released into fresh or saline waters. The proportions of the sites' total metal contents released to solution varied by up to an order of magnitude between different landfills due to the different physical and chemical characteristics of the solid wastes, but the proportions released were typically ≪1% in freshwater. Inundation by saline water significantly increases the proportions of the total metal contents released to solution, e.g. 5450% more Pb in one study site (median value), but again the proportions were typically ≪1%. The exception was Cd, where up to 9% of the total Cd load of one site was released in saline water. This puts into question the suitability of current landfill regulatory tests, e.g. the EU Waste Acceptance Criteria, and many risk assessment methods, which only consider freshwater inundation and leaching. However, the very low proportions of metals mobilised from the solid waste and the high dilution ratios in coastal waters, mean EQSs for the Protection of Surface Water are unlikely to be exceeded, and the release of solid wastes through coastal erosion poses a greater threat to coastal ecological health than leaching of soluble metals from contained solid wastes., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aims: Preoperative short-course radiotherapy (SCRT) is an important treatment option for rectal cancer. The length of time between completing SCRT and surgery may influence postoperative outcomes, but the evidence available to determine the optimal interval is limited and often conflicting., Materials and Methods: Information was extracted from a colorectal cancer data repository (CORECT-R) on all surgically treated rectal cancer patients who received SCRT in the English National Health Service between April 2009 and December 2014. The time from radiotherapy to surgery was described across the population. Thirty-day postoperative mortality, returns to theatre, length of stay and 1-year survival were investigated in relation to the interval between radiotherapy and surgery., Results: Within the cohort of 3469 patients, the time to surgery was 0-7 days for 76% of patients, 8-14 days for 19% of patients and 15-27 days for 5% of patients. There was a clear variation in relation to different patient characteristics. There was, however, no evidence of differences in postoperative outcomes in relation to interval length., Conclusions: This study suggests that the time interval between SCRT and surgery does not influence postoperative outcomes up to a year after surgery. The study provides population-level, real-world evidence to complement that from clinical trials., (Copyright © 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Metal-rich sediments have the potential to impair life in freshwater streams and rivers and, thereby, to inhibit recovery of ecological conditions after any remediation of mine water discharges. Sediments remain metal-rich over long time periods and have long-term potential ecotoxicological interactions with local biota, unless the sediments themselves are physically removed or replaced by less metal-rich sediment. Laboratory-derived environmental quality standards are difficult to apply to the field situation, as many complicating factors exist in the real world. Therefore, there is a strong case to consider other, field-relevant, measures of toxic effects as alternatives to laboratory-derived standards and to seek better biological tools to detect, diagnose and ideally predict community-level ecotoxicological impairment. Hence, this review concentrated on field measures of toxic effects of metal-rich sediment in freshwater streams, with less emphasis on laboratory-based toxicity testing approaches. To this end, this review provides an overview of the impact of metal-rich sediments on freshwater stream life, focusing on biological impacts linked to metal contamination.

Background: Stereotactic radiotherapy (SBRT) might improve pain and local control in patients with bone metastases compared to conventional radiotherapy, although an overall estimate of these outcomes is currently unknown., Methods: A systematic review was carried out following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Pubmed, Embase, and Cochrane databases were systematically searched to identify studies reporting pain response and local control among patients with bone metastases from solid-organ tumors who underwent SBRT in 1-6 fractions. All studies prior to April 15, 2017, were included. Study quality was assessed by predefined criteria, and pain response and local control rates were extracted., Results: A total of 2619 studies were screened; 57 were included (reporting outcomes for 3995 patients) of which 38 reported pain response and 45 local control rates. Local control rates were high with pain response rates above those previously reported for conventional radiotherapy. Marked heterogeneity in study populations and delivered treatments were identified such that quantitative synthesis was not appropriate. Reported toxicity was limited. Of the pain response studies, 73.7% used a retrospective cohort design and only 10.5% used the international consensus endpoint definitions of pain response. The median survival within the included studies ranged from 8 to 30.4 months, suggesting a high risk of selection bias in the included observational studies., Conclusions: This review demonstrates the potential benefit of SBRT over conventional palliative radiotherapy in improving pain due to bone metastases. Given the methodological limitations of the published literature, however, large randomized trials are now urgently required to better quantify this benefit., (© The Author(s) 2019. Published by Oxford University Press.)

Historically solid waste was commonly landfilled in the coastal zone in sites with limited engineering to isolate waste from adjacent coastal environments. Climate change is increasing the likelihood that these historic coastal landfills will erode releasing solid waste to the coastal zone. Historic coastal landfills are frequently located near designated ecological sites; yet, there is little understanding of the environmental risk posed by released waste. This research investigated inorganic and organic contaminant concentrations in a range of solid waste materials excavated from two historic coastal landfills, and the potential ecological impact should eroded waste be released to the coastal environment. Contaminant concentrations in the analysed waste materials exceeded sediment quality guidelines, indicating erosion of historic coastal landfills may pose a significant environmental threat. Paper and textile wastes were found to make a significant contribution to the total contaminant load, suggesting risk assessments should consider a wide range of solid waste materials., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Surgery is the standard of care for early-stage lung cancer, with stereotactic ablative body radiotherapy (SABR) a lower morbidity alternative for patients with limited physiological reserve. Comparisons of outcomes between these treatment options are limited by competing comorbidities and differences in pre-treatment pathological information. This study aims to address these issues by assessing both overall and cancer-specific survival for presumed stage I lung cancer on an intention-to-treat basis., Methods: This retrospective intention-to-treat analysis identified all patients treated for presumed stage I lung cancer within a single large UK centre. Overall survival, cancer-specific survival, and combined cancer and treatment-related survival were assessed with adjustment for confounding variables using Cox proportional hazards and Fine-Gray competing risks analyses., Results: 468 patients (including 316 surgery and 99 SABR) were included in the study population. Compared with surgery, SABR was associated with inferior overall survival on multivariable Cox modelling (SABR HR 1.84 (95% CI 1.32-2.57)), but there was no difference in cancer-specific survival (SABR HR 1.47 (95% CI 0.80-2.69)) or combined cancer and treatment-related survival (SABR HR 1.27 (95% CI 0.74-2.17)). Combined cancer and treatment-related death was no different between SABR and surgery on Fine-Gray competing risks multivariable modelling (subdistribution hazard 1.03 (95% CI 0.59-1.81)). Non-cancer-related death was significantly higher in SABR than surgery (subdistribution hazard 2.16 (95% CI 1.41-3.32))., Conclusion: In this analysis, no difference in cancer-specific survival was observed between SABR and surgery. Further work is needed to define predictors of outcome and help inform treatment decisions., Competing Interests: Conflict of interest: K.L. Spencer has nothing to disclose. Conflict of interest: M.P.T. Kennedy has nothing to disclose. Conflict of interest: K.L. Lummis has nothing to disclose. Conflict of interest: D.A.B. Ellames has nothing to disclose. Conflict of interest: M. Snee has nothing to disclose. Conflict of interest: A. Brunelli has nothing to disclose. Conflict of interest: K. Franks reports personal fees for advisory board work from Pfizer and BMS, personal fees for advisory board work and support for conference attendance from AstraZeneca, and personal fees for educational meetings and support for conference attendance from Boehringer Ingelheim, outside the submitted work. Conflict of interest: M.E.J. Callister has nothing to disclose., (Copyright ©ERS 2019.)

Managed realignment (MR) schemes are being implemented to compensate for the loss of intertidal saltmarsh habitats by breaching flood defences and inundating the formerly defended coastal hinterland. However, studies have shown that MR sites have lower biodiversity than anticipated, which has been linked with anoxia and poor drainage resulting from compaction and the collapse of sediment pore space caused by the site's former terrestrial land use. Despite this proposed link between biodiversity and soil structure, the evolution of the sediment sub-surface following site inundation has rarely been examined, particularly over the early stages of the terrestrial to marine or estuarine transition. This paper presents a novel combination of broad- and intensive-scale analysis of the sub-surface evolution of the Medmerry Managed Realignment Site (West Sussex, UK) in the three years following site inundation. Repeated broad-scale sediment physiochemical datasets are analysed to assess the early changes in the sediment subsurface and the preservation of the former terrestrial surface, comparing four locations of different former land uses. Additionally, for two of these locations, high-intensity 3D-computed X-ray microtomography and Itrax micro-X-ray fluorescence spectrometry analyses are presented. Results provide new data on differences in sediment properties and structure related to the former land use, indicating that increased agricultural activity leads to increased compaction and reduced porosity. The presence of anoxic conditions, indicative of poor hydrological connectivity between the terrestrial and post-inundation intertidal sediment facies, was only detected at one site. This site has experienced the highest rate of accretion over the terrestrial surface (ca. 7 cm over 36 months), suggesting that poor drainage is caused by the interaction (or lack of) between sediment facies rather than the former land use. This has significant implications for the design of future MR sites in terms of preparing sites, their anticipated evolution, and the delivery of ecosystem services., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The term patient noncompliance emerged in the 1970s as a tool for analyzing why people do not follow medical directives. Despite its early popularity, the term has languished in sociology while flourishing in biomedical arenas. It seems flaccid in a contemporary healthcare context as it overestimates physician authority and is tone-deaf to biomedicalization. I draw from sociological and anthropological traditions, as well as qualitative interviews with terminally ill patients ( N = 26) and their caregivers ( N = 16), to consider facets of a biomedicalized health experience and implications for an updated vision of compliance. First, pathways to care have proliferated under biomedicalization. With increased pathways comes increased need for understanding how treatment plans are socially constituted and assessed. Finally, increased complexity demands a more diverse vocabulary for understanding health related decisions. This paper is a call to sociologists to take the lead in transforming and updating this consequential concept.

Metals are concerning pollutants in estuaries, where contamination can undergo significant remobilisation driven by physico-chemical forcing. Environmental concentrations of metals in estuarine sediments are often higher than natural backgrounds, but show no contiguity to potential sources. Thus, better understanding the metal mobility in estuaries is essential to improve identification of pollution sources and their accountability for environmental effects. This study aims to identify the key biogeochemical drivers of metal mobilisation on contaminated estuarine sediments through (1) evaluation of the potential mobilisation under controlled conditions, and (2) investigation of the relevance of metal mobilisation for in situ pollution levels in an area with multiple contaminant sources. Sediments from a saltmarsh adjacent to a coastal landfill, a marina, and a shipyard on the Thames Estuary (Essex, UK) were exposed in the laboratory (24h, N=96, 20°C) to water under various salinity, pH, and redox potential. Major cations, Fe(II), and trace metal concentrations were analysed in the leachate and sediment. Salinity, pH and redox had a significant effect on metal mobilisation (p<0.001), e.g. under certain conditions Fe(II) leaching was increased ~1000-fold. Measurements in situ of surface and subsurface sediment cores revealed that landfill proximity poorly explained metal spatial distribution. However, physicochemical parameters explained up to 97% of geochemically normalized metal concentrations in sediments. Organic matter and pH were dominant factors for most of the metal concentrations at the sediment surface. At subsurface, major cations (Ca, Na, Mg and K) were determinant predictors of metal concentrations. Applying the empirical model obtained in the laboratory to geochemical conditions of the studied saltmarsh it was possible to demonstrate that Fe mobilisation regulates the fate of this (and other) metal in that area. Thus, present results highlight the importance of metal mobility to control sediment pollution and estuarine fate of metals., (Copyright © 2017 Elsevier B.V. All rights reserved.)

A growing body of social science literature is devoted to describing processes of biomedicalization. The issue of biomedicalization is especially relevant for individuals suffering from end-stage cancer and hoping that aggressive end-of-life interventions, which are riddled with uncertainty around quantity or quality of life, will produce a 'cure'. To examine hospice underutilization among end-stage cancer patients, we apply the anthropological concept 'political economy of hope,' which describes how personal and collective 'hope' is associated with the political and economic structures that produce biomedicalization processes. Previous studies have examined hospice underutilization among end-stage cancer patients and have identified barriers stemming from patient and physician characteristics or health insurance reimbursement policies. Yet, these studies do not provide an organized synthesis of how barriers articulate, how they are part of the longitudinal decision-making process, or describe the sociocultural context surrounding hospice care enrollment decisions. This paper focuses on US-specific mechanisms and is based on qualitative, in-depth, interviews with physicians at an academic hospital (N = 24). We find that hospice underutilization results from a web of interconnected constraints surrounding end-stage cancer patients. Our research reveals how hospice care contradicts the political and economic structures associated with end-stage cancer care and illustrates how end-stage cancer patients are transformed into a form of biovalue, a fundamental commodity sustaining the political economy of hope., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Prior to modern environmental regulation landfills in low-lying coastal environments were frequently constructed without leachate control, relying on natural attenuation within inter-tidal sediments to dilute and disperse contaminants reducing environmental impact. With sea level rise and coastal erosion these sites may now pose a pollution risk, yet have received little investigation. This work examines the extent of metal contamination in saltmarsh sediments surrounding a historic landfill in the UK. Patterns of sediment metal data suggest typical anthropogenic pollution chronologies for saltmarsh sediments in industrialised nations. However, many metals were also enriched at depth in close proximity to the landfill boundary and are indicative of a historical leachate plume. Though this total metal load is low, e.g., c. 1200 and 1650kg Pb and Zn respectively, with >1000 historic landfills on flood risk or eroding coastlines in the UK this could represent a significant, yet under-investigated, source of diffuse pollution., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Suspended particulate matter (SPM) is present in the natural aquatic environment as loosely bound aggregates or "flocs" and is responsible for the transport and fate of sediment, carbon, nutrients, pollutants, pathogens and manufactured nanoparticles from catchment to coast. Accurate prediction of SPM hydrodynamics requires the quantification of 3D floc properties (size, shape, density and porosity) that span several spatial scales. Yet, current techniques (video camera systems, optical microscopy and transmission electron microscopy, TEM) can only provide 2D simplifications of size and shape with a spatial resolution gap between the "gross" (>100s μm) and nanoscale (<1 μm). Here, we translate 3D-microscopy techniques (focused ion beam nanotomography, FIB-nt) typically used in the biomedical sciences to the study of natural flocculated SPM filling both this spatial and dimensional gap. Fragile 3D floc samples were successfully captured and stabilized, identifying five basic organic and inorganic floc components and quantifying porosity and bacteria numbers. This provides new 3D floc geometric data sets at the nanoscale that will be critical in the development of cohesive sediment transport models. Detailed compositional and structural information could provide novel insights into the association of pathogens and pollutants with SPM and their impact on aquatic life.

Objectives: This study aimed to calculate the fluoride concentrations of commonly consumed foods and beverages for 2-years-old children utilizing market basket information for the US Midwest region., Methods: Total Diet Study food lists were cross-referenced with National Health and Nutrition Examination Survey-What We Eat in America data to determine the foods and beverages to be included. Fluoride concentrations were determined using a modification of the hexamethyldisiloxane microdiffusion technique. Fluoride concentrations were summarized for each of the food categories. Daily dietary fluoride intake was estimated using a simulation analysis., Results: Food and beverage fluoride concentrations varied widely, ranging from nondetectable for some oils and dairy products to more than 3.0 μgF/g food for some processed meats, fish and fruits. The estimated mean (±SD) daily dietary fluoride intake, excluding dentifrice and supplements, was 412±114 μgF/d. The estimated average ingestion for a 2-years-old weighing 12.24 kg was 0.034±0.009 mg/kg/d. A diet based on foods and beverages in the fifth percentile of fluoride intake distribution for an average child would result in 247 μgF/d or 0.020 mg/kg/d, while a diet with foods and beverages in the 95th percentile would result in a total intake of 622 μgF/d or 0.051 mg/kg/d., Conclusions: The fluoride concentrations of foods and beverages vary widely, and, if items in the 95th percentile of fluoride intake distribution are ingested, children could consume more fluoride than the recommended 0.05 mg/kg/d. Fluoride intake calculated in this study was higher than historically reported dietary levels., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Saltmarshes are being lost or degraded as a result of human activity resulting in loss of critical ecosystem services including the provision of wild species diversity, water quality regulation and flood regulation. To compensate, saltmarshes are being restored or re-created, usually driven by legislative requirements for increased habitat diversity, flood regulation and sustainable coastal defense. Yet, there is increasing evidence that restoration may not deliver anticipated ecosystem services; this is frequently attributed to poor drainage and sediment anoxia. However, physical sediment characteristics, hydrology and the sediment geochemical environment are rarely examined in restoration schemes, despite such factors being critical for plant succession. This study presents the novel integration of 3D-computed X-ray microtomography to quantify sediment structure and porosity, with water level and geochemical data to understand the impact of pre-restoration land use and disturbance on the structure and functioning of restored saltmarshes. The study combines a broad-scale investigation of physical sediment characteristics in nine de-embanked saltmarshes across SE England, with an intensive study at one site examining water levels, sediment structure and the sediment geochemical environment. De-embankment does not restore the hydrological regime, or the physical/chemical framework in the saltmarshes and evidence of disturbance includes a reduction in microporosity, pore connectivity and water storage capacity, a lack of connectivity between the sub-surface environment and overlying floodwaters, and impeded sub-surface water flow and drainage. This has significant consequences for the sediment geochemical environment. This disturbance is evident for at least two decades following restoration and is likely to be irreversible. It has important implications for plant establishment in particular, ecosystem services including flood regulation, nutrient cycling and wild species diversity and for future restoration design., (Copyright © 2016 Elsevier B.V. All rights reserved.)

P (phosphorus) and Fe (iron) are limiting elements and S (sulfur) is an important element of the biogeochemical cycle in the mangrove environment. To assess the effects of sulfur on the geochemical cycling of Fe and P at the sediment-plant interface, the speciation distributions of Fe, P and S in sediments were examined. The data showed that higher proportions of amorphous Fe, Fe-bound phosphate, chromium reducible sulfur and elemental sulfur were found in the rhizosphere, while more crystalline Fe, exchangeable phosphate and acid-volatile sulfide were determined in the non-rhizosphere. Sulfate application induced an increase in the Ex-P concentration, high P accumulation and high iron plaque deposition in the roots. In conclusion, sulfate applications had a significant influence on the geochemical cycling of Fe and P in the sediments. It significantly curtailed the Fe and P limit to plant growth and enhanced plant resistance to the rugged surroundings in mangrove., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: Substantial progress has been made in identifying susceptibility variants for AMD in European populations; however, few studies have been conducted to understand the role these variants play in AMD risk in diverse populations. The present study aims to examine AMD risk across diverse populations in known and suspected AMD complement factor and lipid-related loci., Methods: Targeted genotyping was performed across study sites for AMD and lipid trait-associated single nucleotide polymorphism (SNPs). Genetic association tests were performed at individual sites and then meta-analyzed using logistic regression assuming an additive genetic model stratified by self-described race/ethnicity. Participants included cases with early or late AMD and controls with no signs of AMD as determined by fundus photography. Populations included in this study were European Americans, African Americans, Mexican Americans, and Singaporeans from the Population Architecture using Genomics and Epidemiology (PAGE) study., Results: Index variants of AMD, rs1061170 (CFH) and rs10490924 (ARMS2), were associated with AMD at P=3.05×10(-8) and P=6.36×10(-6), respectively, in European Americans. In general, none of the major AMD index variants generalized to our non-European populations with the exception of rs10490924 in Mexican Americans at an uncorrected P value<0.05. Four lipid-associated SNPS (LPL rs328, TRIB1 rs6987702, CETP rs1800775, and KCTD10/MVK rs2338104) were associated with AMD in African Americans and Mexican Americans (P<0.05), but these associations did not survive strict corrections for multiple testing., Conclusions: While most associations did not generalize in the non-European populations, variants within lipid-related genes were found to be associated with AMD. This study highlights the need for larger well-powered studies in non-European populations., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

Background: Multiple genome-wide association studies (GWAS) within European populations have implicated common genetic variants associated with insulin and glucose concentrations. In contrast, few studies have been conducted within minority groups, which carry the highest burden of impaired glucose homeostasis and type 2 diabetes in the U.S., Methods: As part of the 'Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we investigated the association of up to 10 GWAS-identified single nucleotide polymorphisms (SNPs) in 8 genetic regions with glucose or insulin concentrations in up to 36,579 non-diabetic subjects including 23,323 European Americans (EA) and 7,526 African Americans (AA), 3,140 Hispanics, 1,779 American Indians (AI), and 811 Asians. We estimated the association between each SNP and fasting glucose or log-transformed fasting insulin, followed by meta-analysis to combine results across PAGE sites., Results: Overall, our results show that 9/9 GWAS SNPs are associated with glucose in EA (p = 0.04 to 9 × 10-15), versus 3/9 in AA (p= 0.03 to 6 × 10-5), 3/4 SNPs in Hispanics, 2/4 SNPs in AI, and 1/2 SNPs in Asians. For insulin we observed a significant association with rs780094/GCKR in EA, Hispanics and AI only., Conclusions: Generalization of results across multiple racial/ethnic groups helps confirm the relevance of some of these loci for glucose and insulin metabolism. Lack of association in non-EA groups may be due to insufficient power, or to unique patterns of linkage disequilibrium.

The vast majority of genome-wide association study (GWAS) findings reported to date are from populations with European Ancestry (EA), and it is not yet clear how broadly the genetic associations described will generalize to populations of diverse ancestry. The Population Architecture Using Genomics and Epidemiology (PAGE) study is a consortium of multi-ancestry, population-based studies formed with the objective of refining our understanding of the genetic architecture of common traits emerging from GWAS. In the present analysis of five common diseases and traits, including body mass index, type 2 diabetes, and lipid levels, we compare direction and magnitude of effects for GWAS-identified variants in multiple non-EA populations against EA findings. We demonstrate that, in all populations analyzed, a significant majority of GWAS-identified variants have allelic associations in the same direction as in EA, with none showing a statistically significant effect in the opposite direction, after adjustment for multiple testing. However, 25% of tagSNPs identified in EA GWAS have significantly different effect sizes in at least one non-EA population, and these differential effects were most frequent in African Americans where all differential effects were diluted toward the null. We demonstrate that differential LD between tagSNPs and functional variants within populations contributes significantly to dilute effect sizes in this population. Although most variants identified from GWAS in EA populations generalize to all non-EA populations assessed, genetic models derived from GWAS findings in EA may generate spurious results in non-EA populations due to differential effect sizes. Regardless of the origin of the differential effects, caution should be exercised in applying any genetic risk prediction model based on tagSNPs outside of the ancestry group in which it was derived. Models based directly on functional variation may generalize more robustly, but the identification of functional variants remains challenging., Competing Interests: The authors have declared that no competing interests exist. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIH, the Centers for Disease Control, the Indian Health Service, or any other funding agency.

Study Question: Do genetic associations identified in genome-wide association studies (GWAS) of age at menarche (AM) and age at natural menopause (ANM) replicate in women of diverse race/ancestry from the Population Architecture using Genomics and Epidemiology (PAGE) Study?, Summary Answer: We replicated GWAS reproductive trait single nucleotide polymorphisms (SNPs) in our European descent population and found that many SNPs were also associated with AM and ANM in populations of diverse ancestry., What Is Known Already: Menarche and menopause mark the reproductive lifespan in women and are important risk factors for chronic diseases including obesity, cardiovascular disease and cancer. Both events are believed to be influenced by environmental and genetic factors, and vary in populations differing by genetic ancestry and geography. Most genetic variants associated with these traits have been identified in GWAS of European-descent populations., Study Design, Size, Duration: A total of 42 251 women of diverse ancestry from PAGE were included in cross-sectional analyses of AM and ANM., Materials, Setting, Methods: SNPs previously associated with ANM (n = 5 SNPs) and AM (n = 3 SNPs) in GWAS were genotyped in American Indians, African Americans, Asians, European Americans, Hispanics and Native Hawaiians. To test SNP associations with ANM or AM, we used linear regression models stratified by race/ethnicity and PAGE sub-study. Results were then combined in race-specific fixed effect meta-analyses for each outcome. For replication and generalization analyses, significance was defined at P < 0.01 for ANM analyses and P < 0.017 for AM analyses., Main Results and the Role of Chance: We replicated findings for AM SNPs in the LIN28B locus and an intergenic region on 9q31 in European Americans. The LIN28B SNPs (rs314277 and rs314280) were also significantly associated with AM in Asians, but not in other race/ethnicity groups. Linkage disequilibrium (LD) patterns at this locus varied widely among the ancestral groups. With the exception of an intergenic SNP at 13q34, all ANM SNPs replicated in European Americans. Three were significantly associated with ANM in other race/ethnicity populations: rs2153157 (6p24.2/SYCP2L), rs365132 (5q35/UIMC1) and rs16991615 (20p12.3/MCM8). While rs1172822 (19q13/BRSK1) was not significant in the populations of non-European descent, effect sizes showed similar trends., Limitations, Reasons for Caution: Lack of association for the GWAS SNPs in the non-European American groups may be due to differences in locus LD patterns between these groups and the European-descent populations included in the GWAS discovery studies; and in some cases, lower power may also contribute to non-significant findings., Wider Implications of the Findings: The discovery of genetic variants associated with the reproductive traits provides an important opportunity to elucidate the biological mechanisms involved with normal variation and disorders of menarche and menopause. In this study we replicated most, but not all reported SNPs in European descent populations and examined the epidemiologic architecture of these early reported variants, describing their generalizability and effect size across differing ancestral populations. Such data will be increasingly important for prioritizing GWAS SNPs for follow-up in fine-mapping and resequencing studies, as well as in translational research.

A loss-of-function mutation (Q141K, rs2231142) in the ATP-binding cassette, subfamily G, member 2 gene (ABCG2) has been shown to be associated with serum uric acid levels and gout in Asians, Europeans, and European and African Americans; however, less is known about these associations in other populations. Rs2231142 was genotyped in 22,734 European Americans, 9,720 African Americans, 3,849 Mexican Americans, and 3,550 American Indians in the Population Architecture using Genomics and Epidemiology (PAGE) Study (2008-2012). Rs2231142 was significantly associated with serum uric acid levels (P = 2.37 × 10(-67), P = 3.98 × 10(-5), P = 6.97 × 10(-9), and P = 5.33 × 10(-4) in European Americans, African Americans, Mexican Americans, and American Indians, respectively) and gout (P = 2.83 × 10(-10), P = 0.01, and P = 0.01 in European Americans, African Americans, and Mexican Americans, respectively). Overall, the T allele was associated with a 0.24-mg/dL increase in serum uric acid level (P = 1.37 × 10(-80)) and a 1.75-fold increase in the odds of gout (P = 1.09 × 10(-12)). The association between rs2231142 and serum uric acid was significantly stronger in men, postmenopausal women, and hormone therapy users compared with their counterparts. The association with gout was also significantly stronger in men than in women. These results highlight a possible role of sex hormones in the regulation of ABCG2 urate transporter and its potential implications for the prevention, diagnosis, and treatment of hyperuricemia and gout.

Genetic association studies have rapidly become a major tool for identifying the genetic basis of common human diseases. The advent of cost-effective genotyping coupled with large collections of samples linked to clinical outcomes and quantitative traits now make it possible to systematically characterize genotype-phenotype relationships in diverse populations and extensive datasets. To capitalize on these advancements, the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) project, as part of the collaborative Population Architecture using Genomics and Epidemiology (PAGE) study, accesses two collections: the National Health and Nutrition Examination Surveys (NHANES) and BioVU, Vanderbilt University's biorepository linked to de-identified electronic medical records. We describe herein the workflows for accessing and using the epidemiologic (NHANES) and clinical (BioVU) collections, where each workflow has been customized to reflect the content and data access limitations of each respective source. We also describe the process by which these data are generated, standardized, and shared for meta-analysis among the PAGE study sites. As a specific example of the use of BioVU, we describe the data mining efforts to define cases and controls for genetic association studies of common cancers in PAGE. Collectively, the efforts described here are a generalized outline for many of the successful approaches that can be used in the era of high-throughput genotype-phenotype associations for moving biomedical discovery forward to new frontiers of data generation and analysis.

Age at menarche (AM) and age at natural menopause (ANM) define the boundaries of the reproductive lifespan in women. Their timing is associated with various diseases, including cancer and cardiovascular disease. Genome-wide association studies have identified several genetic variants associated with either AM or ANM in populations of largely European or Asian descent women. The extent to which these associations generalize to diverse populations remains unknown. Therefore, we sought to replicate previously reported AM and ANM findings and to identify novel AM and ANM variants using the Metabochip (n = 161,098 SNPs) in 4,159 and 1,860 African American women, respectively, in the Women's Health Initiative (WHI) and Atherosclerosis Risk in Communities (ARIC) studies, as part of the Population Architecture using Genomics and Epidemiology (PAGE) Study. We replicated or generalized one previously identified variant for AM, rs1361108/CENPW, and two variants for ANM, rs897798/BRSK1 and rs769450/APOE, to our African American cohort. Overall, generalization of the majority of previously-identified variants for AM and ANM, including LIN28B and MCM8, was not observed in this African American sample. We identified three novel loci associated with ANM that reached significance after multiple testing correction (LDLR rs189596789, p = 5×10⁻⁰⁸; KCNQ1 rs79972789, p = 1.9×10⁻⁰⁷; COL4A3BP rs181686584, p = 2.9×10⁻⁰⁷). Our most significant AM association was upstream of RSF1, a gene implicated in ovarian and breast cancers (rs11604207, p = 1.6×10⁻⁰⁶). While most associations were identified in either AM or ANM, we did identify genes suggestively associated with both: PHACTR1 and ARHGAP42. The lack of generalization coupled with the potentially novel associations identified here emphasize the need for additional genetic discovery efforts for AM and ANM in diverse populations.

The discovery and optimization of a series of 6,7-dihydro-5H-cyclopenta[d]pyrimidine compounds that are ATP-competitive, selective inhibitors of protein kinase B/Akt is reported. The initial design and optimization was guided by the use of X-ray structures of inhibitors in complex with Akt1 and the closely related protein kinase A. The resulting compounds demonstrate potent inhibition of all three Akt isoforms in biochemical assays and poor inhibition of other members of the cAMP-dependent protein kinase/protein kinase G/protein kinase C extended family and block the phosphorylation of multiple downstream targets of Akt in human cancer cell lines. Biological studies with one such compound, 28 (GDC-0068), demonstrate good oral exposure resulting in dose-dependent pharmacodynamic effects on downstream biomarkers and a robust antitumor response in xenograft models in which the phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin pathway is activated. 28 is currently being evaluated in human clinical trials for the treatment of cancer.

A novel series of spirochromane pan-Akt inhibitors is reported. SAR optimization furnished compounds with improved enzyme potencies and excellent selectivity over the related AGC kinase PKA. Attempted replacement of the phenol hinge binder provided compounds with excellent Akt enzyme and cell activities but greatly diminished selectivity over PKA., (Copyright © 2011 Elsevier Ltd. All rights reserved.)