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Habitat restoration may depend on the recovery of plant microbial symbionts such as arbuscular mycorrhizal (AM) fungi, but this requires a better understanding of the rules that govern their community assembly. We examined the interactions of soil and host-associated AM fungal communities between remnant and restored patches of subtropical montane forests. While AM fungal richness did not differ between habitat types, community membership did and was influenced by geography, habitat and host. These differences were largely driven by rare host-specific AM fungi that displayed near-complete turnover between forest types, while core AM fungal taxa were highly abundant and ubiquitous. The bipartite networks in the remnant forest were more specialized and hosts more specific than in the restored forest. Host-associated AM fungal communities nested within soil communities in both habitats, but only significantly so in the restored forest. Our results provide evidence that restored and remnant forests harbour the same core fungal symbionts, while rare host-specific taxa differ, and that geography, host identity and taxonomic resolution strongly affect the observed distribution patterns of these fungi. We suggest that host-specific interactions with AM fungi, as well as spatial processes, should be explicitly considered to effectively re-establish target host and symbiont communities.

Context The significance of thyroid peroxidase (TPOAb) and thyroglobulin antibody (TgAb) in the pathogenesis of thyroid immune-related adverse events (irAEs) is unknown. Objective To characterize the association of anti-thyroid antibodies with the development of thyroid immune related adverse events. Methods A retrospective cohort study was conducted of patients with melanoma receiving immune checkpoint inhibitor (ICI) treatment. TPOAb, TgAb, and interleukin-6 (IL-6) were measured retrospectively using tumor-banked samples at baseline and at time of diagnosis of a thyroid irAE. In euthyroid patients (without thyroid irAEs) measures were repeated 30 to 60 days after ICI commencement, which was similar to the median time to onset of thyroid irAEs in other patients. Results A total of 122 patients were included—31 remained euthyroid, 47 developed subclinical thyrotoxicosis, 37 developed overt thyrotoxicosis, and 7 developed overt hypothyroidism without preceding thyrotoxicosis. Baseline elevation of TPOAb or TgAb was present in 19 (16%) and 28 (23%) patients, respectively. Positive TPOAb or TgAb at baseline was 97% and 100% specific for eventual development of a thyroid irAE, respectively. During ICI treatment, overt thyrotoxicosis, but not other subtypes of thyroid irAE, was associated with statistically significant increases in the titer of TgAb and TPOAb. Baseline IL-6 levels were not associated with thyroid irAE onset but statistically significantly increased during treatment in patients who developed overt hypothyroidism. Conclusions TPOAb and TgAb positivity at baseline was more prevalent in patients who developed thyroid irAEs. Statistically significant increases or new antibody positivity was observed in association with overt thyrotoxicosis. TPOAb and TgAb positivity or increases during ICI treatment may be a useful biomarker to identify patients at increased risk of thyroid irAEs, particularly overt thyrotoxicosis.

There is accumulating evidence that novel glucose-lowering agents infer potent cardiovascular and renal benefits. Therefore, it is imperative to reassess the management of post-transplant diabetes mellitus and consider the role of newer agents. With improved transplant-related survival and high prevalence of post-transplant diabetes, management of long-term complications such as diabetes are increasingly important. There are limited guidelines to assist in choice of appropriate agents after solid organ transplantation. Traditional therapies including insulin and sulfonylureas may still have a role; however, other agents should be considered prior. The evidence of novel glucose-lowering agents in post-transplant care is limited, and most studies have focused on kidney transplant recipients. While there are some parallels between renal and cardiac transplant recipients, the potential cardiovascular benefits, particularly on cardiac fibrosis are unique to cardiac transplantation. The treatment of diabetes, with a focus on additional cardiac and renal benefits, needs to be brought to the forefront of post-transplant care with incorporation of recent evidence outside of transplantation. The role for novel glucose-lowering agents in cardiac transplant recipients will be explored, with a summary of available evidence.

The efficacy of glucagon-like peptide-1 receptor agonists in type 2 diabetes is well established, but their role in type 1 diabetes (T1DM) is less clear. A 36-year-old woman with a 27-year history of T1DM and undetectable c-peptide presented for review of weight management, with body mass index 29.3 kg/m2. A previous trial of dapagliflozin led to no improvement in weight or glycemic control. Semaglutide was introduced (0.25 mg weekly increased to 0.5 mg weekly) and was well tolerated. After 6 months, weight had decreased by 16 kg and insulin dose by 36%. Despite less insulin, hemoglobin A1c improved, with reduced glycemic variability and no increase in hypoglycemia. Semaglutide may exert significant metabolic benefits in patients with established T1DM, even where c-peptide is no longer detectable. This case supports the need for a dedicated trial examining potential benefits of semaglutide in T1DM.

There is accumulating evidence that novel glucose-lowering agents infer potent cardiovascular and renal benefits. Therefore, it is imperative to reassess the management of post-transplant diabetes mellitus and consider the role of newer agents. With improved transplant-related survival and high prevalence of post-transplant diabetes, management of long-term complications such as diabetes are increasingly important. There are limited guidelines to assist in choice of appropriate agents after solid organ transplantation. Traditional therapies including insulin and sulfonylureas may still have a role; however, other agents should be considered prior. The evidence of novel glucose-lowering agents in post-transplant care is limited, and most studies have focused on kidney transplant recipients. While there are some parallels between renal and cardiac transplant recipients, the potential cardiovascular benefits, particularly on cardiac fibrosis are unique to cardiac transplantation. The treatment of diabetes, with a focus on additional cardiac and renal benefits, needs to be brought to the forefront of post-transplant care with incorporation of recent evidence outside of transplantation. The role for novel glucose-lowering agents in cardiac transplant recipients will be explored, with a summary of available evidence.

Many traits covary with environmental gradients to form phenotypic clines. While local adaptation to the environment can generate phenotypic clines, other nonadaptive processes may also. If local adaptation causes phenotypic clines, then the direction of genotypic selection on traits should shift from one end of the cline to the other. Traditionally, genotypic selection on non-Gaussian traits like germination rate have been hampered because it is challenging to measure their genetic variance.Here we used quantitative genetics and reciprocal transplants to test whether a previously discovered cline in germination rate showed additional signatures of adaptation in the scarlet monkeyflower (Mimulus cardinalis). We measured genotypic and population level covariation between germination rate and early survival, a component of fitness. We developed a novel discrete log-normal model to estimate genetic variance in germination rate.Contrary to our adaptive hypothesis, we found no evidence that genetic variation in germination rate contributed to variation in early survival. Across populations, southern populations in both gardens germinated earlier and survived more.Southern populations have higher early survival but it is not caused by faster germination. This pattern is consistent with nonadaptive forces driving the phenotypic cline in germination rate, but future work will need to assess whether there is selection at other life stages. This statistical framework should help expand quantitative genetic analyses for other waiting-time traits.

Premise Across taxa, vegetative and floral traits that vary along a fast-slow life-history axis are often correlated with leaf functional traits arrayed along the leaf economics spectrum, suggesting a constrained set of adaptive trait combinations. Such broad-scale convergence may arise from genetic constraints imposed by pleiotropy (or tight linkage) within species, or from natural selection alone. Understanding the genetic basis of trait syndromes and their components is key to distinguishing these alternatives and predicting evolution in novel environments. Methods We used a line-cross approach and quantitative trait locus (QTL) mapping to characterize the genetic basis of twenty leaf functional/physiological, life history, and floral traits in hybrids between annualized and perennial populations of scarlet monkeyflower (Mimulus cardinalis). Results We mapped both single and multi-trait QTLs for life history, leaf function and reproductive traits, but found no evidence of genetic co-ordination across categories. A major QTL for three leaf functional traits (thickness, photosynthetic rate, and stomatal resistance) suggests that a simple shift in leaf anatomy may be key to adaptation to seasonally dry habitats. Conclusions Our results suggest that the co-ordination of resource-acquisitive leaf physiological traits with a fast life-history and more selfing mating system results from environmental selection rather than functional or genetic constraint. Independent assortment of distinct trait modules, as well as a simple genetic basis to leaf physiological traits associated with drought escape, may facilitate adaptation to changing climates.

IntroductionCardiac transplantation (CTx) is a life-saving operation that can improve the quality and length of a recipient’s life. Immunosuppression medication, required to prevent rejection, can result in adverse metabolic and renal effects. Clinically significant complications include metabolic effects such as diabetes and weight gain, renal impairment, and cardiac disease such as allograft vasculopathy and myocardial fibrosis. Sodium glucose co-transporter 2 (SGLT2) inhibitors are a class of oral medication that increase urinary excretion of glucose. In patients with type 2 diabetes, SGLT2 inhibitors improve cardiovascular, metabolic and renal outcomes. Similar benefits have been shown in patients with heart failure and reduced ejection fraction irrespective of diabetes status. In patients with post-transplant diabetes mellitus, SGLT2 inhibitors improve metabolic parameters; however, their benefit and safety have not been evaluated in randomised prospective studies. This study will potentially provide a novel therapy to improve or prevent complications (diabetes, kidney failure and heart fibrosis) that occur with immunosuppressive medications.MethodsThe EMPA-HTx study is a randomised, placebo-controlled trial of the SGLT2 inhibitor empagliflozin 10 mg daily versus placebo in recent CTx recipients. One hundred participants will be randomised 1:1 and commence the study medication within 6–8 weeks of transplantation with treatment and follow-up until 12 months after transplantation. Demographic information, anthropomorphic measurements, pathology tests and cardiac magnetic resonance (CMR) scan will be recorded at baseline and follow-up. Patients will be reviewed monthly during the study until 12 months post-CTx and data will be collected for each patient at each study visit. The overall aim of the study is to assess the safety and efficacy of empagliflozin in CTx recipients. The primary outcome is glycaemic improvement measured as change in glycated haemoglobin and/or fructosamine. Key secondary outcomes are cardiac interstitial fibrosis measured by CMR and renal function measured by estimated glomerular filtration rate.Ethics and disseminationThis study has been approved by St Vincent’s Hospital Human Research Ethics Committee (2021/ETH12184). The findings will be presented at national and international scientific meetings and published in peer-reviewed journals.Trial registration numberACTRN12622000978763.

Approximately 0.6% of the adult population identifies as transgender. Gender affirming hormone treatment (GAHT) is required by many to develop physical and psychological characteristics that align with their gender identity. Once started, GAHT is continued lifelong and at higher doses than conventionally used in the management of cis-gendered women. Hyperprolactinemia and pituitary lactotroph adenomas are a potential consequence of GAHT. Case series of three transfeminine women with hyperprolactinemia during gender affirming hormone treatment. We report two new cases of prolactinoma and one new case of marked hyperprolactinemia without pituitary adenoma associated with GAHT in transwomen at different stages of hormonal transition. Novel aspects of our case series include the first report of a prolactinoma in a transwoman associated with spironolactone and the alternate progestin medroxyprogesterone acetate and documentation of the transient changes in prolactin from baseline (prior to feminizing hormones) in two transwomen which demonstrate that marked hyperprolactinemia develops early in the course of GAHT. Transgender women receiving GAHT may be at increased risk for prolactinoma. As the number of transwomen seeking GAHT continues to increase, hyperprolactinemia and GAHT-associated prolactinoma may become an increasingly important component of endocrine practice. Screening of prolactin levels in transwomen receiving GAHT could potentially prevent morbidity related to hyperprolactinemia and allow for early detection of prolactin secreting pituitary adenomas.

International audience; Leaf optical properties impact leaf energy balance and thus leaf temperature. The effect of leaf development on mid-infrared (MIR) reflectance, and hence thermal emissivity, has not been investigated in detail. We measured a suite of morphological characteristics, as well as directional-hemispherical reflectance from ultraviolet to thermal infrared wavelengths (250 nm to 20 µm) of leaves from five temperate deciduous tree species over the 8 wk following spring leaf emergence. By contrast to reflectance at shorter wavelengths, the shape and magnitude of MIR reflectance spectra changed markedly with development. MIR spectral differences among species became more pronounced and unique as leaves matured. Comparison of reflectance spectra of intact vs dried and ground leaves points to cuticular developmentand not internal structural or biochemical changesas the main driving factor. Accompanying the observed spectral changes was a drop in thermal emissivity from about 0.99 to 0.95 over the 8 wk following leaf emergence. Emissivity changes were not large enough to substantially influence leaf temperature, but they could potentially lead to a bias in radiometrically measured temperatures of up to 3 K. Our results also pointed to the potential for using MIR spectroscopy to better understand species-level differences in cuticular development and composition.

Background: Inhibitory antibodies against cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) have antitumor efficacy and are now standard of care in the management of multiple cancer subtypes. However, the use is complicated by the development of autoimmunity, which can occur in multiple organ systems. Thyroiditis is the most common immune-related adverse event. Summary: Immune checkpoint inhibitor (ICI)-associated thyroiditis affects over 10% of treated patients. PD-1 inhibitors are associated with greater risk of thyroid dysfunction relative to CTLA-4 inhibitors, although the highest risk occurs with combined anti-CTLA-4 and anti-PD-1 treatment. Onset is typically rapid, within weeks to months and both hyperthyroidism and hypothyroidism can occur. The most frequent pattern of thyroid dysfunction is transient hyperthyroidism with evolution to hypothyroidism over four to six weeks. Most cases are asymptomatic and resolve without dedicated treatment. There is no sex or age predominance, and predictive risk factors have not been reliably identified. Thyroid autoantibodies are variably present and are not clearly related to the risk or progression of thyroid dysfunction following treatment with an ICI. Observational data suggest that development of ICI-associated thyroiditis may predict improved survival. Conclusions: ICI-associated thyroiditis is a distinct clinical entity. Mechanisms underlying etiology remain largely unknown. Awareness among health professionals is important to limit morbidity and avoid unnecessary periods of untreated hypothyroidism.

Background and Objectives: Subclinical hypothyroidism in pregnancy has been inconsistently associated with an increased risk of developing gestational diabetes mellitus (GDM). Materials and Methods: We retrospectively examined whether an antenatal thyroid stimulating hormone (TSH) level ≥2.5 mIU/L was associated with increased risk of GDM in 1147 pregnant women residing in a multi-ethnic suburban area of Sydney, Australia. Results: Despite a high prevalence of GDM and hypothyroidism in our study, women with antenatal TSH concentrations ≥2.5 mIU/L were not at increased risk for development of gestational diabetes. Traditional risk factors for GDM, such as maternal body mass index, ethnicity, previous GDM pregnancy and family history of type 2 diabetes were significant predictors of incident GDM on multivariable analyses. Conclusion: Mild elevations in antenatal TSH concentration did not significantly increase risk of incident GDM compared to healthy euthyroid women.

PremiseMany traits covary with environmental gradients to form phenotypic clines. While local adaptation to the environment can generate phenotypic clines, other nonadaptive processes may also. If local adaptation causes phenotypic clines, then the direction of genotypic selection on traits should shift from one end of the cline to the other. Traditionally genotypic selection on non-Gaussian traits like germination rate have been hampered because it is challenging to measure their genetic variance.MethodsHere we used quantitative genetics and reciprocal transplants to test whether a previously discovered cline in germination rate showed additional signatures of adaptation in the scarlet monkeyflower (Mimulus cardinalis). We measured genotypic and population level covariation between germination rate and early survival, a component of fitness. We developed a novel discrete log-normal model to estimate genetic variance in germination rate.ResultsContrary to our adaptive hypothesis, we found no evidence that genetic variation in germination rate contributed to variation in early survival. Across populations, southern populations in both gardens germinated earlier and survived more.ConclusionsSouthern populations have higher early survival but this is not caused by faster germination. This pattern is consistent with nonadaptive forces driving the phenotypic cline in germination rate, but future work will need to assess whether there is selection at other life stages. This statistical framework should help expand quantitative genetic analyses for other waiting-time traits.

Functional and developmental constraints on phenotypic variation may cause traits to covary over millions of years and slow populations from reaching their adaptive optima. Alternatively, trait covariation may result from selective constraint if some trait combinations are generally maladaptive. Quantifying the relative contribution of functional, developmental, and selective constraints on phenotypic variation is a longstanding goal of macroevolution, but it is often difficult to distinguish different types of constraints. The anatomy of leaves with stomata on both surfaces (amphistomatous) present a unique opportunity to test the importance of functional and developmental constraints on phenotypyic evolution. The key insight is that stomata on each leaf surface encounter the same functional and developmental constraints, but potentially different selective constraints because of leaf asymmetry in light capture, gas exchange, and other features. Independent evolution of stomatal traits on each surface imply that functional and developmental constraints alone likely do not explain trait covariance. Packing limits on how many stomata can fit into a finite epidermis and cell-size-mediated developmental integration are hypothesized to constrain variation in stomatal anatomy. The simple geometry of the planar leaf surface and knowledge of stomatal development make it possible to derive equations for phenotypic (co)variance caused by these constraints and compare them with data. We analyzed evolutionary covariance between stomatal density and length in amphistomatous leaves from 236 phylogenetically independent contrasts using a robust Bayesian model. Stomatal anatomy on each surface diverges partially independently, meaning that packing limits and developmental integration are not sufficient to explain phenotypic (co)variation. Hence, selective constraints, which require an adaptive explanation, likely contribute to (co)variation in ecologically important traits like stomata. We show how it is possible to evaluate the contribution of different constraints by deriving expected patterns of (co)variance and testing them using similar but separate tissues, organs, or sexes.

Plant ecophysiology is founded on a rich body of physical and chemical theory, but it is challenging to connect theory with data in unambiguous, analytically rigorous and reproducible ways. Custom scripts written in computer programming languages (coding) enable plant ecophysiologists to model plant processes and fit models to data reproducibly using advanced statistical techniques. Since many ecophysiologists lack formal programming education, we have yet to adopt a unified set of coding principles and standards that could make coding easier to learn, use and modify. We identify eight principles to help in plant ecophysiologists without much programming experience to write resilient code: (i) standardized nomenclature, (ii) consistency in style, (iii) increased modularity/extensibility for easier editing and understanding, (iv) code scalability for application to large data sets, (v) documented contingencies for code maintenance, (vi) documentation to facilitate user understanding; (vii) extensive tutorials and (viii) unit testing and benchmarking. We illustrate these principles using a new R package, {photosynthesis}, which provides a set of analytical and simulation tools for plant ecophysiology. Our goal with these principles is to advance scientific discovery in plant ecophysiology by making it easier to use code for simulation and data analysis, reproduce results and rapidly incorporate new biological understanding and analytical tools., Tired: Remembering whether ‘ACi_solanum_C_final.xlsx’ or ‘ACi_solanum_D_v3.xlsx’ has the correct parameter estimates. Wired: Using reproducible, scalable, open-source code to analyse your ecophysiological data. Get started with a gentle introduction to eight principles of coding and an R software package called photosynthesis! We cover naming functions and variables, style, modularity, scalability, documenting contingencies, help documentation, tutorials and testing. The photosynthesis package implements these principles for gas exchange and hydraulic curve fitting and modelling.

While the fundamental biophysics of C 3 photosynthesis is highly conserved across plants, substantial leaf structural and enzymatic variation translates into variability in rates of carbon assimilation. Although this variation is well documented, it remains poorly understood how photosynthetic rates evolve, and whether macroevolutionary changes are related to the evolution of leaf morphology and biochemistry. A substantial challenge in large-scale comparative studies is disentangling evolutionary adaptation from environmental acclimation. We overcome this by using a ‘macroevolutionary common garden’ approach in which we measured metabolic traits ( J max and V cmax ) from 111 phylogenetically diverse species in a shared environment. We find substantial phylogenetic signal in these traits at moderate phylogenetic timescales, but this signal dissipates quickly at deeper scales. Morphological traits exhibit phylogenetic signal over much deeper timescales, suggesting that these are less evolutionarily constrained than metabolic traits. Furthermore, while morphological and biochemical traits (LMA, N area and C area ) are weakly predictive of J max and V c max , evolutionary changes in these traits are mostly decoupled from changes in metabolic traits. This lack of tight evolutionary coupling implies that it may be incorrect to use changes in these functional traits in response to global change to infer that photosynthetic strategy is also evolving.

The size and density of stomatal pores limit the maximum rate of leaf carbon gain and water loss (gmax) in land plants. The limits of gmax due to anatomy, and its constraint by the negative correlation of stomatal size and density at broad phylogenetic scales, has been unclear and controversial. The prevailing hypothesis posits that adaptation to higher gmax is typically constrained by geometry and/or an economic need to reduce the allocation of epidermal area to stomata (stomatal-area minimization), and this would require the evolution of greater numbers of smaller stomata. Another view, supported by the data, is that across plant diversity, epidermal area allocated to guard cells versus other cells can be optimized without major trade-offs, and higher gmax would typically be achieved with a higher allocation of epidermal area to stomata (stomatal-area increase). We tested these hypotheses by comparing their predictions for the structure of the covariance of stomatal size and density across species, applying macroevolutionary models and phylogenetic regression to data for 2408 species of angiosperms, gymnosperms, and ferns from forests worldwide. The observed stomatal size-density scaling and covariance supported the stomatal-area increase hypothesis for high gmax. A higher gmax involves construction costs and maintenance costs that should be considered in models assessing optimal stomatal conductance for predictions of water use, photosynthesis, and water-use efficiency as influences on crop productivity or in Earth System models.

Context Thyroid dysfunction occurs commonly following immune checkpoint inhibition. The etiology of thyroid immune-related adverse events (irAEs) remains unclear and clinical presentation can be variable. Objective This study sought to define thyroid irAEs following immune checkpoint inhibitor (ICI) treatment and describe their clinical and biochemical associations. Methods We performed a retrospective cohort study of thyroid dysfunction in patients with melanoma undergoing cytotoxic T-lymphocyte antigen-4 (CTLA-4) and/or programmed cell death protein-1 (PD-1) based ICI treatment from November 1, 2009, to December 31, 2019. Thyroid function was measured at baseline and at regular intervals following the start of ICI treatment. Clinical and biochemical features were evaluated for associations with ICI-associated thyroid irAEs. The prevalence of thyroid autoantibodies and the effect of thyroid irAEs on survival were analyzed. Results A total of 1246 patients were included with a median follow-up of 11.3 months. Five hundred and eighteen (42%) patients developed an ICI-associated thyroid irAE. Subclinical thyrotoxicosis (n = 234) was the most common thyroid irAE, followed by overt thyrotoxicosis (n = 154), subclinical hypothyroidism (n = 61), and overt hypothyroidism (n = 39). Onset of overt thyrotoxicosis occurred a median of 5 weeks (interquartile range [IQR] 2-8) after receipt of a first dose of ICI. Combination immunotherapy was strongly associated with development of overt thyrotoxicosis (odds ratio [OR] 10.8, 95% CI 4.51-25.6 vs CTLA-4 monotherapy; P Conclusion Thyroid irAEs are common and there are multiple distinct phenotypes. Different thyroid irAE subtypes have unique clinical and biochemical associations, suggesting potentially distinct etiologies for thyrotoxicosis and hypothyroidism arising in this context.

Anthropogenic climate change is generating mismatches between the environmental conditions that populations historically experienced and those in which they reside. Understanding how climate change affects population performance is a critical scientific challenge. We combine a quantitative synthesis of field transplant experiments with a novel statistical approach based in evolutionary theory to quantify the effects of temperature and precipitation variability on population performance. We find that species’ average performance is affected by both temperature and precipitation, but populations show signs of local adaptation to temperature only. Contemporary responses to temperature are strongly shaped by the local climates under which populations evolved, resulting in performance declines when temperatures deviate from historic conditions. Adaptation to other local environmental factors is strong, but temperature deviations as small as 2°C erode the advantage that these non-climatic adaptations historically gave populations in their home sites.One sentence summaryClimate change is pulling the thermal rug out from under populations, reducing average performance and eroding their historical home-site advantage.

Approximately 0.6% of the adult population identifies as transgender. Gender affirming hormone treatment (GAHT) is required by many to develop physical and psychological characteristics that align with their gender identity. Once started, GAHT is continued lifelong and at higher doses than conventionally used in the management of cis-gendered women. Hyperprolactinemia and pituitary lactotroph adenomas are a potential consequence of GAHT.Case series of three transfeminine women with hyperprolactinemia during gender affirming hormone treatment.We report two new cases of prolactinoma and one new case of marked hyperprolactinemia without pituitary adenoma associated with GAHT in transwomen at different stages of hormonal transition. Novel aspects of our case series include the first report of a prolactinoma in a transwoman associated with spironolactone and the alternate progestin medroxyprogesterone acetate and documentation of the transient changes in prolactin from baseline (prior to feminizing hormones) in two transwomen which demonstrate that marked hyperprolactinemia develops early in the course of GAHT.Transgender women receiving GAHT may be at increased risk for prolactinoma. As the number of transwomen seeking GAHT continues to increase, hyperprolactinemia and GAHT-associated prolactinoma may become an increasingly important component of endocrine practice. Screening of prolactin levels in transwomen receiving GAHT could potentially prevent morbidity related to hyperprolactinemia and allow for early detection of prolactin secreting pituitary adenomas.

Objective: Everolimus, a mammalian target-ofrapamycin (mTOR) inhibitor, is increasingly used post-transplantation due to favorable effects on renal function and malignancy risk when compared to other immunosuppressive treatments such as calcineurin inhibitors. However, it can confer adverse effects such as dyslipidemia, which is not underpinned by any long-term screening and management of dyslipidemia in heart transplant recipients treated with everolimus. Methods: We report a case of severe hypertriglyceridemia which developed after commencement of everolimus in a heart transplant recipient with a background of Dunnigan-type familial partial lipodystrophy. Results: The patient is a 36-year-old woman who underwent heart transplantation for dilated cardiomyopathy. About 11 weeks following commencement of everolimus as part of her antirejection medication regime, serum triglyceride level concentration peaked at 5,093 mg/dL (normal, 0.0 to 177.2 mg/dL). There were no clinical complications with triglycerides at this elevated level and it improved substantially following cessation of everolimus and initiation of a high dose intravenous insulin-dextrose infusion. Conclusion: This case highlights dyslipidemia as a potential complication of everolimus treatment and that appropriate screening is important as lipid lowering medication can effectively control levels and minimize adverse outcomes. Abbreviations: FPLD familial partial lipodystrophy LPL lipoprotein lipase MMF mycophenolate mofetil mTOR mammalian target-of-rapamycin

PREMISEAcross taxa, vegetative and floral traits that vary along a fast-slow life-history axis are often correlated with leaf functional traits arrayed along the leaf economics spectrum, suggesting a constrained set of adaptive trait combinations. Such broad-scale convergence may arise from genetic constraints imposed by pleiotropy (or tight linkage) within species, or from natural selection alone. Understanding the genetic basis of trait syndromes and their components is key to distinguishing these alternatives and predicting evolution in novel environments.METHODSWe used a line-cross approach and quantitative trait locus (QTL) mapping to characterize the genetic basis of twenty leaf functional/physiological, life history, and floral traits in hybrids between annualized and perennial populations of scarlet monkeyflower (Mimulus cardinalis).RESULTSWe mapped both single and multi-trait QTLs for life history, leaf function and reproductive traits, but found no evidence of genetic co-ordination across categories. A major QTL for three leaf functional traits (thickness, photosynthetic rate, and stomatal resistance) suggests that a simple shift in leaf anatomy may be key to adaptation to seasonally dry habitats.CONCLUSIONSOur results suggest that the co-ordination of resource-acquisitive leaf physiological traits with a fast life history and more selfing mating system results from environmental selection rather than functional or genetic constraint. Independent assortment of distinct trait modules, as well as a simple genetic basis to leaf physiological traits associated with drought escape, may facilitate adaptation to changing climates.

The acquisitive-conservative axis of plant ecological strategies results in a pattern of leaf trait covariation that captures the balance between leaf construction costs and plant growth potential. Studies evaluating trait covariation within species are scarcer, and have mostly dealt with variation in response to environmental gradients. Little work has been published on intraspecific patterns of leaf trait covariation in the absence of strong environmental variation.Methods: We analysed covariation of four leaf functional traits (SLA: specific leaf area, LDMC: leaf dry matter content, Ft: force to tear, and Nm: leaf nitrogen content) in six Poaceae and four Fabaceae species common in the dry Chaco forest of Central Argentina, growing in the field and in a common garden. We compared intraspecific covariation patterns (slopes, correlation and effect size) of leaf functional traits with global interspecific covariation patterns. Additionally, we checked for possible climatic and edaphic factors that could affect the intraspecific covariation pattern.Key Results: We found negative correlations for the LDMC-SLA, Ft-SLA, LDMC-Nm , and Ft-Nm trait pairs. This intraspecific covariation pattern found both in the field and in the common garden and not be explained by climatic or edaphic variation in the field follows the expected acquisitive-conservative axis. At the same time, we found quantitative differences in slopes among different species, and between these intraspecific patterns and the interspecific ones. Many of these differences seem to be idiosyncratic, but some appear consistent among species (e.g.all the intraspecific LDMC-SLA and LDMC-Nm slopes tend to be shallower than the global).Conclusions: Our study indicates that the acquisitive-conservative leaf functional trait covariation pattern occurs at the intraspecific level even in the absence of relevant environmental variation in the field. This suggests a high degree of variation-covariation in leaf functional traits not driven by environmental variables. Fil: Gorne, Lucas Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina Fil: Díaz, Sandra Myrna. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina Fil: Minden, Vanessa. University of Oldenburg; Alemania. Vrije Universiteit Brussel; Bélgica Fil: Onoda, Yusuke. Kyoto University. School of Agriculture; Japón Fil: Kramer, Koen. Wageningen University; Países Bajos Fil: Muir, Christopher. University Of Hawaii; Estados Unidos Fil: Michaletz, Sean T. University of British Columbia; Canadá Fil: Lavorel, Sandra. Centre National de la Recherche Scientifique; Francia Fil: Sharpe, Joanne. Sharplex Services, Edgecomb; Estados Unidos Fil: Jansen, Steven. Universitat Ulm; Alemania Fil: Slot, Martijn. Smithsonian Tropical Research Institute; Panamá Fil: Chacon, Maximiliano Eduardo. Universidad de Costa Rica; Costa Rica Fil: Boenisch, Gerhard. Max Planck Institute For Biogeochemistry; Alemania

Objective: Graves disease is an autoimmune disease characterized by production of autoantibodies directed against the thyroid gland. Thyrotropin-receptor antibodies (TRABs) are clearly pathogenic, but the role of thyroid-peroxidase antibodies (TPOAb) in Graves disease is unknown. Design: We retrospectively studied whether TPOAb positivity reduced risk of relapse following anti-thyroid drug treatment in newly diagnosed Graves disease. Results: During follow-up of 204 patients with TRAB positive Graves disease, 107 (52%) relapsed following withdrawal of anti-thyroid medication. Mean age was 40.0 years and 82% were female. The average duration of anti-thyroid drug (ATD) treatment was 23.5 months and was not different between patients who relapsed and those with sustained remission. Absence of TPOAb significantly increased risk of Graves relapse (OR 2.21) and displayed a trend towards shorter time to relapse. Male sex and younger age were additional factors significantly associated with increased risk of relapse. Conclusion: TPO-antibody positivity significantly improves odds of remission following ATD treatment in newly diagnosed Graves disease.

Objective: Graves’ disease is an autoimmune disease characterized by production of autoantibodies directed against the thyroid gland. Thyrotropin-receptor antibodies (TRAbs) are clearly pathogenic, but the role of thyroidperoxidase antibodies (TPOAbs) in Graves disease is unknown. Methods: We retrospectively studied whether TPOAb positivity reduced risk of relapse following antithyroid drug (ATD) treatment in newly diagnosed Graves disease. Results: During follow-up of 204 patients with TRAb-positive Graves disease, 107 (52%) relapsed following withdrawal of ATD. Mean age was 40.0 years, and 82% were female. The average duration of ATD treatment was 23.5 months and was not different between patients who relapsed and those with sustained remission. Absence of TPOAbs significantly increased risk of Graves relapse (odds ratio, 2.21). Male sex and younger age were other factors significantly associated with increased risk of relapse. Conclusion: TPOAb positivity significantly improves the odds of remission following ATD treatment in newly diagnosed Graves’ disease.

Stomatal pores control both leaf gas exchange and are one route for infection of internal plant tissues by many foliar pathogens, setting up the potential for tradeoffs between photosynthesis and defense. Anatomical shifts to lower stomatal density and/or size may also limit pathogen colonization, but such developmental changes could permanently reduce the gas exchange capacity for the life of the leaf. I developed and analyzed a spatially explicit model of pathogen colonization on the leaf as a function of stomatal size and density, anatomical traits which partially determine maximum rates of gas exchange. The model predicts greater stomatal size or density increases the probability of colonization, but the effect is most pronounced when the fraction of leaf surface covered by stomata is low. I also derived scaling relationships between stomatal size and density that preserves a given probability of colonization. These scaling relationships set up a potential anatomical conflict between limiting pathogen colonization and minimizing the fraction of leaf surface covered by stomata. Although a connection between gas exchange and pathogen defense has been suggested empirically, this is the first mathematical model connecting gas exchange and pathogen defense via stomatal anatomy. A limitation of the model is that it does not include variation in innate immunity and stomatal closure in response to pathogens. Nevertheless, the model makes predictions that can be tested with experiments and may explain variation in stomatal anatomy among plants. The model is generalizable to many types of pathogens, but lacks significant biological realism that may be needed for precise predictions.

Background: Thyroid toxicity is common following immune checkpoint inhibitor (ICI) treatment. Published studies estimate the incidence at 10-20%, although rates vary widely between different ICIs. The etiology of ICI-associated thyroid immune related adverse events (irAEs) is unknown & not all patients develop a classic thyroiditis-like presentation of transient hyperthyroidism followed by a hypothyroid phase. Only small observational cohorts have been reported & the clinical & biochemical features of thyroid irAEs have not been well characterized. The current study aimed to describe thyroid irAEs in a large cohort of patients with melanoma. Methods: We reviewed outcomes in a prospective cohort of adult patients undergoing ICI treatment for advanced melanoma. Thyroid function was measured at baseline & at regular intervals during treatment. Thyroid irAEs were defined as new biochemical thyroid dysfunction developing over the course of routine follow-up. Results: Thyroid irAEs occurred in 518 of 1246 (42%) patients. Median follow-up was 11.3 months. Multiple patterns of thyroid-irAEs were observed, such as hyperthyroidism (subclinical or overt) in 31%, hypothyroidism in 8%, & euthyroid hyperthyroxinemia, hypothyroxinemia & isolated low FT3 syndrome each in 1% of participants. Thyroid irAEs were more frequent following combination (CTLA-4 + PD-1) ICI treatment (56%) than following PD-1 (38%) or CTLA-4 (25%) based monotherapies (p=0.001). The severity of thyroid irAEs differed by ICI, with higher rates of overt (vs. subclinical) thyroid dysfunction following combination ICI treatment (47%) relative to PD-1 (37%) & CTLA-4 (19%) monotherapies (p=0.001). Younger age (OR 0.88 per 10-yrs; 95% CI 0.81-0.96), female sex (OR 1.62; 95% CI 1.27-2.08) & combination ICI-treatment (vs. CTLA-4, OR 3.76, 95% CI 2.49-5.75; vs. PD-1, OR 1.90, 95% CI 1.45-2.49) were associated with higher odds of thyroid irAE. Time to onset of thyroid dysfunction was shorter in patients with overt hyperthyroidism relative to other types of thyroid irAE (log rank p=0.001). Overt hyperthyroidism was associated with increased irAEs in other organ systems (colitis, hepatitis, etc), increased irAE severity & increased multi-system irAEs than euthyroid patients or patients with other subtypes of thyroid irAE (p=0.003). Overt hyperthyroidism was also associated with improved progression free survival (HR 0.57; 95% CI 0.39-0.84; p=0.005) & overall survival (HR 0.68; 95% CI 0.49-0.94; p=0.02). No benefit to cancer survival was observed with other thyroid irAE subtypes. Conclusions: Thyroid irAEs were common. Combination ICI treatment resulted in more frequent, more severe, & earlier onset thyroid irAEs. Of thyroid irAE subtypes, overt hyperthyroidism was uniquely associated with increased immune responsiveness, as evidenced by higher incidence of extra-thyroidal irAEs & improvements in cancer survival.

Beneficial microbes such as plant mutualistic fungi, hold the promise of ameliorating challenges faced in native plant conservation such as disease management. As an alternative to costly chemical pest control, conservation efforts could potentially harness the benefits of plant mutualistic fungi to aid in defense and disease resistance, but there are few tests of this notion. We set out to test the efficacy of controlling a common foliar pathogen, the powdery mildew Neoerysiphe galeopsidis, by inoculating the endangered Hawaiian plant species Phyllostegia kaalaensis with potentially beneficial members of its wild-type mycobiome. We tested whether inoculating plants with above or belowground fungal mutualists, or both, led to increased disease resistance in the host. We found that while all treatments reduced average disease incidence, colonization by the foliar yeast Moesziomyces aphidis was the only treatment to do so significantly. These results provide an exciting new strategy for plant conservation practices.

Trait integration arises through both selection on functional coordination and shared developmental pathways. Different anatomical components must both work well and develop together to generate individuals with the appropriate physiology to survive and reproduce in their environment. In this study, we used a common garden experiment and Bayesian multilevel models to test whether stomatal anatomy coordinates leaf gas exchange, Rubisco kinetics, and leaf size across 10 closely related species of Limonium from the Balearic Islands. The results indicate that the anatomical determinants of maximum stomatal conductance, stomatal density and size, were functionally coordinated with Rubisco kinetics – species whose stomatal anatomy was correlated with low stomatal conductance have evolved Rubisco enzymes better adapted to low operational chloroplastic CO2 concentrations. Lower stomatal density was associated with greater leaf size, which can be explained by a greater proportion of pavement cells in large-leaved species. These results suggest that both selection for functional coordination (stomata and Rubisco kinetics) and shared development pathways (stomatal density and leaf area) likely shape patterns of trait integration between species.

The genus Mimulus is a well-studied group of plant species, which has for decades allowed researchers to address a wide array of fundamental questions in biology (Wu & al. 2008; Twyford & al. 2015). Linnaeus named the type species of Mimulus (ringens L.), while Darwin (1876) used Mimulus (luteus L.) to answer key research questions. The incredible phenotypic diversity of this group has made it the focus of ecological and evolutionary study since the mid-20th century, initiated by the influential work of Clausen, Keck, and Hiesey as well as their students and collaborators (Clausen & Hiesey 1958; Hiesey & al. 1971, Vickery 1952, 1978). Research has continued on this group of diverse taxa throughout the 20th and into the 21st century (Bradshaw & al. 1995; Schemske & Bradshaw 1999; Wu & al. 2008; Twyford & al. 2015; Yuan 2019), and Mimulus guttatus was one of the first non-model plants to be selected for full genome sequencing (Hellsten & al. 2013). Mimulus has played a key role in advancing our general understanding of the evolution of pollinator shifts (Bradshaw & Schemske 2003; Cooley & al. 2011; Byers & al. 2014), adaptation (Lowry & Willis 2010; Kooyers & al. 2015; Peterson & al. 2016; Ferris & Willis 2018; Troth & al. 2018), speciation (Ramsey & al. 2003; Wright & al. 2013; Sobel & Streisfeld 2015; Zuellig & Sweigart 2018), meiotic drive (Fishman & Saunders 2008), polyploidy (Vallejo-Marín 2012; Vallejo-Marín & al. 2015), range limits (Angert 2009; Sexton et al. 2011; Grossenbacher & al. 2014; Sheth & Angert 2014), circadian rhythms (Greenham & al. 2017), genetic recombination (Hellsten & al. 2013), mating systems (Fenster & Ritland 1994; Dudash & Carr 1998; Brandvain & al. 2014) and developmental biology (Moody & al. 1999; Baker & al. 2011, 2012; Yuan 2019). This combination of a rich history of study coupled with sustained modern research activity is unparalleled among angiosperms. Across many interested parties, the name Mimulus therefore takes on tremendous biological significance and is recognizable not only by botanists, but also by zoologists, horticulturalists, naturalists, and members of the biomedical community. Names associated with a taxonomic group of this prominence should have substantial inertia, and disruptive name changes should be avoided. As members of the Mimulus community, we advocate retaining the genus name Mimulus to describe all monkeyflowers. This is despite recent nomenclature changes that have led to a renaming of most monkeyflower species to other genera.

Plants must regulate leaf temperature to optimize photosynthesis, control water loss and prevent damage caused by overheating or freezing. Physical models of leaf energy budgets calculate the energy fluxes and leaf temperatures for a given set leaf and environmental parameters. These models can provide deep insight into the variation in leaf form and function, but there are few computational tools available to use these models. Here I introduce a new R package called tealeaves to make complex leaf energy budget models accessible to a broader array of plant scientists. This package enables novice users to start modelling leaf energy budgets quickly while allowing experts to customize their parameter settings. The code is open source, freely available and readily integrates with other R tools for scientific computing. This paper describes the current functionality of tealeaves, but new features will be added in future releases. This software tool will advance new research on leaf thermal physiology to advance our understanding of basic and applied plant science., tealeaves is a new R package to implement complex, customizable leaf energy budget models as part of an open source, transparent workflow.

Weight gain on clozapine is highly variable and poorly predictable. Its mechanisms are not well understood. This study explores the factors that predict weight gain between 3 and 12 months of clozapine therapy in community-dwelling patients.We conducted a retrospective audit of patients attending an outpatient clozapine clinic. Weight change from 3 to 12 months of therapy was recorded, expressed as a percentage of the 3-month weight. Univariate analyses compared percent weight change according to sex, smoking status, country of birth, and baseline body mass index. Correlations between weight gain, age, and clozapine dose were explored. A general linear model identified independent predictors of weight gain.The mean weight change from 3 to 12 months in 117 patients was +3.1% (range, -17% to +30%). Females gained more weight than males (+5.5% vs +1.3%, P = 0.01), smokers gained more than nonsmokers (+5.1% vs +1.2%, P = 0.02), and obese patients gained less than normal or overweight individuals (0.15% vs 4.6% and 5.2%, respectively, P = 0.01). Age and clozapine dose had no relation to weight change. On multivariate analysis, baseline BMI and smoking status remained independent predictors of percent weight change in females. These 2 predictors explained 25% of weight change in females in the first 3 to 12 months of therapy. These associations were not observed in males.We hypothesize that smoking affects weight change by promoting clozapine metabolism to norclozapine via cytochrome P450 enzymes. Verifying this hypothesis and exploring the mechanisms underpinning the sex dichotomy are areas for further research.

Climate can affect plant populations through direct effects on physiology and fitness, and through indirect effects on their relationships with pollinating mutualists. We therefore expect that geographic variation in climate might lead to variation in plant mating systems. Biogeographic processes, such as range expansion, can also contribute to geographic patterns in mating system traits. We manipulated pollinator access to plants in eight sites spanning the geographic range of Clarkia pulchella to investigate geographic and climatic drivers of fruit production and seed set in the absence of pollinators (reproductive assurance). We examined how reproductive assurance and fruit production varied with the position of sites within the range of the species and with temperature and precipitation. We found that reproductive assurance in C. pulchella was greatest in populations in the northern part of the species’ range and was not well explained by any of the climate variables that we considered. In the absence of pollinators, some populations of C. pulchella have the capacity to increase fruit production, perhaps through resource reallocation, but this response is climate dependent. Pollinators are important for reproduction in this species, and recruitment is sensitive to seed input. The degree of autonomous self-pollination that is possible in populations of this mixed-mating species may be shaped by historic biogeographic processes or variation in plant and pollinator community composition rather than variation in climate.

The West-Brown-Enquist (WBE) metabolic scaling theory posits that many organismal features scale predictably with body size because of selection to minimize transport costs in resource distribution networks. Many scaling exponents are quarter-powers, as predicted by WBE, but there are also biologically significant deviations that could reflect adaptation to different environments. A central but untested prediction of the WBE model is that wide deviation from optimal scaling is penalized, leading to a pattern of constraint on scaling exponents. Here, we demonstrate, using phylogenetic comparative methods, that variation in allometric scaling between mass and leaf area across 17 wild tomato taxa is constrained around a value indistinguishable from that predicted by WBE but significantly greater than 2/3 (geometric-similarity model). The allometric-scaling exponent was highly correlated with fecundity, water use, and drought response, suggesting that it is functionally significant and therefore could be under selective constraints. However, scaling was not strictly log-log linear but rather declined during ontogeny in all species, as has been observed in many plant species. We caution that although our results supported one prediction of the WBE model, it did not strongly test the model in other important respects. Nevertheless, phylogenetic comparative methods such as those used here are powerful but underutilized tools for metabolic ecology that complement existing methods to adjudicate between models.

Hybrid incompatibilities contribute to reproductive isolation between species, allowing them to follow independent evolutionary trajectories. Since hybrid incompatibilities are by definition deleterious, they cannot be selected for directly and must arise as a by-product of evolutionary divergence. Divergent resolution of duplicate genes, a special case of Dobzhansky-Muller incompatibilities, is one mechanism by which hybrid incompatibility can evolve. Following whole-genome duplication, loss of gene copies could possibly increase the opportunity for divergent resolution and, hence, the evolution of hybrid incompatibilities. However, divergent resolution can take place only when populations are isolated in allopatry; genes lost within a species cannot contribute to future speciation. Furthermore, nearly complete allopatry is necessary for passive divergent resolution. Using mathematical models, we demonstrate that these two factors severely impede the ability of divergent resolution alone to increase speciation rates, except under very particular conditions. Instead, we find that the population dynamics of diverging lineages dominate this process, leading to a larger role for ecology relative to genetics in the origin of new species, even by passive mechanisms. Divergent resolution of duplicate genes might increase speciation rates in some clades at some times, but our results indicate that it alone is unlikely to account for the macroevolutionary success of polyploid clades.

Local adaptation is commonly observed in nature: organisms perform well in their natal environment, but poorly outside it. Correlations between traits and latitude, or latitudinal clines, are among the most common pieces of evidence for local adaptation, but identifying the traits under selection and the selective agents is challenging. Here, we investigated a latitudinal cline in growth and photosynthesis across 16 populations of the perennial herbErythranthe cardinalis(Phrymaceae). Using machine learning methods, we identify interannual variation in precipitation as a likely selective agent: Southern populations from more variable environments had higher photosynthetic rates and grew faster. We hypothesize that selection may favor a more annualized life history – grow now rather than save for next year – in environments where severe droughts occur more often. Thus our study provides insight into how species may adapt if Mediterranean climates become more variable due to climate change.

Summary Diamond–Blackfan anaemia (DBA) is a rare cause of bone marrow failure. The incidence of malignancy and endocrine complications are increased in DBA, relative to other inherited bone marrow failure syndromes. We describe an adult woman with DBA who developed osteoporosis and avascular necrosis (AVN) of both distal femora. Such endocrine complications are not uncommon in DBA, but under-appreciated, especially in adulthood. Further, rectal adenocarcinoma was diagnosed at age 32 years, requiring hemi-colectomy and adjuvant chemotherapy. Elevated cancer risk may warrant disease-specific screening guidelines. Genetic predictors of extra-haematopoetic complications in DBA are yet to be established. Learning points: Endocrine complications are common in DBA. Clinical vigilance is required in managing bone health of DBA patients treated with glucocorticoids. There is currently no reliable way to predict which patients will develop complications of therapy or premature malignancy related to DBA. Complaints of bone or joint pain should prompt screening with targeted magnetic resonance imaging. Osteoporosis screening should be performed routinely.

Summary Background and objectives The relative merits of buttonhole (or blunt needle) versus rope ladder (or sharp needle) cannulation for hemodialysis vascular access are unclear. Design, setting, participants, & measurements Clinical outcomes by cannulation method were reviewed in 90 consecutive home hemodialysis patients. Initially, patients were trained in rope ladder cannulation. From 2004 on, all incident patients were started on buttonhole cannulation, and prevalent patients were converted to this cannulation method. Coprimary outcomes were arteriovenous fistula-attributable systemic infections and a composite of arteriovenous fistula loss or requirement for surgical intervention. Secondary outcomes were total arteriovenous fistula-related infections and staff time requirements. Additionally, a systematic review evaluating infections by cannulation method was performed. Results Seventeen systemic arteriovenous fistula-attributable infections were documented in 90 patients who were followed for 3765 arteriovenous fistula-months. Compared with rope ladder, buttonhole was not associated with a significantly higher rate of systemic arteriovenous fistula-attributable infections (incidence rate ratio, 2.71; 95% confidence interval, 0.66 to 11.09; P=0.17). However, use of buttonhole was associated with a significantly higher rate of total arteriovenous fistula infections (incidence rate ratio, 3.85; 95% confidence interval, 1.66 to 12.77; P=0.03). Initial and ongoing staff time requirements were significantly higher with buttonhole cannulation. Arteriovenous fistula loss or requirement for surgical intervention was not different between cannulation methods. A systematic review found increased arteriovenous fistula-related infections with buttonhole compared with rope ladder in four randomized trials (relative risk, 3.34; 95% confidence interval, 0.91 to 12.20), seven observational studies comparing before with after changes (relative risk, 3.15; 95% confidence interval, 1.90 to 5.21), and three observational studies comparing units with different cannulation methods (relative risk, 3.27; 95% confidence interval, 1.44 to 7.43). Conclusion Buttonhole cannulation was associated with higher rates of infectious events, increased staff support requirements, and no reduction in surgical arteriovenous fistula interventions compared with rope ladder in home hemodialysis patients. A systematic review of the published literature found that buttonhole is associated with higher risk of arteriovenous fistula-related infections.

Species barriers, expressed as hybrid inviability and sterility, are often due to epistatic interactions between divergent loci from two lineages. Theoretical models indicate that the strength, direction, and complexity of these genetic interactions can strongly affect the expression of interspecific reproductive isolation and the rates at which new species evolve. Nonetheless, empirical analyses have not quantified the frequency with which loci are involved in interactions affecting hybrid fitness, and whether these loci predominantly interact synergistically or antagonistically, or preferentially involve loci that have strong individual effects on hybrid fitness. We systematically examined the prevalence of interactions between pairs of short chromosomal regions from one species (Solanum habrochaites) co-introgressed into a heterospecific genetic background (Solanum lycopersicum), using lines containing pairwise combinations of 15 chromosomal segments from S. habrochaites in the background of S. lycopersicum (i.e., 95 double introgression lines). We compared the strength of hybrid incompatibility (either pollen sterility or seed sterility) expressed in each double introgression line to the expected additive effect of its two component single introgressions. We found that epistasis was common among co-introgressed regions. Interactions for hybrid dysfunction were substantially more prevalent in pollen fertility compared to seed fertility phenotypes, and were overwhelmingly antagonistic (i.e., double hybrids were less unfit than expected from additive single introgression effects). This pervasive antagonism is expected to attenuate the rate at which hybrid infertility accumulates among lineages over time (i.e., giving diminishing returns as more reproductive isolation loci accumulate), as well as decouple patterns of accumulation of sterility loci and hybrid incompatibility phenotypes. This decoupling effect might explain observed differences between pollen and seed fertility in their fit to theoretical predictions of the accumulation of isolation loci, including the ‘snowball’ effect., Author summary A characteristic feature of new species is their inability to produce fertile or viable hybrids with other lineages. This post-zygotic reproductive isolation is caused by dysfunctional interactions between genes that have newly evolved changes in the diverging lineages. Whether these interactions occur between pairs of divergent alleles, or involve more complex networks of genes, can have strong effects on how rapidly reproductive isolation—and therefore new species—evolve. The complexity of these interactions, however, is poorly understood in empirical systems. We examined the fertility of hybrids that carried one or two chromosomal regions from a close relative, finding that hybrids with two of these heterospecific regions were frequently less sterile than would be expected from the joint fitness of hybrids that have the same regions singly. This ‘less-than-additive’ effect on hybrid sterility was widespread (observed in 20% of pairwise combinations), and especially pronounced for male sterility. We infer that genes contributing to male sterility form a more tightly connected network than previously thought, implying that reproductive isolation is evolving by incremental dysfunction of complex interactions rather than by independent pairwise incompatibilities. We use simulations to illustrate these expected patterns of accumulation of reproductive isolation when it involves highly interconnected gene networks.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is prevalent in patients undergoing heart transplant, and in those without preexisting T2DM, posttransplant diabetes mellitus may develop. Both T2DM and posttransplant diabetes mellitus have been associated with increased morbidity and mortality following heart transplantation. Empagliflozin is an effective glucose-lowering therapy that reduces the incidence of major cardiovascular events in patients with T2DM. The safety and efficacy of empagliflozin in transplant patients with diabetes mellitus has yet to be established. METHODS: Clinical outcomes were retrospectively examined in 22 heart transplant recipients treated with empagliflozin and compared with those of 79 heart transplant patients with diabetes mellitus receiving alternative glucose-lowering therapies. RESULTS: Three adverse events were recorded in empagliflozin-treated patients, leading to treatment discontinuation in 1. There were no genitourinary infections. Treatment with empagliflozin for 12 months was associated with reductions in weight, body mass index, glycated hemoglobin, and frusemide dose that were not seen in the control group. There were no large changes observed in blood pressure (systolic or diastolic) or renal function (serum urea, creatinine, or estimated glomerular filtration rate) after 12 months of treatment with empagliflozin or alternative glucose-lowering therapies. CONCLUSIONS: Empagliflozin appears safe and effective in the management of selected patients with diabetes mellitus following heart transplantation.