Efficacy and Safety of Lerodalcibep in Patients With or at High Risk of Cardiovascular Disease: A Randomized Clinical Trial.

Importance: Recent changes in national and international lipid guidelines for reducing cardiovascular events recommend additional drugs, greater reductions, and lower targets for low-density lipoprotein cholesterol (LDL-C) if not attained with statins. The achievement of these targets with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has not yet been evaluated in a randomized clinical trial. Objective: To evaluate the 52-week safety and efficacy of lerodalcibep, a small anti-PCSK9-binding protein, in patients with cardiovascular disease (CVD) or who are at very high or high risk of CVD and requiring addition LDL-C-lowering treatment. Design, Setting, and Participants: This was a randomized, double-blind, placebo-controlled phase 3 trial. The trial was conducted at 66 clinics in 11 countries between April 23, 2021, and November 15, 2023. Individuals 18 years and older taking maximally tolerated statin therapy with LDL-C of 70 mg/dL or greater with CVD or 100 mg/dL or greater if at high risk of CVD were included. Interventions: Patients were randomized 2:1 to monthly 1.2-mL subcutaneous lerodalcibep, 300 mg, or placebo for 52 weeks. Main Outcomes and Measures: The safety analysis included all randomized patients. The co-primary efficacy end points were percent change from baseline in LDL-C at week 52 and the mean of weeks 50 and 52. Secondary efficacy outcomes included additional lipid apolipoprotein measures and achievement of guideline-recommended LDL-C targets. Results: Of 922 randomized participants (mean [range] age, 64.5 [27-87] years; 414 [44.9%] female; mean [SD] baseline LDL-C, 116.2 [43.5] mg/dL), 811 (88%) completed the trial. The mean (SE) placebo-adjusted reduction in LDL-C with lerodalcibep by modified intention-to-treat (mITT) analysis was 56.2% (2.2%) at week 52 and 62.7% (1.9%) for the mean of weeks 50 and 52; 49.7% (2.4%) and 55.3% (2.2%) by ITT with imputation using a washout model, and 60.3% (2.3%) and 65.9% (1.9%) by per-protocol analysis at week 52 and the mean of weeks 50 and 52, respectively (P < .001 for all). With lerodalcibep, 555 of 615 participants (90%) achieved both a reduction in LDL-C of 50% or greater and recommended LDL-C targets during the study. Treatment-emergent adverse events were similar between lerodalcibep and placebo, except for injection site reactions. These occurred in 42 of 613 participants receiving lerodalcibep (6.9%) compared to 1 of 307 receiving placebo (0.3%), were graded mild or moderate, and did not result in higher discontinuation of treatment, at 26 of 613 (4.2%) and 14 of 307 (4.6%), respectively. Sporadic in vitro antidrug antibodies were detected, which had no impact on free PCSK9 or LDL-C-lowering efficacy. Conclusions and Relevance: In this trial, lerodalcibep, a novel anti-PCSK9 small binding protein, dosed monthly and stable at ambient temperatures significantly reduced LDL-C in patients with CVD or at high risk of atherosclerotic cardiovascular disease with a safety profile similar to placebo. These results support long-term use of lerodalcibep in patients with CVD or at high risk of CVD who are unable to achieve adequate LDL-C reduction while receiving maximal tolerated statins alone. Trial Registration: ClinicalTrials.gov Identifier: NCT04806893.

Native myocardial T1 and right ventricular size by CMR predict outcome in systemic sclerosis-associated pulmonary hypertension.

OBJECTIVES: Measures of right heart size and function are prognostic in systemic sclerosis-associated pulmonary hypertension (SSc-PH), but the importance of myocardial tissue characterisation remains unclear. We aimed to investigate the predictive potential and interaction of cardiovascular magnetic resonance (CMR) myocardial tissue characterisation and right heart size and function in SSc-PH. METHODS: A retrospective, single-centre, observational study of 148 SSc-PH patients confirmed by right heart catheterization who underwent clinically-indicated CMR including native myocardial T1 and T2 mapping from 2016 to 2023 was performed. RESULTS: Sixty-six (45%) patients died during follow-up (median 3.5 years, range 0.1-7.3). Patients who died were older (65 vs 60 years, p= 0.035) with more dilated (RVEDVi and RVESVi, p< 0.001), hypertrophied (RVMi, p= 0.013) and impaired (RVEF, p< 0.001) right ventricles, more dilated right atria (RAi, p= 0.043) and higher native myocardial T1 (p< 0.001).After adjustment for age, RVESVi (p = 0.0023) and native T1 (p = 0.0024) were independent predictors of all-cause mortality. Both RVESVi and native T1 remained independently predictive after adjusting for age and PH subtype (RVESVi p < 0.001, T1 p = 0.0056). Optimal prognostic thresholds for RVESVi and native T1 were ≤38 mL/m2 and ≤1119 ms, respectively (p < 0.001). Patients with RVESVi ≤ 38 mL/m2 and native T1 ≤ 1119 ms had significantly better outcomes than all other combinations (p < 0.001). Furthermore, patients with RVESVi > 38mL/m2 and native T1 ≤ 1119 ms had significantly better survival than patients with RVESVi > 38mL/m2 and native T1 > 1119ms (p = 0.017). CONCLUSION: We identified prognostically relevant CMR metrics and thresholds for patients with SSc-PH. Assessing myocardial tissue characterisation alongside RV function confers added value in SSc-PH and may represent an additional treatment target.

Not enough known about fenofibrate's kidney effects in people with Type 2 diabetes.

Globally ≈10% of adults have diabetes, with 80% in disadvantaged regions, hence low-cost renoprotective agents are desirable. Fenofibrate demonstrated microvascular benefits in several cardiovascular end-point diabetes trials, but knowledge of effects in late-stage kidney disease is limited. We report new FIELD substudy data and call for further kidney outcomes data.

Fim de emergências de saúde inacabadas e as redes de cuidados com a síndrome congênita do Zika vírus / The end of unfinished health emergencies and the Congenital Zika Syndrome

Resumo Entendendo que problemas de saúde sempre são inacabadas, este trabalho examina consequências da declaração do fim de uma emergência de saúde sobre práticas de diferentes redes de cuidado interconectadas. Parte da pesquisa "Etnografando Cuidados...", é um estudo de caso qualitativo de três documentos produzidos depois do anúncio do fim da epidemia da síndrome congênita de Zika vírus. Mostra contextos de produção de narrativas envolvendo redes de pesquisadores, gestores/prestadores de serviço, mães e famílias de acometidos e associações de mães e suas perspectivas diferentes sobre o que é cuidado. Análises de uma apresentação para pesquisadores e de um texto de discussão no IPEA questionam a narrativa técnica da celebração do fim da emergência com base em conhecimento e atendimento, sem tomar em conta a importância dos cuidados relacionais e afetivos e políticos (das redes de mães/familiares e de associações), deixando-os invisibilizados. Descreve o processo da elaboração da moção para o Fórum Zika na Pandemia, elencando e sistematizando propostas de ações através de um diálogo explícito entre integrante das diferentes redes para abordar questões inacabadas pós-emergenciais. Sugere que práticas semelhantes de diálogo entre redes possam promover maior inclusão e sensibilidade a cuidados que contribuem para diminuir sofrimento e defender direitos de pessoas que continuam a conviver cotidianamente com uma síndrome ou doença cujas consequências persistem.

Abstract Understanding health problems as always unfinished, this article examines consequences of the declaration of the end of a health emergency on the practice of different and interconnected care networks. As part of the "Action Ethnography on Care…" research project, this is a qualitative case study of three documents produced after the announcement of the end of the Congenital Zika Virus Syndrome epidemic. It shows the contexts of narrative production involving researchers, managers/ public service workers, mothers and families of the ill, and mothers' associations and their different perspectives about what care is. Analyses of a presentation for researchers and of a working paper for the Applied Economics Research Institute (IPEA) question the technical narrative celebrating the end of the emergency based on knowledge and health service without taking into account the relational, affective and political care (of mothers, families and associations), leaving the latter invisible. It describes the process of elaboration of a motion by the Zika Pandemic Forum, listing and systematizing action proposals produced in an explicit dialogue among participants in different care networks to approach unfinished post-emergency questions. It suggests that similar practices of dialogue between networks can promote greater inclusion and sensitivity to care that contribute to reducing suffering and defending the rights of people who continue to live daily with a syndrome or disease whose consequences persist.

RNA interference targeting ANGPTL3 for triglyceride and cholesterol lowering: phase 1 basket trial cohorts.

Elevated triglycerides and non-high-density lipoprotein cholesterol (HDL-C) are risk factors for atherosclerotic cardiovascular disease (ASCVD). ARO-ANG3 is an RNA interference therapy that targets angiopoietin-like protein 3 (ANGPTL3), a regulator of lipoprotein metabolism. This first-in-human, phase 1, randomized, placebo-controlled, open-label trial investigated single and repeat ARO-ANG3 doses in four cohorts of fifty-two healthy participants and one cohort of nine participants with hepatic steatosis, part of a basket trial. Safety (primary objective) and pharmacokinetics (in healthy participants) and pharmacodynamics (secondary objectives) of ARO-ANG3 were evaluated. ARO-ANG3 was generally well tolerated, with similar frequencies of treatment-emergent adverse events in active and placebo groups. Systemic absorption of ARO-ANG3 in healthy participants was rapid and sustained, with a mean Tmax of 6.0-10.5 h and clearance from plasma within 24-48 h after dosing with a mean t½ of 3.9-6.6 h. In healthy participants, ARO-ANG3 treatment reduced ANGPTL3 (mean -45% to -78%) 85 days after dose. Reductions in triglyceride (median -34% to -54%) and non-HDL-C (mean -18% to -29%) (exploratory endpoints) concentrations occurred with the three highest doses. These early-phase data support ANGPTL3 as a potential therapeutic target for ASCVD treatment. ClinicalTrials.gov identifier: NCT03747224.

Long-term efficacy and safety of lerodalcibep in heterozygous familial hypercholesterolaemia: the LIBerate-HeFH trial.

BACKGROUND AND AIMS: Lerodalcibep, a novel small recombinant fusion protein of a proprotein convertase subtilisin/kexin type 9 gene-binding domain (adnectin) and human serum albumin, demonstrated highly effective low-density lipoprotein cholesterol (LDL-C) reduction with monthly 300 mg in 1.2 mL subcutaneous dosing in Phase 2. In this global Phase 3 trial, the safety and efficacy of lerodalcibep were evaluated in heterozygous familial hypercholesterolaemia patients requiring additional LDL-C lowering. METHODS: Patients were randomized 2:1 to monthly subcutaneous injections of either lerodalcibep 300 mg or placebo for 24 weeks. The primary efficacy endpoints were the per cent change from baseline in LDL-C at Week 24 and the mean of Weeks 22 and 24. RESULTS: In 478 randomized subjects [mean age (range); 53 (18-80) years, 51.7% female, mean (SD) baseline LDL-C 3.88 (1.66) mmol/L], lerodalcibep reduced LDL-C, compared with placebo by an absolute amount of 2.08 (0.11) mmol/L [LS mean (SE); 95% confidence interval -2.30 to -1.87] with a percentage difference of -58.61 (3.25)% at Week 24 and by 2.28 (0.10) mmol/L (95% confidence interval -2.47 to -2.09) with a percentage difference of -65.0 (2.87)% at the mean of Weeks 22 and 24 (P < .0001 for all). With lerodalcibep, 68% of subjects achieved both a reduction in LDL-C ≥ 50% and the recommended European Society of Cardiology LDL-C targets during the study. Except for mild injection site reactions, treatment-emergent adverse events were similar between lerodalcibep and placebo. CONCLUSIONS: Lerodalcibep, a novel anti-proprotein convertase subtilisin/kexin type 9 gene small binding protein dosed monthly as an alternative to monoclonal antibodies, significantly reduced LDL-C in subjects with heterozygous familial hypercholesterolaemia with a safety profile similar to placebo.

Thermography captures the differential sensitivity of dryland functional types to changes in rainfall event timing and magnitude.

Drylands of the southwestern United States are rapidly warming, and rainfall is becoming less frequent and more intense, with major yet poorly understood implications for ecosystem structure and function. Thermography-based estimates of plant temperature can be integrated with air temperature to infer changes in plant physiology and response to climate change. However, very few studies have evaluated plant temperature dynamics at high spatiotemporal resolution in rainfall pulse-driven dryland ecosystems. We address this gap by incorporating high-frequency thermal imaging into a field-based precipitation manipulation experiment in a semi-arid grassland to investigate the impacts of rainfall temporal repackaging. All other factors held constant, we found that fewer/larger precipitation events led to cooler plant temperatures (1.4°C) compared to that of many/smaller precipitation events. Perennials, in particular, were 2.5°C cooler than annuals under the fewest/largest treatment. We show these patterns were driven by: increased and consistent soil moisture availability in the deeper soil layers in the fewest/largest treatment; and deeper roots of perennials providing access to deeper plant available water. Our findings highlight the potential for high spatiotemporal resolution thermography to quantify the differential sensitivity of plant functional groups to soil water availability. Detecting these sensitivities is vital to understanding the ecohydrological implications of hydroclimate change.

Bark beetle impacts on forest evapotranspiration and its partitioning.

Insect outbreaks affect forest structure and function and represent a major category of forest disturbance globally. However, the resulting impacts on evapotranspiration (ET), and especially hydrological partitioning between the abiotic (evaporation) and biotic (transpiration) components of total ET, are not well constrained. As a result, we combined remote sensing, eddy covariance, and hydrological modeling approaches to determine the effects of bark beetle outbreak on ET and its partitioning at multiple scales throughout the Southern Rocky Mountain Ecoregion (SRME), USA. At the eddy covariance measurement scale, 85 % of the forest was affected by beetles, and water year ET as a fraction of precipitation (P) decreased by 30 % relative to a control site, with 31 % greater reductions in growing season transpiration relative to total ET. At the ecoregion scale, satellite remote sensing masked to areas of >80 % tree mortality showed corresponding ET/P reductions of 9-15 % that occurred 6-8 years post-disturbance, and indicated that the majority of the total reduction occurred during the growing season; the Variable Infiltration Capacity hydrological model showed an associated 9-18 % increase in the ecoregion runoff ratio. Long-term (16-18 year) ET and vegetation mortality datasets extend the length of previously published analyses and allowed for clear characterization of the forest recovery period. During that time, transpiration recovery outpaced total ET recovery, which was lagged in part due to persistently reduced winter sublimation, and there was associated evidence of increasing late summer vegetation moisture stress. Overall, comparison of three independent methods and two partitioning approaches demonstrated a net negative impact of bark beetles on ET, and a relatively greater negative impact on transpiration, following bark beetle outbreak in the SRME.

Satellite solar-induced chlorophyll fluorescence tracks physiological drought stress development during 2020 southwest US drought.

Monitoring and estimating drought impact on plant physiological processes over large regions remains a major challenge for remote sensing and land surface modeling, with important implications for understanding plant mortality mechanisms and predicting the climate change impact on terrestrial carbon and water cycles. The Orbiting Carbon Observatory 3 (OCO-3), with its unique diurnal observing capability, offers a new opportunity to track drought stress on plant physiology. Using radiative transfer and machine learning modeling, we derive a metric of afternoon photosynthetic depression from OCO-3 solar-induced chlorophyll fluorescence (SIF) as an indicator of plant physiological drought stress. This unique diurnal signal enables a spatially explicit mapping of plants' physiological response to drought. Using OCO-3 observations, we detect a widespread increasing drought stress during the 2020 southwest US drought. Although the physiological drought stress is largely related to the vapor pressure deficit (VPD), our results suggest that plants' sensitivity to VPD increases as the drought intensifies and VPD sensitivity develops differently for shrublands and grasslands. Our findings highlight the potential of using diurnal satellite SIF observations to advance the mechanistic understanding of drought impact on terrestrial ecosystems and to improve land surface modeling.

Distinct cardiovascular phenotypes are associated with prognosis in systemic sclerosis: a cardiovascular magnetic resonance study.

AIMS: Cardiovascular involvement in systemic sclerosis (SSc) is heterogeneous and ill-defined. This study aimed to: (i) discover cardiac phenotypes in SSc by cardiovascular magnetic resonance (CMR); (ii) provide a CMR-based algorithm for phenotypic classification; and (iii) examine for associations between phenotypes and mortality. METHODS AND RESULTS: A retrospective, single-centre, observational study of 260 SSc patients who underwent clinically indicated CMR including native myocardial T1 and T2 mapping from 2016 to 2019 was performed. Agglomerative hierarchical clustering using only CMR variables revealed five clusters of SSc patients with shared CMR characteristics: dilated right hearts with right ventricular failure (RVF); biventricular failure dilatation and dysfunction (BVF); and normal function with average cavity (NF-AC), normal function with small cavity (NF-SC), and normal function with large cavity (NF-LC) sizes. Phenotypes did not co-segregate with clinical or antibody classifications. A CMR-based decision tree for phenotype classification was created. Sixty-three (24%) patients died during a median follow-up period of 3.4 years. After adjustment for age and presence of pulmonary hypertension (PH), independent CMR predictors of all-cause mortality were native T1 (P < 0.001) and right ventricular ejection fraction (RVEF) (P = 0.0032). NF-SC and NF-AC groups had more favourable prognoses (P≤0.036) than the other three groups which had no differences in prognoses between them (P > 0.14). Hazard ratios (HR) were statistically significant for RVF (HR = 8.9, P < 0.001), BVF (HR = 5.2, P = 0.006), and NF-LC (HR = 4.9, P = 0.002) groups. The NF-LC group remained significantly predictive of mortality after adjusting for RVEF, native T1, and PH diagnosis (P = 0.0046). CONCLUSION: We identified five CMR-defined cardiac SSc phenotypes that did not co-segregate with clinical data and had distinct outcomes, offering opportunities for a more precision-medicine based management approach.

A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Loss-of-function HSD17ß13 mutations protect against the development of chronic liver disease. HSD17ß13 inhibition represents a potential approach to treat liver diseases, such as non-alcoholic steatohepatitis (NASH). ARO-HSD is an RNA interference (RNAi) therapeutic designed to selectively reduce expression of HSD17ß13 mRNA in hepatocytes. In this study, we evaluated the effects of ARO-HSD in normal healthy volunteers (NHVs) and patients with confirmed or clinically suspected NASH. METHODS: The safety, tolerability, and pharmacodynamics of ARO-HSD were evaluated in 32 NHVs and 18 patients with confirmed/clinically suspected NASH. Double-blind NHV cohorts received single escalating doses of ARO-HSD (25, 50, 100, or 200 mg) or placebo subcutaneously on Day 1. Open-label patient cohorts received ARO-HSD (25, 100, or 200 mg) subcutaneously on Days 1 and 29. Liver biopsy was performed pre-dose and on Day 71 to evaluate expression levels of HSD17ß13 mRNA and protein. RESULTS: ARO-HSD treatment was well tolerated with no treatment-related serious adverse events or drug discontinuations. The most frequently reported treatment-emergent adverse events were mild injection site reactions, which were short in duration. Mean changes in hepatic HSD17ß13 mRNA from baseline to Day 71 were: -56.9% (25 mg), -85.5% (100 mg), and -93.4% (200 mg). The mean HSD17ß13 mRNA reduction was 78.6% (p <0.0001) across pooled cohorts. Hepatic HSD17ß13 protein levels were similarly reduced across doses. In patients, mean changes in alanine aminotransferase from baseline to Day 71 were -7.7% (25 mg), -39.3% (100 mg), and -42.3% (200 mg) (p <0.001 for pooled cohorts). CONCLUSIONS: ARO-HSD was well tolerated at doses ≤200 mg. This proof-of-concept study demonstrated that short-term treatment with ARO-HSD reduces hepatic HSD17ß13 mRNA and protein expression, which is accompanied by reductions in alanine aminotransferase. GOV NUMBER: NCT04202354. IMPACTS AND IMPLICATIONS: There is an unmet medical need for new therapies to treat alcohol-related and non-alcoholic liver disease. ARO-HSD is a small-interfering RNA designed to silence HSD17ß13 expression and hence to phenocopy the protective effect seen in individuals with HSD17ß13 loss-of-function. The reductions in HSD17ß13 expression and in transaminases seen with ARO-HSD administration represent an initial step towards clinical validation of HSD17ß13, a drug target with substantial genetic validation, as an important modulator of human liver disease.

Indicators of water use efficiency across diverse agroecosystems and spatiotemporal scales.

Understanding the relationship between water and production within and across agroecosystems is essential for addressing several agricultural challenges of the 21st century: providing food, fuel, and fiber to a growing human population, reducing the environmental impacts of agricultural production, and adapting food systems to climate change. Of all human activities, agriculture has the highest demand for water globally. Therefore, increasing water use efficiency (WUE), or producing 'more crop per drop', has been a long-term goal of agricultural management, engineering, and crop breeding. WUE is a widely used term applied across a diverse array of spatial scales, spanning from the leaf to the globe, and over temporal scales ranging from seconds to months to years. The measurement, interpretation, and complexity of WUE varies enormously across these spatial and temporal scales, challenging comparisons within and across diverse agroecosystems. The goals of this review are to evaluate common indicators of WUE in agricultural production and assess tradeoffs when applying these indicators within and across agroecosystems amidst a changing climate. We examine three questions: (1) what are the uses and limitations of common WUE indicators, (2) how can WUE indicators be applied within and across agroecosystems, and (3) how can WUE indicators help adapt agriculture to climate change? Addressing these agricultural challenges will require land managers, producers, policy makers, researchers, and consumers to evaluate costs and benefits of practices and innovations of water use in agricultural production. Clearly defining and interpreting WUE in the most scale-appropriate way is crucial for advancing agroecosystem sustainability.

RNA Interference Therapy Targeting Apolipoprotein C-III in Hypertriglyceridemia.

BACKGROUND: Apolipoprotein C-III (APOC3) inhibits triglyceride clearance by reducing lipoprotein lipase­mediated hydrolysis and hepatocyte uptake of triglyceride-rich lipoproteins. ARO-APOC3, a hepatocyte-targeting RNA interference therapeutic, inhibits APOC3 messenger ribonucleic acid expression, lowering triglyceride levels. The objective of this trial was to assess the safety, pharmacodynamic variables, and pharmacokinetic variables of ARO-APOC3 treatment. METHODS: Healthy participants and adults with hypertriglyceridemia were randomly assigned to receive escalating single (day 1) or repeat (days 1 and 29) doses, respectively, of subcutaneous injections of ARO-APOC3 10, 25, 50, or 100 mg or placebo; they were followed up until day 113. Additional cohorts of healthy participants and adults with chylomicronemia received repeat doses of open-label ARO-APOC3. The primary objective was to evaluate the safety and side effect profile of ARO-APOC3. Key secondary and exploratory objectives included pharmacokinetic variables and changes in serum APOC3, triglyceride, and cholesterol levels. RESULTS: Eighty-eight participants received ARO-APOC3 and 24 participants received placebo across double-blind and open-label cohorts. Treatment-emergent adverse events (AEs) of transient, mild to moderate liver transaminase changes occurred in 10 participants: 1 patient receiving ARO-APOC3 25 mg, 5 patients receiving ARO-APOC3 50 mg, and 4 participants receiving ARO-APOC3 100 mg (1 healthy participant and 3 patients with hypertriglyceridemia). These events were asymptomatic, and transaminase levels returned to near baseline by the end of the trial. No AEs related to thrombocytopenia or platelet declines were reported. In the hypertriglyceridemia cohorts, the day 113 mean changes from baseline in APOC3 at the 10-, 25-, 50-, and 100-mg doses were −62.0%, −81.7%, −90.1%, and −94.4%, respectively, compared with −1.6% with placebo. This corresponded to median changes in triglyceride levels of −65.6%, −69.9%, −81.2%, and −81.0% compared with −2.8% with placebo. CONCLUSIONS: In this small trial of short duration, ARO-APOC3 was associated with few AEs and reduced serum levels of APOC3 and triglycerides in healthy participants and patients with hypertriglyceridemia. (Funded by Arrowhead Pharmaceuticals, Inc.; ClinicalTrials.gov number, NCT03783377.)

Exceptional heat and atmospheric dryness amplified losses of primary production during the 2020 U.S. Southwest hot drought.

Earth's ecosystems are increasingly threatened by "hot drought," which occurs when hot air temperatures coincide with precipitation deficits, intensifying the hydrological, physiological, and ecological effects of drought by enhancing evaporative losses of soil moisture (SM) and increasing plant stress due to higher vapor pressure deficit (VPD). Drought-induced reductions in gross primary production (GPP) exert a major influence on the terrestrial carbon sink, but the extent to which hotter and atmospherically drier conditions will amplify the effects of precipitation deficits on Earth's carbon cycle remains largely unknown. During summer and autumn 2020, the U.S. Southwest experienced one of the most intense hot droughts on record, with record-low precipitation and record-high air temperature and VPD across the region. Here, we use this natural experiment to evaluate the effects of hot drought on GPP and further decompose those negative GPP anomalies into their constituent meteorological and hydrological drivers. We found a 122 Tg C (>25%) reduction in GPP below the 2015-2019 mean, by far the lowest regional GPP over the Soil Moisture Active Passive satellite record. Roughly half of the estimated GPP loss was attributable to low SM (likely a combination of record-low precipitation and warming-enhanced evaporative depletion), but record-breaking VPD amplified the reduction of GPP, contributing roughly 40% of the GPP anomaly. Both air temperature and VPD are very likely to continue increasing over the next century, likely leading to more frequent and intense hot droughts and substantially enhancing drought-induced GPP reductions.

Fenofibrate, which reduces risk of sight-threatening diabetic retinopathy in type 2 diabetes, is associated with early narrowing of retinal venules: a FIELD trial substudy.

Retinal vessel calibre metrics were evaluated at baseline and 2 years in a FIELD substudy (n = 208). Central retinal venule calibre was significantly reduced by fenofibrate and unchanged by placebo. Arteriole metrics did not change. Larger studies relating retinal vessel calibre to future diabetes complications and response to therapy are merited.

Retinopathy risk calculators in the prediction of sight-threatening diabetic retinopathy in type 2 diabetes: A FIELD substudy.

AIMS: To evaluate the risk algorithm by Aspelund et al. for predicting sight-threatening diabetic retinopathy (STDR) in Type 2 diabetes (T2D), and to develop a new STDR prediction model. METHODS: The Aspelund et al. algorithm was used to calculate STDR risk from baseline variables in 1012 participants in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) ophthalmological substudy, compared to on-trial STDR status, and receiver operating characteristic analysis performed. Using multivariable logistic regression, traditional risk factors and fenofibrate allocation as STDR predictors were evaluated, with bootstrap-based optimism-adjusted estimates of predictive performance calculated. RESULTS: STDR developed in 28 participants. The Aspelund et al. algorithm predicted STDR at 2- and 5-years with area under the curve (AUC) 0.86 (95% CI 0.77-0.94) and 0.86 (0.81-0.92), respectively. In the second model STDR risk factors were any DR at baseline (OR 24.0 [95% CI 5.53-104]), HbA1c (OR 1.95 [1.43-2.64]) and male sex (OR 4.34 [1.32-14.3]), while fenofibrate (OR 0.13 [0.05-0.38]) was protective. This model had excellent discriminatory ability (AUC = 0.89). CONCLUSIONS: The algorithm by Aspelund et al. predicts STDR well in the FIELD ophthalmology substudy. Logistic regression analysis found DR at baseline, male sex, and HbA1c were predictive of STDR and, fenofibrate was protective.

Confronting the water potential information gap.

Water potential directly controls the function of leaves, roots, and microbes, and gradients in water potential drive water flows throughout the soil-plant-atmosphere continuum. Notwithstanding its clear relevance for many ecosystem processes, soil water potential is rarely measured in-situ, and plant water potential observations are generally discrete, sparse, and not yet aggregated into accessible databases. These gaps limit our conceptual understanding of biophysical responses to moisture stress and inject large uncertainty into hydrologic and land surface models. Here, we outline the conceptual and predictive gains that could be made with more continuous and discoverable observations of water potential in soils and plants. We discuss improvements to sensor technologies that facilitate in situ characterization of water potential, as well as strategies for building new networks that aggregate water potential data across sites. We end by highlighting novel opportunities for linking more representative site-level observations of water potential to remotely-sensed proxies. Together, these considerations offer a roadmap for clearer links between ecohydrological processes and the water potential gradients that have the 'potential' to substantially reduce conceptual and modeling uncertainties.

Type 1 diabetes diagnosed before age 15 years in Canterbury, New Zealand: A 50 year record of increasing incidence.

OBJECTIVE: To describe the epidemiology of pediatric type 1 diabetes over 50 years in Canterbury, New Zealand. Further, to explore variation in case presentation according to age, gender, ethnicity, urban/rural character, socio-economic deprivation and immunogenetic features. RESEARCH DESIGN AND METHODS: Prospective ascertainment of cases commenced in 1982, and incident cases presenting 1970-1982 were ascertained retrospectively from clinical records. Eligibility criteria included diagnosis of type 1 diabetes by a physician and commencement of insulin therapy at diagnosis and age less than 15 years. Data collection included name, hospital number, date of birth, date of diagnosis, and date of initiation of insulin treatment. Full address at diagnosis was assigned an urban-rural classification, and a deprivation score. HLA-DQ susceptibility alleles and diabetes associated autoantibodies were determined. RESULTS: The incidence of type 1 diabetes increased more than 5-fold (3.9% per annum) over 50 years for the entire cohort. The mean for 5-year periods, starting from 1970, increased from 5.3 to 29.0 cases per 100,000 person years. Incidence was greatest in the 10-14 year age group. The cohort is predominantly European (89.4%), but there has been an increase in cases identifying as New Zealand Maori in the last three decades. Weak evidence was found for reduced incidence of type 1 diabetes in rural regions (adjusted IRR = 0.70, 95%CI 0.52 to 0.91, p = 0.011). CONCLUSIONS: The incidence of type 1 diabetes in children aged less than 15 years continues to increase with time. Incidence was significantly affected by age, ethnicity, and urban/rural characterization of address at diagnosis.

Relationship of low molecular weight fluorophore levels with clinical factors and fenofibrate effects in adults with type 2 diabetes.

People with diabetes are at risk of chronic complications and novel biomarkers, such as Advanced glycation end-products (AGEs) may help stratify this risk. We assessed whether plasma low-molecular weight AGEs, also known as LMW-fluorophores (LMW-F), are associated with risk factors, predict complications, and are altered by fenofibrate in adults with type 2 diabetes. Plasma LMW-F were quantified at baseline, after six weeks fenofibrate, and one year post-randomisation to fenofibrate or placebo. LMW-F associations with existing and new composite vascular complications were determined, and effects of fenofibrate assessed. LMW-F correlated positively with age, glycated haemoglobin (HbA1c), pulse pressure, kidney dysfunction and inflammation; and negatively with urate, body mass index, oxidative stress and leptin, albeit weakly (r = 0.04-0.16, all p < 0.01). Independent determinants of LMW-F included smoking, diastolic blood pressure, prior cardiovascular disease or microvascular complications, Caucasian ethnicity, kidney function, HbA1c and diabetes duration (all p ≤ 0.01). Baseline LMW-F tertiles correlated with on-trial macrovascular and microvascular complications (trend p < 0.001) on univariate analyses only. Six weeks of fenofibrate increased LMW-F levels by 21% (p < 0.001). In conclusion, LMW-F levels correlate with many risk factors and chronic diabetes complications, and are increased with fenofibrate. LMW-F tertiles predict complications, but not independently of traditional risk factors.