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Summary: Persistent albuminuria (PA) is common in sickle cell anaemia (SCA). With the association of chronic kidney disease (CKD) with increased mortality, biomarkers that predict its development or progression are needed. We evaluated the association of select biomarkers with PA in adults with SCA using Kruskal–Wallis rank‐sum test and logistic regression models, with adjustment for multiple testing. Of 280 subjects, 100 (35.7%) had PA. Median plasma levels of soluble vascular cell adhesion molecule‐1 (VCAM‐1) (1176.3 vs. 953.4 ng/mL, false discovery rate [FDR] q‐value <0.003), thrombin–antithrombin complex (5.5 vs. 4.7 ng/mL, FDR q‐value = 0.04), and urinary angiotensinogen (AGT) (12.2 vs. 5.3 ng/mg, FDR q‐value <0.003), urinary nephrin (30.6 vs. 27.2 ng/mg, FDR q‐value = 0.04), and urinary kidney injury molecule‐1 (KIM‐1) (0.8 vs. 0.5 ng/mg, FDR q‐value <0.003), normalized to urine creatinine, were significantly higher in subjects with PA. In multivariable analysis, only urinary AGT (odds ratio = 1.058, FDR q‐value <0.0001) remained a significant predictor of PA. In addition, soluble VCAM‐1 (FDR q‐value <0.0001), D‐dimer (FDR q‐value <0.0001), urinary AGT (FDR q‐value <0.0001), KIM‐1 (FDR q‐value <0.0001), and nephrin (FDR q‐value <0.0001) were significantly associated with urine albumin–creatinine ratio in multivariable analyses. Longitudinal studies to evaluate the predictive capacity of biomarkers for the development and progression of CKD in SCA are warranted. [ABSTRACT FROM AUTHOR]

Summary: Clinical and laboratory correlates of chronic kidney disease (CKD) in sickle cell anaemia remain incompletely defined. In a multicenter cohort study, we evaluated the prevalence of persistent albuminuria (PA) and characteristics associated with PA, albumin–creatinine ratio (ACR) and decreased estimated glomerular filtration rate (eGFR) using logistic, linear and multinomial regression models, respectively. Of 269 participants (median age: 30 years; 57.2% females), the prevalence of PA was 35.7%. Using baseline ACR values of <100 and ≥100 mg/g, the probabilities of PA were 30.0% and 94.6%, respectively. In multivariable logistic regression analyses, male sex (β = 0.80 [SE = 0.36], p = 0.024) and ACE inhibitors/ARBs use (β = 1.54 [SE = 0.43], p < 0.001) were associated with higher likelihoods of PA, while higher haemoglobin (β = −0.33 [SE = 0.13], p = 0.009) and HbF (β = −0.04 [SE = 0.02], p = 0.041) were associated with lower likelihoods of PA. In multivariable multinomial regression analyses, older age (β = 0.06 [SE = 0.02], p = 0.004) and higher alkaline phosphatase (β = 0.01 [SE = 0.00], p = 0.004) were associated with higher odds of having eGFR 60–90 versus eGFR>90 mL/min/1.73 m2 using the cystatin C‐based CKD‐EPI‐2012 equation. Additionally, higher systolic blood pressure (β = 0.11 [SE = 0.03], p = 0.001) and blood urea nitrogen (β = 0.45 [SE = 0.12], p < 0.001) were associated with higher odds, while higher haemoglobin (β = −1.22 [SE = 0.43], p = 0.004) was associated with lower odds of having eGFR<60 versus eGFR>90 mL/min/1.73 m2. PA and decreased eGFR are associated with measures of disease severity and comorbid conditions (Clinicaltrials.gov Identifier: NCT03277547). [ABSTRACT FROM AUTHOR]

Dose optimization of sirolimus may further improve outcomes in allogeneic hematopoietic cell transplant (HCT) patients receiving post‐transplantation cyclophosphamide (PTCy) to prevent graft‐versus‐host disease (GVHD). Sirolimus exposure–response association studies in HCT patients (i.e., the association of trough concentration with clinical outcomes) have been conflicting. Sirolimus has important effects on T‐cells, including conventional (Tcons) and regulatory T‐cells (Tregs), both of which have been implicated in the mechanisms by which PTCy prevents GVHD, but there is an absence of validated biomarkers of sirolimus effects on these cell subsets. Considering the paucity of existing biomarkers and the complexities of the immune system, we conducted a literature review to inform a quantitative systems pharmacology (QSP) model of GVHD. The published literature presented multiple challenges. The sirolimus pharmacokinetic models insufficiently describe sirolimus distribution to relevant physiological compartments. Despite multiple publications describing sirolimus effects on Tcons and Tregs in preclinical and human ex vivo models, consistent parameters relating sirolimus concentrations to circulating Tcons and Tregs could not be found. Each aspect presents a challenge in building a QSP model of sirolimus and its temporal effects on T‐cell subsets and GVHD prevention. To optimize GVHD prevention regimens, phase I studies and systematic studies of immunosuppressant concentration–effect association are needed for QSP modeling. [ABSTRACT FROM AUTHOR]

Pharmacogenomics is a growing area of medicine, and pharmacists across clinical practice settings have the opportunity to individualize medication selection and dosing using genetic data. However, many practicing pharmacists may feel ill‐equipped to interpret pharmacogenomic test results because of insufficient education and training. Evidence‐based, updated, and freely available resources such as the Clinical Pharmacogenetics Implementation Consortium guidelines can help pharmacists interpret and apply pharmacogenomic test results to patient care. Although gaps for the application of pharmacogenomic information exist, this commentary aims to demystify the interpretation of pharmacogenomic test results and empower pharmacists to apply genetic data alongside other clinical variables to optimize medication‐related outcomes for their patients. An "ABCD" framework is proposed to guide pharmacists through the steps: (1) Actionability—Are the gene(s) clinically relevant for the patient? (2) Be Mindful of Limitations—What are the caveats with pharmacogenomic test results and reports? (3) Clinical Practice Guidelines—How do you use pharmacogenomic test results to guide clinical decision‐making? and (4) Document and Discuss—How do you educate the patient about their pharmacogenomic test results and document the results for future use? Key concepts are illustrated using a psychiatric patient case example. [ABSTRACT FROM AUTHOR]

Busulfan is hepatically metabolized through glutathione (GSH) conjugation; in vitro, this process depletes hepatocyte GSH stores and generates the cytotoxic metabolite γ‐glutamyldehydroalanylglycine, which is too unstable to be quantitated in vivo. We sought to evaluate if pre‐graft (i.e., immediately before allograft infusion) concentrations of busulfan metabolites' and of endogenous metabolomic compounds (EMCs) representing the glutathione pathway were associated with clinical outcomes in hematopoietic cell transplant (HCT) recipients receiving busulfan. The clinical outcomes evaluated were relapse, acute graft versus host disease (GVHD), chronic GVHD, non‐relapse mortality, and neutrophil nadir. In pre‐graft samples obtained from patients immediately before allograft infusion, our objectives were to evaluate for: (1) the presence of busulfan and its metabolites tetrahydrothiophenium ion (THT+), tetrahydrothiophene 1‐oxide, sulfolane, and 3‐hydroxysulfolane (N = 124); (2) EMCs using a global metabolomics assay (N = 77); and (3) the association of the busulfan metabolites and the EMCs with clinical outcomes. In the pre‐graft samples, busulfan and THT+ could not be detected. THT 1‐oxide, sulfolane, and 3‐hydroxysulfolane were quantitated in 9.6%, 26%, and 58% of pre‐graft samples; their concentrations were not associated with clinical outcomes. Four pre‐graft EMCs were statistically significantly associated with the neutrophil nadir. The pre‐graft EMCs were not associated with the other clinical outcomes. In conclusion, busulfan's metabolites are present in patients' plasma immediately before allograft infusion; the neutrophil nadir is associated with pre‐graft EMCs. Future research should investigate the association of clinical outcomes with the concentrations of busulfan's metabolites and EMCs in the pre‐graft plasma from allogeneic HCT recipients. [ABSTRACT FROM AUTHOR]

Premise: Dryland ecosystems in the western United States are affected by invasive species, wildfires, livestock grazing, and climate change in ways that are difficult to distinguish. Biocrusts perform important ecological roles in these systems and are sensitive to all of these pressures. Methods: We revisited a Washington, USA, site sampled for biocrusts in 1999 to focus on effects of exotic annual grass invasion and wildfires in the absence of livestock grazing. We examined changes between 1999 and 2020 using a Bayesian directed acyclic graph (DAG) to interpret direct and indirect causal impacts of wildfire on perennial bunchgrasses, exotic annual grasses, and biocrusts. Results: Between 1999 and 2020, exotic annual grass cover increased in all plots and in unburned plots by 16% and 18%, respectively, bunchgrass cover decreased by 21% and 25%, and biocrust cover decreased by 8.9% and 9.8%. Our DAG suggested that decreases in bunchgrass increased exotic annual grass, which reduced biocrust cover. Wildfires did not directly influence changes in bunchgrass, exotic annual grass, or biocrust cover. Areas dominated by exotic annual grass had less abundant and diverse biocrusts than areas with less exotic annual grass. Conclusions: Biocrust community changes were more strongly related to increasing exotic annual grasses than to wildfires. Changes may relate to other soil disturbances or broad‐scale changes in climate or air quality. The minimal influence of wildfire on exotic annual grass and biocrusts suggests that apparent negative impacts of wildfire at other sites may be due to exacerbation by livestock grazing or other surface disturbance. [ABSTRACT FROM AUTHOR]

Background and Aims: The World Health Assembly recommends integration of palliative care into treatment of patients with any life‐limiting condition, yet patients with non‐malignant disease are less likely to receive specialist palliative care (SPC). This study compares SPC offered to patients with hepatocellular carcinoma (HCC) versus patients with chronic liver disease without HCC (CLD without HCC). Methods: Patients who died from CLD or HCC over 5 years (2013–2017) in England were identified using a dataset linking national data on all hospital admissions (Hospital Episode Statistics – HES) with national mortality data from the Office for National Statistics (HES – ONS). The primary outcome was the proportion of patients who received inpatient SPC in their last year of life (LYOL). Secondary outcomes were (1) early inpatient SPC input and (2) the proportion dying in a hospice. The outcomes were compared between patients with HCC and CLD without HCC. Results: 29 669 patients were identified, 8143 of whom had HCC. Patients with HCC were significantly more likely to receive inpatient SPC input—adjusted OR 3.74 (95% CI 3.52–3.97) and early inpatient SPC input—adjusted OR 7.26 (95% CI 6.38–8.25) and die in a hospice OR 8.23 (95% CI 7.33–9.24) than patients with CLD without HCC. Conclusions: These data highlight the stark inequity in access to SPC services between patients with HCC and patients with CLD without HCC in England. Addressing these inequities will improve end‐of‐life care for patients with CLD. [ABSTRACT FROM AUTHOR]

Background: To address long waitlist times and increase pancreas transplantation, our center has implemented a protocol for long‐distance importation of pancreata. Methods: We conducted a retrospective review of pancreas transplantation at our institution from January 1, 2014, the start of our importation program, through September 30, 2021. Outcomes were compared between locally procured grafts and imported grafts, defined as grafts procured greater than 250 nautical miles (NM) from our center. Results: Eighty‐one patients underwent pancreas transplantation during the study time period; 19 (23.5%) received imported grafts. There were no significant differences in recipient demographics or type of transplant received. Mean distance of import was 644.2 ± 234.0 NM. Imported grafts were more likely to be from pediatric donors <18 years old (p =.02) and a significantly higher proportion of imported grafts came from donors weighing <30 kg (26.3 vs. 3.2%, p =.007). Cold ischemic time was longer for imported grafts than for local grafts (13.4 ± 2.3 h vs. 9.8 ± 2.2 h, p <.01). There was no significant difference in deaths or graft losses within 90 days or at 1 year between groups. Conclusion: Centers should consider expanding criteria for acceptance of imported pancreata to increase the number of transplants and combat organ nonutilization. [ABSTRACT FROM AUTHOR]

Green tea is a popular beverage worldwide. The abundant green tea catechin (−)‐epigallocatechin gallate (EGCG) is a potent in vitro inhibitor of intestinal UDP‐glucuronosyltransferase (UGT) activity (Ki ~2 μM). Co‐consuming green tea with intestinal UGT drug substrates, including raloxifene, could increase systemic drug exposure. The effects of a well‐characterized green tea on the pharmacokinetics of raloxifene, raloxifene 4′‐glucuronide, and raloxifene 6‐glucuronide were evaluated in 16 healthy adults via a three‐arm crossover, fixed‐sequence study. Raloxifene (60 mg) was administered orally with water (baseline), with green tea for 1 day (acute), and on the fifth day after daily green tea administration for 4 days (chronic). Unexpectedly, green tea decreased the geometric mean green tea/baseline raloxifene AUC0–96h ratio to ~0.60 after both acute and chronic administration, which is below the predefined no‐effect range (0.75–1.33). Lack of change in terminal half‐life and glucuronide‐to‐raloxifene ratios indicated the predominant mechanism was not inhibition of intestinal UGT. One potential mechanism includes inhibition of intestinal transport. Using established transfected cell systems, a green tea extract normalized to EGCG inhibited 10 of 16 transporters tested (IC50, 0.37–12 μM). Another potential mechanism, interruption by green tea of gut microbe‐mediated raloxifene reabsorption, prompted a follow‐up exploratory clinical study to evaluate the potential for a green tea–gut microbiota–drug interaction. No clear mechanisms were identified. Overall, results highlight that improvements in current models and methods used to predict UGT‐mediated drug interactions are needed. Informing patients about the risk of co‐consuming green tea with raloxifene may be considered. [ABSTRACT FROM AUTHOR]

Copyright of Angewandte Chemie is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

This work showcases the performance of [NiFeSe] hydrogenase from Desulfomicrobium baculatum for solar‐driven hydrogen generation in a variety of organic‐based deep eutectic solvents. Despite its well‐known sensitivity towards air and organic solvents, the hydrogenase shows remarkable performance under an aerobic atmosphere in these solvents when paired with a TiO2 photocatalyst. Tuning the water content further increases hydrogen evolution activity to a TOF of 60±3 s−1 and quantum yield to 2.3±0.4 % under aerobic conditions, compared to a TOF of 4 s−1 in a purely aqueous solvent. Contrary to common belief, this work therefore demonstrates that placing natural hydrogenases into non‐natural environments can enhance their intrinsic activity beyond their natural performance, paving the way for full water splitting using hydrogenases. [ABSTRACT FROM AUTHOR]

The switch from primitive to definitive hematopoiesis occurs early in development through the emergence of a wave of definitive hematopoietic stem cells from intraembryonic sites, supplanting the original primitive population of extraembryonically derived stem cells. When it became clear that unique features of the fetal immune system could not be reproduced by adult stem cells, it was hypothesized that a lineage of definitive fetal hematopoietic stem cells predominates antenatally, ultimately giving way to an emerging wave of adult stem cells and resulting in a "layered" fetal immune system consisting of overlapping lineages. It is now clear, however, that the transition from human fetal-to-adult T cell identity and function does not occur due to a binary switch between distinct fetal and adult lineages. Rather, recent evidence from single cell analysis suggests that during the latter half of fetal development a gradual, progressive transition occurs at the level of hematopoietic stem-progenitor cells (HSPCs) which is reflected in their T cell progeny. At a transcriptional level, clusters of genes are up-and down-regulated with sequenced timing, suggesting that the transition is under the control of master regulatory factors, including epigenetic modifiers. The net effect is still one of "molecular layering," that is, the continuous layering of iterative generations of HSPCs and T cells that arise through progressive changes in gene expression. This review will focus on recent discoveries that elucidate mechanisms of fetal T cell function and the transition from fetal to adult identity. The epigenetic landscape of fetal T cells facilitates their ability to fulfill the dominant fetal mandate of generating tolerance against self, maternal, and environmental antigens by supporting their predisposition to differentiate into CD25+FoxP3+ regulatory T cells (TRegs). We will explore how the coordinated development of two complementary populations of fetal T cells--conventional T cells dominated by TRegs and tissue-associated memory effector cells with innate-like inflammatory potential--is crucial not only for maintaining intrauterine immune quiescence but also for facilitating an immune response that is appropriately tuned for the bombardment of antigen stimulation that happens at birth. [ABSTRACT FROM AUTHOR]

Objective: Proteinase 3 (PR3) is the major antigen for antineutrophil cytoplasmic antibodies (ANCAs) in the systemic autoimmune vasculitis, granulomatosis with polyangiitis (GPA). PR3‐targeting ANCAs (PR3‐ANCAs) recognize different epitopes on PR3. This study was undertaken to study the effect of mutations on PR3 antigenicity. Methods: The recombinant PR3 variants, iPR3 (clinically used to detect PR3‐ANCAs) and iHm5 (containing 3 point mutations in epitopes 1 and 5 generated for epitope mapping studies) immunoassays and serum samples from patients enrolled in ANCA‐associated vasculitis (AAV) trials were used to screen for differential PR3‐ANCA binding. A patient‐derived monoclonal ANCA 518 (moANCA518) that selectively binds to iHm5 within the mutation‐free epitope 3 and is distant from the point mutations of iHm5 was used as a gauge for remote epitope activation. Selective binding was determined using inhibition experiments. Results: Rather than reduced binding of PR3‐ANCAs to iHm5, we found substantially increased binding of the majority of PR3‐ANCAs to iHm5 compared to iPR3. This differential binding of PR3‐ANCA to iHm5 is similar to the selective moANCA518 binding to iHm5. Binding of iPR3 to monoclonal antibody MCPR3‐2 also induced recognition by moANCA518. Conclusion: The preferential binding of PR3‐ANCAs from patients, such as the selective binding of moANCA518 to iHm5, is conferred by increased antigenicity of epitope 3 on iHm5. This can also be induced on iPR3 when captured by monoclonal antibody MCPR2. This previously unrecognized characteristic of PR3‐ANCA interactions with its target antigen has implications for studying antibody‐mediated autoimmune diseases, understanding variable performance characteristics of immunoassays, and design of potential novel treatment approaches. [ABSTRACT FROM AUTHOR]

Purpose: We wanted to compare glycemic control post pancreas transplantation with newer therapeutic options. Methods: We conducted a retrospective analysis of pancreas transplantation at our institution from January 1, 2008, through September 30, 2021. All patients who underwent pancreatic transplantation were 18 years and older. We compared pre‐transplant glycemic control of those patients, whether self‐monitoring or continuous glucose monitor to their post‐transplant glycemic control. Outcomes were assessed by HgbA1C level at evaluation (eval), pretransplant (pre), within the first 5 months posttransplant (post) and 1 year post transplant (1 year). Results: One hundred and thirty‐four patients underwent pancreas transplantation during the 14‐year study period. Overall, 1‐year patient and graft survival were 95% and 88%. The mean HgbA1C (%) for eval and pre were 8.5(SD ± 1.7) and 8.3(SD ± 1.7), which was significantly higher than post, and 1 year at 5.1(SD ±.6, p <.01) and 5.2(SD ±.6, p <.01). Of those, 38 patients presented with continuous glucose monitors (CGM) +/− pump. Their mean HgbA1C(%) was 8.2(SD ± 1.5) at eval 8.1(SD ± 1.3). These were also significantly higher than post 5.0(SD ±.6, p <.01), and 1 year 5.1(SD ±.5, p <.01). Conclusion: Pancreas transplant provides superior glycemic control to continuous glucose monitoring and remains the optimal therapy for appropriately selected patients with diabetes. [ABSTRACT FROM AUTHOR]

Background: Alcohol use increases the risk of many conditions in addition to liver disease; patients with alcohol‐related liver disease (ALD) are therefore at risk from both extra‐hepatic and hepatic disease. Aims: This review synthesises information about non‐liver‐related mortality in persons with ALD. Methods: A systematic literature review was performed to identify studies describing non‐liver outcomes in ALD. Information about overall non‐liver mortality was extracted from included studies and sub‐categorised into major causes: cardiovascular disease (CVD), non‐liver cancer and infection. Single‐proportion meta‐analysis was done to calculate incidence rates (events/1000 patient‐years) and relative risks (RR) compared with control populations. Results: Thirty‐seven studies describing 50 302 individuals with 155 820 patient‐years of follow‐up were included. Diabetes, CVD and obesity were highly prevalent amongst included patients (5.4%, 10.4% and 20.8% respectively). Outcomes varied across the spectrum of ALD: in alcohol‐related fatty liver the rate of non‐liver mortality was 43.4/1000 patient‐years, whereas in alcoholic hepatitis the rate of non‐liver mortality was 22.5/1000 patient‐years. The risk of all studied outcomes was higher in ALD compared with control populations: The RR of death from CVD was 2.4 (1.6–3.8), from non‐hepatic cancer 2.2 (1.6–2.9) and from infection 8.2 (4.7–14.3). Conclusion: Persons with ALD are at high risk of death from non‐liver causes such as cardiovascular disease and non‐hepatic cancer. [ABSTRACT FROM AUTHOR]

Intravenous busulfan doses are often personalized to a target plasma exposure (targeted busulfan) using an individual's busulfan clearance (BuCL). We evaluated whether BuCL could be predicted by a predose plasma panel of 841 endogenous metabolomic compounds (EMCs). In this prospective cohort of 132 hematopoietic cell transplantation (HCT) patients, all had samples collected immediately before busulfan administration (preBU) and 96 had samples collected 2 weeks before busulfan (2‐week‐preBU). BuCL was significantly associated with 37 EMCs after univariate linear regression analysis and controlling for false discovery (< 0.05) in the 132 preBU samples. In parallel, with preBU samples, we included all 841 EMCs in a least absolute shrinkage and selection operator–penalized regression which selected 13 EMCs as predominantly associated with BuCL. Then, we constructed a prediction model by estimating coefficients for these 13 EMCs, along with sex, using ordinary least‐squares. When the resulting linear prediction model was applied to the 2‐week‐preBU samples, it explained 40% of the variation in BuCL (adjusted R2 = 0.40). Pathway enrichment analysis revealed 18 pathways associated with BuCL. Lysine degradation followed by steroid biosynthesis, which aligned with the univariate analysis, were the top two pathways. BuCL can be predicted before busulfan administration with a linear regression model of 13 EMCs. This pharmacometabolomics method should be prioritized over use of a busulfan test dose or pharmacogenomics to guide busulfan dosing. These results highlight the potential of pharmacometabolomics as a precision medicine tool to improve or replace pharmacokinetics to personalize busulfan doses. [ABSTRACT FROM AUTHOR]

Conservation decisions must be made with limited funding and incomplete information. Ecological surveys can help reduce uncertainty and, in turn, potentially lead to better management decisions. However, conducting surveys can reduce funds available for implementing management actions and, in turn, can potentially lead to worse conservation outcomes.Here we develop a value of information framework to evaluate and optimize survey plans. Our framework evaluates survey plans based on their ability to improve how likely resulting protected area systems are to secure species of interest, and accounts for survey and land acquisition costs. Using an example of eight imperilled plant species in Middlesex County (Ontario, Canada), we assessed our framework against conventional approaches for designing survey plans that involve selecting places with (i) maximal geographic coverage, (ii) diverse environmental conditions, (iii) highly uncertain information, (iv) high imperilled species richness and (v) low protected area establishment costs.We found that optimized survey plans could improve the protected area system by, on average, 57.52% (0.21 SD) (up to 105.25%) over conventional survey approaches. These optimized plans could also improve the protected area system by, on average, 19.91% (up to 32.37%) over simply prioritizing based on existing information. Survey plans designed using conventional approaches, in many cases, led to a worse protected area system than simply using existing information. Such conventional approaches performed the worst when they allocated a large percentage of the available budget to data collection.Synthesis and applications. Our findings demonstrate that conventional approaches for designing ecological surveys can impede conservation efforts by squandering funds on data that have little chance of improving decision making. Indeed, conventional approaches for designing surveys had the poorest performance under limited budgets, which are typical in real world planning exercises. We recommend that conservation practitioners carefully consider how data collection efforts can potentially improve conservation decisions, and also the costs associated with data collection. By applying the principles of value of information, our framework enables conservation practitioners to cost‐effectively collect data in places that will maximize conservation outcomes. [ABSTRACT FROM AUTHOR]

Copyright of Canadian Geographer is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Biomarker‐guided dosing may improve the efficacy and toxicity of cyclophosphamide (CY); however, clinical studies evaluating their association with the area under the plasma concentration–time curve (AUC) of CY and its metabolites are time‐ and resource‐intensive. Therefore, we sought to identify lipidomic biomarkers associated with the time‐varying differences in CY formation clearance to 4‐hydroxycyclophosphamide (4HCY), the principal precursor to CY's cytotoxic metabolite. Hematopoietic cell transplant (HCT) patients receiving post‐transplant CY (PT‐CY) were enrolled, cohort 1 (n = 25) and cohort 2 (n = 26) donating longitudinal blood samples before they started HCT (pre‐HCT), before infusion of the donor allograft (pre‐graft), before the first dose of PT‐CY (pre‐CY) and 24 h after the first dose of PT‐CY (24‐h post‐CY) which is also immediately before the second dose of CY. A total of 409 and 387 lipids were quantitated in the two cohorts, respectively. Associations between lipids, individually and at a class level, and the ratio of 4HCY/CY AUC (i.e., 4HCY formation clearance) were evaluated using linear regression with a false discovery rate <0.05. There were no individual lipids that passed control for false discovery at any time point. These results demonstrate the feasibility of lipidomics, but future studies in larger samples with multiple omic tools are warranted to optimize CY dosing in HCT. [ABSTRACT FROM AUTHOR]

Species distribution models (SDMs) are widely used in ecology. In theory, SDMs capture (at least part of) species' ecological niches and can be used to make inferences about the distribution of suitable habitat for species of interest. Because habitat suitability is expected to influence population demography, SDMs have been used to estimate a variety of population parameters, from occurrence to genetic diversity. However, a critical look at the ability of SDMs to predict independent data across different aspects of population biology is lacking. Here, we systematically reviewed the literature, retrieving 201 studies that tested predictions from SDMs against independent assessments of occurrence, abundance, population performance, and genetic diversity. Although there is some support for the ability of SDMs to predict occurrence (~53% of studies depending on how support was assessed), the predictive performance of these models declines progressively from occurrence to abundance, to population mean fitness, to genetic diversity. At the same time, we observed higher success among studies that evaluated performance for single versus multiple species, pointing to a possible publication bias. Thus, the limited accuracy of SDMs reported here may reflect the best‐case scenario. We discuss the limitations of these models and provide specific recommendations for their use for different applications going forward. However, we emphasize that predictions from SDMs, especially when used to inform conservation decisions, should be treated as hypotheses to be tested with independent data rather than as stand‐ins for the population parameters we seek to know. [ABSTRACT FROM AUTHOR]

Sandra McCune volunteered at her local animal shelter aged 13 and, fascinated by dog and cat behaviour, she went on to become an RVN and then a leading researcher in the field of human‐animal interactions. [ABSTRACT FROM AUTHOR]

The widely used alkylating agent cyclophosphamide (CY) has substantive interpatient variability in the area under the curve (AUC) of it and its metabolites. Numerous factors may influence the drug‐metabolizing enzymes that metabolize CY to 4‐hydroxycyclophosphamide (4HCY), the principal precursor to CY's cytotoxic metabolite. We sought to identify endogenous metabolomics compounds (EMCs) associated with 4HCY formation clearance (ratio of 4HCY/CY AUC) using global metabolomics. Patients who undergo hematopoietic cell transplantation receiving post‐transplant CY (PT‐CY) were enrolled, cohort 1 (n = 26) and cohort 2 (n = 25) donating longitudinal blood samples before they started HCT (pre‐HCT), before infusion of the donor allograft (pre‐graft), before the first dose of PT‐CY (pre‐CY), and 24 h after the first dose of PT‐CY (24‐h post‐CY), which is also immediately before the second dose of CY. A total of 512 and 498 EMCs were quantitated in two cohorts, respectively. Both univariate linear regression with false discovery rate (FDR), and pathway enrichment analyses using a global association test were performed. At the pre‐CY time point, no EMCs were associated at FDR less than 0.1. At pre‐HCT, cohort 1 had one EMC (levoglucosan) survive the FDR threshold. At pre‐graft, cohort 1 and cohort 2 had 20 and 13 EMCs, respectively, exhibiting unadjusted p values less than 0.05, with the only EMCs having an FDR less than 0.1 being two unknown EMCs. At 24‐h post‐CY, there were three EMCs, two ketones, and threitol, at FDR less than 0.1 in cohort 2. These results demonstrate the potential of pharmacometabonomics, but future studies in larger samples are needed to optimize CY. [ABSTRACT FROM AUTHOR]

We examined the impact of language on addiction stigma when using postmodified nouns versus premodified nouns. Use of postmodified nouns was associated with less authoritarian stigmatizing attitudes and higher benevolence than those who received the version with premodified nouns. [ABSTRACT FROM AUTHOR]

Training in the scientific method and research design in doctor of pharmacy (Pharm.D.) curricula enables critical thinking, acquisition of reliable information, rigorous evaluation of emerging literature, and application of evidence‐based medicine in practice. Although research skills are essential for clinical pharmacists and many professional societies recognize the critical need for research in the Pharm.D. curriculum, standardization regarding essential research curricular competencies and content is lacking. Consequently, research skill development is often de‐emphasized in pharmacy education in favor of clinical knowledge and skills. This update to the recommendations of the American College of Clinical Pharmacy's 2008‐2009 Task Force on Research in the Professional Curriculum is provided to meet the evolving needs of contemporary pharmacy practice. The update discusses the importance of research training for Pharm.D. students, proposes essential research competencies and curriculum content for Pharm.D. programs, and highlights several successful strategies for fostering research among Pharm.D. students. In particular, the update advocates enhanced adoption of minimum standards for research skill development across Pharm.D. programs and integration of advanced research competencies to support the development of Pharm.D.‐trained scientists. [ABSTRACT FROM AUTHOR]

Pharmacokinetic drug interactions precipitated by botanical and other natural products (NPs) remain critically understudied. Investigating these complex interactions is fraught with difficulties due to the methodologic and technical challenges associated with the inherently complex chemistries and product variability of NPs. This knowledge gap is perpetuated by a continuing absence of a harmonized framework regarding the design of clinical pharmacokinetic studies of NPs and NP‐drug interactions. Accordingly, this Recommended Approach, the fourth in a series of Recommended Approaches released by the Center of Excellence for Natural Product Drug Interaction Research (NaPDI Center), provides recommendations for the design of clinical pharmacokinetic studies involving NPs. Building on prior Recommended Approaches and data generated from the NaPDI Center, such a framework is presented for the design of (1) phase 0 studies to assess the pharmacokinetics of an NP and (2) clinical pharmacokinetic NP‐drug interaction studies. Suggestions for NP sourcing, dosing, study design, participant selection, sampling periods, and data analysis are presented. With the intent to begin addressing the gap between regulatory agencies' guidance documents about drug‐drug interactions and contemporary NPDI research, the objective of this Recommended Approach is to propose methods for the design of clinical pharmacokinetic studies of NPs and NP‐drug interactions. [ABSTRACT FROM AUTHOR]

Although job crafting has many beneficial outcomes for organisations, research on the antecedents of this behaviour is lacking. Through a two‐wave study including 87 managers and 342 employees of nine Chinese firms, an integrated content and process model of human resource management (HRM) systems is developed and used to demonstrate that HRM systems have a crucial influence on employee job crafting. The results of multilevel structural equation models reveal that implemented HRM systems can increase employee task and relational crafting through the mediating effect of perceived HRM systems. Furthermore, the HRM system features of distinctiveness, consistency and consensus positively moderate the strength of the relationship between implemented and perceived HRM systems, as well as the indirect effect of implemented HRM systems on employee task and relational crafting. [ABSTRACT FROM AUTHOR]

The article discusses the potential implications of a "cure" for HIV on future HIV programs supported by the U.S. President's Emergency for AIDS Relief (PEPFAR). While PEPFAR has made significant progress in providing antiretroviral treatment (ART) to over 20 million people with HIV in low- and middle-income countries, external financial support for HIV programs remains insufficient. The prospect of a durable ART-free suppression of HIV, known as an HIV "cure," is seen as an attractive alternative to ongoing resource commitments. The article highlights a study that demonstrates the potential health benefits and cost-effectiveness of an HIV cure intervention, particularly in settings with high HIV burdens and low ART adherence. The authors emphasize the need for early anticipation of resource needs and tailored pricing to ensure widespread access to an HIV cure in diverse income levels and HIV disease burdens. They suggest that PEPFAR, along with other donors and stakeholders, can play a crucial role in catalyzing efforts to realize the promise of an HIV cure and accelerate the elimination of the virus worldwide. [Extracted from the article]

Objective: Medication access and adherence are important determinants of health outcomes. We investigated factors associated with access and cost‐related nonadherence to prescriptions in a population‐based cohort of systemic lupus erythematosus (SLE) patients and controls. Methods: Detailed sociodemographic and prescription data were collected by structured interview in 2014–2015 from participants in the Michigan Lupus Epidemiology and Surveillance (MILES) cohort. We compared access between cases and frequency‐matched controls and examined associated factors in separate multivariable logistic regression models. Results: A total of 654 participants (462 SLE patients, 192 controls) completed the baseline visit; 584 (89%) were female, 285 (44%) were Black, and the mean age was 53 years. SLE patients and controls reported similar frequencies of being unable to access prescribed medications (12.1% versus 9.4%, respectively; P was not significant). SLE patients were twice as likely as controls to report cost‐related prescription nonadherence in the preceding 12 months to save money (21.7% versus 10.4%; P = 0.001) but were also more likely to ask their doctor for lower cost alternatives (23.8% versus 15.6%; P = 0.02). Disparities were found in association with income, race, and health insurance status, but the main findings persisted after adjusting for these and other variables in multivariable models. Conclusion: SLE patients were more likely than controls from the general population to report cost‐related prescription nonadherence, including skipping doses, taking less medicine, and delaying filling prescriptions; yet, <1 in 4 patients asked providers for lower cost medications. Consideration of medication costs in patient decision‐making could provide a meaningful avenue for improving access and adherence to medications. [ABSTRACT FROM AUTHOR]

The high incidence of osteomyelitis associated with critical‐sized bone defects raises clinical challenges in fracture healing. Clinical use of antibiotic‐loaded bone cement as an adjunct therapy is limited by incompatibility with many antimicrobials, sub‐optimal release kinetics, and requirement of surgical removal. Furthermore, overuse of antibiotics can lead to bacterial modifications that increase efflux, decrease binding, or cause inactivation of the antibiotics. Herein, we compared the efficacy of gallium maltolate, a new metal‐based antimicrobial, to gentamicin sulfate released from electrospun poly(lactic‐co‐glycolic) acid (PLGA) wraps in the treatment of osteomyelitis. In vitro evaluation demonstrated sustained release of each antimicrobial up to 14 days. A Kirby Bauer assay indicated that the gentamicin sulfate‐loaded wrap inhibited the growth of osteomyelitis‐derived isolates, comparable to the gentamicin sulfate powder control. In contrast, the gallium maltolate‐loaded wrap did not inhibit bacteria growth. Subsequent microdilution assays indicated a lower than expected sensitivity of the osteomyelitis strain to the gallium maltolate with release concentrations below the threshold for bactericidal activity. A comparison of the selectivity indices indicated that gentamicin sulfate was less toxic and more efficacious than gallium maltolate. A pilot study in a contaminated femoral defect model confirmed that the sustained release of gentamicin sulfate from the electrospun wrap resulted in bacteria density reduction on the surrounding bone, muscle, and hardware below the threshold that impedes healing. Overall, these findings demonstrate the efficacy of a resorbable, antimicrobial wrap that can be used as an adjunct or stand‐alone therapy for controlled release of antimicrobials in the treatment of osteomyelitis. [ABSTRACT FROM AUTHOR]

The Orphan Drug Act (ODA) of 1983 was enacted to provide financial incentives to drug sponsors to develop therapies for rare diseases. Although this act increased the number of orphan products approved, there are still a limited number of products available for the pediatric population because orphan drug products are exempt from the Pediatric Research Equity Act. The objectives of this study were (i) to evaluate the pediatric orphan drug studies submitted to the US Food and Drug Administration (FDA) in the period of 2007–2018 and (ii) to examine whether orphan drug products were fully labeled with a pediatric indication in infants and neonates. Out of the 468 indications evaluated, 171 (37%) were FDA‐labeled for use in the pediatric population. Labeling for the 12 to < 18 years age group was most common (98%). Fifty‐two percent of FDA‐labeled pediatric indications included the newborn to < 2 years of age group. In this newborn to < 2 years age group, the indication was labeled without pivotal clinical trials in 43% of the programs. Of the 60 new indications not labeled down to birth, 50% were found to have an age of onset and diagnosis that occurs earlier than the age approved for use of the product for that indication. In summary, although the ODA has been successful in improving pediatric access to medications for rare diseases, our analysis identified the incomplete labeling for pediatric patients under 2 years of age. Strategies to include the birth to < 2 years old group of pediatric patients in orphan drug development programs should be explored. [ABSTRACT FROM AUTHOR]

Background: Households represent important settings for transmission of influenza and other respiratory viruses. Current influenza diagnosis and treatment relies upon patient visits to healthcare facilities, which may lead to under‐diagnosis and treatment delays. This study aimed to assess the feasibility of an at‐home approach to influenza diagnosis and treatment via home testing, telehealth care, and rapid antiviral home delivery. Methods: We conducted a pilot interventional study of remote influenza diagnosis and treatment in Seattle‐area households with children during the 2019‐2020 influenza season using pre‐positioned nasal swabs and home influenza tests. Home monitoring for respiratory symptoms occurred weekly; if symptoms were reported within 48 hours of onset, participants collected mid‐nasal swabs and used a rapid home‐based influenza immunoassay. An additional home‐collected swab was returned to a laboratory for confirmatory influenza RT‐PCR testing. Baloxavir antiviral treatment was prescribed and delivered to symptomatic and age‐eligible participants, following a telehealth encounter. Results: 124 households comprising 481 individuals self‐monitored for respiratory symptoms, with 58 home tests administered. 12 home tests were positive for influenza, of which eight were true positives confirmed by RT‐PCR. The sensitivity and specificity of the home influenza test were 72.7% and 96.2%, respectively. There were eight home deliveries of baloxavir, with 7 (87.5%) occurring within 3 hours of prescription and all within 48 hours of symptom onset. Conclusions: We demonstrate the feasibility of self‐testing combined with rapid home delivery of influenza antiviral treatment. This approach may be an important control strategy for influenza epidemics and pandemics. [ABSTRACT FROM AUTHOR]

Objective: Epidemiologic data on systemic lupus erythematosus (SLE) are limited, particularly for racial/ethnic subpopulations in the US. This meta‐analysis leveraged data from the Centers for Disease Control and Prevention (CDC) National Lupus Registry network of population‐based SLE registries to estimate the overall prevalence of SLE in the US. Methods: The CDC National Lupus Registry network includes 4 registries from unique states and a fifth registry from the Indian Health Service. All registries defined cases of SLE according to the American College of Rheumatology (ACR) 1997 revised classification criteria for SLE. Case findings spanned either 2002–2004 or 2007–2009. Given the heterogeneity across sites, a random‐effects model was used to calculate the pooled prevalence of SLE. An estimate of the number of SLE cases in the US was generated by applying sex/race‐stratified estimates to the 2018 US Census population. Results: In total, 5,417 cases were identified as fulfilling the ACR SLE classification criteria. The pooled prevalence of SLE from the 4 state‐specific registries was 72.8 per 100,000 person‐years (95% confidence interval [95% CI] 65.3–81.0). The prevalence estimate was 9 times higher among females than among males (128.7 versus 14.6 per 100,000), and highest among Black females (230.9 per 100,000), followed by Hispanic females (120.7 per 100,000), White females (84.7 per 100,000), and Asian/Pacific Islander females (84.4 per 100,000). Among males, the prevalence of SLE was highest in Black males (26.7 per 100,000), followed by Hispanic males (18.0 per 100,000), Asian/Pacific Islander males (11.2 per 100,000), and White males (8.9 per 100,000). The American Indian/Alaska Native population had the highest race‐specific SLE estimates, both among females (270.6 per 100,000) and among males (53.8 per 100,000). In 2018, an estimated 204,295 individuals (95% CI 160,902–261,725) in the US fulfilled the ACR classification criteria for SLE. Conclusion: A coordinated network of population‐based SLE registries provides more accurate estimates of the prevalence of SLE and the numbers of individuals affected with SLE in the US in 2018. [ABSTRACT FROM AUTHOR]

A crucial mutational mechanism in malignancy is structural variation, in which chromosomal rearrangements alter gene functions that drive cancer progression. Herein, the presence and pattern of structural variations were investigated in twelve prospectively acquired treatment‐naïve pancreatic cancers specimens obtained via endoscopic ultrasound (EUS). In many patients, this diagnostic biopsy procedure and specimen is the only opportunity to identify somatic clinically relevant actionable alterations that may impact their care and outcome. Specialized mate pair sequencing (MPseq) provided genome‐wide structural variance analysis (SVA) with a view to identifying prognostic markers and possible therapeutic targets. MPseq was successfully performed on all specimens, identifying highly rearranged genomes with complete SVA on all specimens with > 20% tumour content. SVA identified chimeric fusion proteins and potentially immunogenic readthrough transcripts, change of function truncations, gains and losses of key genes linked to tumour progression. Complex localized rearrangements, termed chromoanagenesis, with broad pattern heterogeneity were observed in 10 (83%) specimens, impacting multiple genes with diverse cellular functions that could influence theragnostic evaluation and responsiveness to immunotherapy regimens. This study indicates that genome‐wide MPseq can be successfully performed on very limited clinically EUS obtained specimens for chromosomal rearrangement detection and potential theragnostic targets. [ABSTRACT FROM AUTHOR]

Aims: It is important to understand the effect of landscape context on biological communities to predict how biodiversity will be affected on human‐dominated landscapes. While many studies have tested the effects of landscape context on the species richness and composition of vascular plants, few have compared the responses of vascular plants and bryophytes on the same landscape. We sampled non‐epiphytic bryophytes and vascular plants in 184 plots to test whether three landscape context factors measured four years or four decades previously could predict bryophyte or vascular plant species richness and composition after accounting for local factors. Location: Temperate forests and oak savannahs, Vancouver Island, British Columbia, Canada. Methods: We used model selection and comparisons to test the effects of surrounding road density, total amount of forest, and distance to the nearest forest edge on species richness, species richness of non‐disturbance‐associated species, and community composition after controlling for important local predictors including substrate availability and topography. Results: The species richness of non‐disturbance‐associated vascular plants was lower in plots with greater surrounding historical road density, and perennial stayer bryophyte richness declined with increasing historical road density and lower historical forest amount, suggesting a potential extinction debt. Landscape context significantly affected total species richness and community composition of vascular plants, but not bryophytes. Conclusion: While bryophytes appear to be less sensitive overall to landscape context than vascular plants, disturbance‐intolerant perennial stayer bryophytes may decline in the future in response to the increased road density and loss of forest cover that has occurred over the past four decades. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID‐19) has become a pandemic since first being described in January 2020. Clinical manifestations in non‐transplant patients range from asymptomatic infection to severe pneumonia with acute respiratory distress syndrome, multiorgan system failure, and death. Limited reports in kidney transplant recipients suggest similar characteristics in that population. We report here the first case series of COVID‐19 infection occurring in pancreas transplant recipients. [ABSTRACT FROM AUTHOR]

Objective: The release of neutrophil extracellular traps (NETs) by hyperactive neutrophils has recently been recognized to play an important role in antiphospholipid syndrome (APS). This study was undertaken to evaluate autoantibodies targeting NETs in patients with primary APS, and to determine their potential functions and clinical associations. Methods: We measured global anti‐NET activity in 76 patients with primary APS, 23 patients with systemic lupus erythematosus without antiphospholipid antibodies (aPL), 11 patients with a history of unprovoked venous thrombosis without aPL, and 44 healthy controls. The ability of APS sera to degrade NETs was also assessed. Results: We found markedly elevated levels of anti‐NET IgG and IgM in patients with primary APS compared with healthy controls (for IgG, mean ± SD optical density 0.55 ± 0.34 versus 0.33 ± 0.17; for IgM, mean ± SD optical density 0.76 ± 0.51 versus 0.26 ± 0.23). This anti‐NET activity did not correlate with levels of traditional aPL and was relatively stable over time. Mechanistically, anti‐NET antibodies (especially of the IgG isotype) impaired the ability of patient sera to degrade NETs (r = 0.4, P = 0.003). Levels of anti‐NET IgM inversely correlated with complement C4 (r = 0.4, P = 0.019). Clinically, anti‐NET antibodies associated with certain APS clinical manifestations, and in particular recurrent venous thrombosis (odds ratio 4.3; P = 0.002). Interestingly, anti‐NET antibody levels also appeared to be associated with unprovoked venous thrombosis in the general population (for IgM, mean ± SD optical density 0.67 ± 0.34 versus 0.26 ± 0.23). Conclusion: Our data indicate high levels of anti‐NET antibodies in patients with primary APS, which may impair NET clearance and activate the complement cascade. These findings may ultimately enable more effective risk stratification. [ABSTRACT FROM AUTHOR]

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Despite legislation incentivizing and requiring drug companies to conduct pediatric clinical trials, there still is a 9‐year delay in drug approval for pediatric labeling after the initial adult drug approval. The aim of this study was to review the experience of the US Food and Drug Administration (FDA) with combined pediatric and adult trials as a means for expediting pediatric approval and labeling. Combined pediatric and adult trials submitted to the FDA from 2012 to 2018 were reviewed. Only the publicly available labels and reviews were utilized for this analysis. Combined trials were identified for 72 products, with a total of 156 combined adult and pediatric trials. The therapeutic areas with the largest number of combined trials were in pulmonology for products reviewed under the Best Pharmaceuticals for Children Act (BPCA) and/or the Pediatric Research Equity Act (PREA), and hematology reviewed under the Orphan Drug Act (ODA). All drugs that utilized combined pediatric and adult clinical trials were approved simultaneously for both the adults and that part of the pediatric population. A separate pediatric subgroup efficacy analysis was reported in 57% and 48% of products under BPCA/PREA and the ODA, respectively, with a separate safety analysis in 48% and 38% of these products. When considering both BPCA/PREA and orphan drug studies, all the combined pediatric and adult trials allowed concurrent approval and labeling for part of the pediatric population at the time of the adult approval. [ABSTRACT FROM AUTHOR]

How modification of gene expression generates novel traits is key to understanding the evolutionary process. We investigated the genetic basis for the origin of the piscine gas bladder from lungs of ancestral bony vertebrates. Distinguishing these homologous organs is the direction of budding from the foregut during development; lungs bud ventrally and the gas bladder buds dorsally. Highlights: The evolution of the piscine gas bladder from ancestral lungs involved a shift in direction of budding from the ventral to dorsal foregut. Tbx5, vital for lung development, shows a concomitant inversion from ventral expression in lung development to dorsal expression in gas bladder development. [ABSTRACT FROM AUTHOR]

The key to understanding the evolutionary origin and modification of phenotypic traits is revealing the responsible underlying developmental genetic mechanisms. An important organismal trait of ray‐finned fishes is the gas bladder, an air‐filled organ that, in most fishes, functions for buoyancy control, and is homologous to the lungs of lobe‐finned fishes. The critical morphological difference between lungs and gas bladders, which otherwise share many characteristics, is the general direction of budding during development. Lungs bud ventrally and the gas bladder buds dorsally from the anterior foregut. We investigated the genetic underpinnings of this ventral‐to‐dorsal shift in budding direction by studying the expression patterns of known lung genes (Nkx2.1, Sox2, and Bmp4) during the development of lungs or gas bladder in three fishes: bichir, bowfin, and zebrafish. Nkx2.1 and Sox2 show reciprocal dorsoventral expression patterns during tetrapod lung development and are important regulators of lung budding; their expression during bichir lung development is conserved. Surprisingly, we find during gas bladder development, Nkx2.1 and Sox2 expression are inconsistent with the hypothesis that they regulate the direction of gas bladder budding. Bmp4 is expressed ventrally during lung development in bichir, akin to the pattern during mouse lung development. During gas bladder development, Bmp4 is not expressed. However, Bmp16, a paralogue of Bmp4, is expressed dorsally in the developing gas bladder of bowfin. Bmp16 is present in the known genomes of Actinopteri (ray‐finned fishes excluding bichir) but absent from mammalian genomes. We hypothesize that Bmp16 was recruited to regulate gas bladder development in the Actinopteri in place of Bmp4. Research Highlight: Ventrally budding lungs and the dorsally budding gas bladder of vertebrates are homologous organs. Paralleling this morphological inversion, paralogous genes, Bmp4 and Bmp16, show an inverted expression pattern during organ developmental outgrowth. [ABSTRACT FROM AUTHOR]

Background: The number of patients undergoing autologous haematopoietic cell transplant (HCT) is growing, but little is known about the factors that predict adverse outcomes. Low muscle mass and obesity are associated with disability and premature mortality in individuals with non‐malignant diseases and may predict outcomes after autologous HCT. Methods: This was a retrospective cohort study of 320 patients who underwent autologous HCT for Hodgkin or non‐Hodgkin lymphoma between 2009 and 2014. Sarcopenia {skeletal muscle index male: <43 cm/m2 [body mass index (BMI) < 25 kg/m2] or < 53 cm/m2 [BMI ≥ 25 kg/m2] and female: <41 cm/m2 [regardless of BMI]) and obesity [total abdominal adiposity ≥450.0 cm2 (male), ≥396.4 cm2 (female)] were assessed from single‐slice abdominal pre‐HCT computed tomography images. Length of hospital stay, first unplanned intensive care unit admission, and 30‐day unplanned readmission were evaluated based on body composition using multivariable regression analysis, and mortality was evaluated with Kaplan–Meier analysis and Gray's test. Results: Median age at HCT was 53.3 years (range, 18.5 to 78.1 years); 26.3% were sarcopenic and an additional 7.8% were sarcopenic obese pre‐HCT. Sarcopenic obesity was associated with increased risk of prolonged hospitalization [odds ratio (OR) = 3.6, 95% confidence interval (CI) 1.3–9.8], intensive care unit admission (OR = 4.7, 95% CI 1.5–16.1), and unplanned readmission after HCT (OR = 13.6, 95% CI 2.5–62.8). Patients who were sarcopenic obese also had the highest mortality risk at 1 year [hazard ratio (HR): 3.9, 95% CI 1.1–11.0] and 5 years (HR: 2.5, 95% CI 1.1–5.5), compared with patients with normal body composition. Sarcopenia alone, but not obesity alone, was associated with an increased risk of these outcomes, albeit with a lower magnitude of risk than in patients who were sarcopenic obese. Conclusions: Sarcopenic obesity was an important predictor of outcomes in patients undergoing autologous HCT. These findings could inform targeted prevention strategies in patients at highest risk of complications after HCT. [ABSTRACT FROM AUTHOR]

Problem: The effects of HIV on the gastrointestinal tract (GIT), including CD4 depletion, epithelial disruption, and collagen deposition, are well documented and only partially reversed by combination antiretroviral therapy (cART). However, the effects of HIV on the female reproductive tract (FRT) are poorly understood, and most studies have focused on ectocervix and vagina without assessing the upper tract. Here, we investigated CD4+ T‐cell frequency, phenotype, and HIV‐specific T‐cell responses in the endocervix and endometrium of HIV‐infected women, comparing these tissues to the GIT. Method of Study: Mucosal samples and blood were obtained from 18 women: four who were HIV‐positive and not on cART for at least 3 years prior to sampling, including two natural controllers (viral load [VL] undetectable and CD4 >350); nine women on cART with low to undetectable VL; and five HIV‐uninfected women. Mucosal samples included terminal ileum, sigmoid colon, endocervical cytobrush, endocervical curettage, and endometrial biopsy. T‐cell frequency, phenotypes, and HIV‐specific T‐cell responses were analyzed by multiparameter flow cytometry. Results: T‐cell activation, measured by CD38/HLA‐DR co‐expression, remained significantly elevated in endometrium following cART, but was lower in gastrointestinal tissues. HIV‐specific CD8+ T‐cell responses were detected in ileum, colon, and endometrial tissues of women both on and off cART, and were of higher magnitude on those not on cART. Conclusion: Our findings reveal differences in CD4+ T‐cell frequencies, immune activation, and HIV‐specific T‐cell responses between the gastrointestinal and reproductive tracts, and highlight differences between HIV controllers and women on cART. [ABSTRACT FROM AUTHOR]

Objective: To examine associations between dietary intake of omega-3 (n-3; generally antiinflammatory) and omega-6 (n-6; generally proinflammatory) fatty acids and patient-reported outcomes in systemic lupus erythematosus (SLE).Methods: This study was based on the population-based Michigan Lupus Epidemiology and Surveillance cohort. Estimates of n-3 and n-6 intake were derived from Diet History Questionnaire II items (past year with portion size version). Patient-reported outcomes included self-reported lupus activity (Systemic Lupus Activity Questionnaire [SLAQ]). Multivariable regression, adjusted for age, sex, race, and body mass index, was used to assess associations between absolute intake of n-3 and n-6, as well as the n-6:n-3 ratio, and patient-reported outcomes.Results: Among 456 SLE cases, 425 (93.2%) were female, 207 (45.4%) were African American, and the mean ± SD age was 52.9 ± 12.3 years. Controlling for potential confounders, the average SLAQ score was significantly higher by 0.3 points (95% confidence interval [95% CI] 0.1, 0.6; P = 0.013) with each unit increase of the n-6:n-3 ratio. Both lupus activity and Patient-Reported Outcomes Measurement Information System (PROMIS) sleep disturbance scores were lower with each 1-gram/1,000 kcal increase of n-3 fatty acids (SLAQ regression coefficient β = -0.8 [95% CI -1.6, 0.0]; P = 0.055; PROMIS sleep β = -1.1 [95% CI -2.0, -0.2]; P = 0.017). Higher n-3 intakes were nonsignificantly associated with lower levels of depressive symptoms and comorbid fibromyalgia, and with higher quality of life, whereas results for the n6:n3 ratio trended in the opposite direction.Conclusion: This population-based study suggests that higher dietary intake of n-3 fatty acids and lower n-6:n-3 ratios are favorably associated with patient-reported outcomes in SLE, particularly self-reported lupus activity and sleep quality. [ABSTRACT FROM AUTHOR]

Marine metapopulations often exhibit subtle population structure that can be difficult to detect. Given recent advances in high‐throughput sequencing, an emerging question is whether various genotyping approaches, in concert with improved sampling designs, will substantially improve our understanding of genetic structure in the sea. To address this question, we explored hierarchical patterns of structure in the coral reef fish Elacatinus lori using a high‐resolution approach with respect to both genetic and geographic sampling. Previously, we identified three putative E. lori populations within Belize using traditional genetic markers and sparse geographic sampling: barrier reef and Turneffe Atoll; Glover's Atoll; and Lighthouse Atoll. Here, we systematically sampled individuals at ~10 km intervals throughout these reefs (1,129 individuals from 35 sites) and sequenced all individuals at three sets of markers: 2,418 SNPs; 89 microsatellites; and 57 nonrepetitive nuclear loci. At broad spatial scales, the markers were consistent with each other and with previous findings. At finer spatial scales, there was new evidence of genetic substructure, but our three marker sets differed slightly in their ability to detect these patterns. Specifically, we found subtle structure between the barrier reef and Turneffe Atoll, with SNPs resolving this pattern most effectively. We also documented isolation by distance within the barrier reef. Sensitivity analyses revealed that the number of loci (and alleles) had a strong effect on the detection of structure for all three marker sets, particularly at small spatial scales. Taken together, these results illustrate empirically that high‐throughput genotyping data can elucidate subtle genetic structure at previously‐undetected scales in a dispersive marine fish. see also the Perspective by Laura E. Timm. [ABSTRACT FROM AUTHOR]

Species distribution models (SDMs) are used to test ecological theory and to direct targeted surveys for species of conservation concern. Several studies have tested for an influence of species traits on the predictive accuracy of SDMs. However, most used the same set of environmental predictors for all species and/or did not use truly independent data to test SDM accuracy. We built eight SDMs for each of 24 plant species of conservation concern, varying the environmental predictors included in each SDM version. We then measured the accuracy of each SDM using independent presence and absence data to calculate area under the receiver operating characteristic curve (AUC) and true positive rate (TPR). We used generalized linear mixed models to test for a relationship between species traits and SDM accuracy, while accounting for variation in SDM performance that might be introduced by different predictor sets. All traits affected one or both SDM accuracy measures. Species with lighter seeds, animal‐dispersed seeds, and a higher density of occurrences had higher AUC and TPR than other species, all else being equal. Long‐lived woody species had higher AUC than herbaceous species, but lower TPR. These results support the hypothesis that the strength of species–environment correlations is affected by characteristics of species or their geographic distributions. However, because each species has multiple traits, and because AUC and TPR can be affected differently, there is no straightforward way to determine a priori which species will yield useful SDMs based on their traits. Most species yielded at least one useful SDM. Therefore, it is worthwhile to build and test SDMs for the purpose of finding new populations of plant species of conservation concern, regardless of these species' traits. [ABSTRACT FROM AUTHOR]