Review and further developments in statistical corrections for Winner's Curse in genetic association studies.

Genome-wide association studies (GWAS) are commonly used to identify genomic variants that are associated with complex traits, and estimate the magnitude of this association for each variant. However, it has been widely observed that the association estimates of variants tend to be lower in a replication study than in the study that discovered those associations. A phenomenon known as Winner's Curse is responsible for this upward bias present in association estimates of significant variants in the discovery study. We review existing Winner's Curse correction methods which require only GWAS summary statistics in order to make adjustments. In addition, we propose modifications to improve existing methods and propose a novel approach which uses the parametric bootstrap. We evaluate and compare methods, first using a wide variety of simulated data sets and then, using real data sets for three different traits. The metric, estimated mean squared error (MSE) over significant SNPs, was primarily used for method assessment. Our results indicate that widely used conditional likelihood based methods tend to perform poorly. The other considered methods behave much more similarly, with our proposed bootstrap method demonstrating very competitive performance. To complement this review, we have developed an R package, 'winnerscurse' which can be used to implement these various Winner's Curse adjustment methods to GWAS summary statistics.

A guide to photosynthetic gas exchange measurements: Fundamental principles, best practice and potential pitfalls.

Gas exchange measurements enable mechanistic insights into the processes that underpin carbon and water fluxes in plant leaves which in turn inform understanding of related processes at a range of scales from individual cells to entire ecosytems. Given the importance of photosynthesis for the global climate discussion it is important to (a) foster a basic understanding of the fundamental principles underpinning the experimental methods used by the broad community, and (b) ensure best practice and correct data interpretation within the research community. In this review, we outline the biochemical and biophysical parameters of photosynthesis that can be investigated with gas exchange measurements and we provide step-by-step guidance on how to reliably measure them. We advise on best practices for using gas exchange equipment and highlight potential pitfalls in experimental design and data interpretation. The Supporting Information contains exemplary data sets, experimental protocols and data-modelling routines. This review is a community effort to equip both the experimental researcher and the data modeller with a solid understanding of the theoretical basis of gas-exchange measurements, the rationale behind different experimental protocols and the approaches to data interpretation.

Reducing stomatal density by expression of a synthetic Epidermal Patterning Factor increases leaf intrinsic water use efficiency and reduces plant water use in a C4 crop.

Enhancing crop water use efficiency (WUE) is a key target trait for climatic resilience and expanding cultivation on marginal lands. Engineering lower stomatal density to reduce stomatal conductance (gs) has improved WUE in multiple C3 crop species. However, reducing gs in C3 species often reduces photosynthetic carbon gain. A different response is expected in C4 plants because they possess specialized anatomy and biochemistry which concentrates CO2 at the site of fixation. This modifies the photosynthesis (AN) relationship with intracellular CO2 concentration (ci) so that photosynthesis is CO2-saturated and reductions in gs are unlikely to limit AN. To test this hypothesis, genetic strategies were investigated to reduce stomatal density in the C4 crop sorghum. Constitutive expression of a synthetic epidermal patterning factor (EPF) transgenic allele in sorghum, led to reduced stomatal densities, reduced gs, reduced plant water use and avoidance of stress during a period of water deprivation. In addition, moderate reduction in stomatal density did not increase stomatal limitation to AN. However, these positive outcomes were associated with negative pleiotropic effects on reproductive development and photosynthetic capacity. Avoiding pleiotropy by targeting expression of the transgene to specific tissues could provide a pathway to improved agronomic outcomes.

Pre-morbid sleep disturbance and its association with stroke severity: results from the international INTERSTROKE study.

BACKGROUND AND PURPOSE: Whilst sleep disturbances are associated with stroke, their association with stroke severity is less certain. In the INTERSTROKE study, the association of pre-morbid sleep disturbance with stroke severity and functional outcome following stroke was evaluated. METHODS: INTERSTROKE is an international case-control study of first acute stroke. This analysis included cases who completed a standardized questionnaire concerning nine symptoms of sleep disturbance (sleep onset latency, duration, quality, nocturnal awakening, napping duration, whether a nap was planned, snoring, snorting and breathing cessation) in the month prior to stroke (n = 2361). Two indices were derived representing sleep disturbance (range 0-9) and obstructive sleep apnoea (range 0-3) symptoms. Logistic regression was used to estimate the magnitude of association between symptoms and stroke severity defined by the modified Rankin Score. RESULTS: The mean age of participants was 62.9 years, and 42% were female. On multivariable analysis, there was a graded association between increasing number of sleep disturbance symptoms and initially severe stroke (2-3, odds ratio [OR] 1.44, 95% confidence interval [CI] 1.07-1.94; 4-5, OR 1.66, 95% CI 1.23-2.25; >5, OR 2.58, 95% CI 1.83-3.66). Having >5 sleep disturbance symptoms was associated with significantly increased odds of functional deterioration at 1 month (OR 1.54, 95% CI 1.01-2.34). A higher obstructive sleep apnoea score was also associated with significantly increased odds of initially severe stroke (2-3, OR 1.48; 95% CI 1.20-1.83) but not functional deterioration at 1 month (OR 1.19, 95% CI 0.93-1.52). CONCLUSIONS: Sleep disturbance symptoms were common and associated with an increased odds of severe stroke and functional deterioration. Interventions to modify sleep disturbance may help prevent disabling stroke/improve functional outcomes and should be the subject of future research.

Estimating and displaying population attributable fractions using the R package: graphPAF.

Here we introduce graphPAF, a comprehensive R package designed for estimation, inference and display of population attributable fractions (PAF) and impact fractions. In addition to allowing inference for standard population attributable fractions and impact fractions, graphPAF facilitates display of attributable fractions over multiple risk factors using fan-plots and nomograms, calculations of attributable fractions for continuous exposures, inference for attributable fractions appropriate for specific risk factor → mediator → outcome pathways (pathway-specific attributable fractions) and Bayesian network-based calculations and inference for joint, sequential and average population attributable fractions in multi-risk factor scenarios. This article can be used as both a guide to the theory of attributable fraction estimation and a tutorial regarding how to use graphPAF in practical examples.

Bias assessment and correction for Levin's population attributable fraction in the presence of confounding.

In 1953, Morton Levin introduced a simple approach to estimating population attributable fractions (PAF) depending only on risk factor prevalence and relative risk. This formula and its extensions are still in widespread use today, particularly to estimate PAF in populations where individual data is unavailable. Unfortunately, Levin's approach is known to be asymptotically biased for the PAF when the risk factor-disease relationship is confounded even if relative risks that are correctly adjusted for confounding are used in the estimator. Here we describe a simple re-expression of Miettinen's estimand that depends on the causal relative risk, the unadjusted relative risk and the population risk factor prevalence. While this re-expression is not new, it has been underappreciated in the literature, and the associated estimator may be useful in estimating PAF in populations when individual data is unavailable provided estimated adjusted and unadjusted relative risks can be transported to the population of interest. Using the re-expressed estimand, we develop novel analytic formulae for the relative and absolute asymptotic bias in Levin's formula, solidifying earlier work by Darrow and Steenland that used simulations to investigate this bias. We extend all results to settings with non-binary valued risk factors and continuous exposures and discuss the utility of these results in estimating PAF in practice.

Effectiveness of HealthTracker for post-caesarean section surgical site infection surveillance: An intervention study.

This intervention study aimed to implement and evaluate the effectiveness of HealthTracker, a post-discharge surgical site infection surveillance system. Participants were 730 women birthing by caesarean section at a large hospital over a 6-month period. Data were downloaded from clinical data systems and HealthTracker. Receiver operating characteristics were used to assess HealthTracker. Over a 6-month period, 382 women completed HealthTracker, with 83 scoring ≥6, indicating signs and symptoms of surgical site infection. Of this 83, 58 sought advice from health professionals, 29 returned to hospital, and 45 received antibiotics. A total of 20 infections from a total population of 730 were confirmed, with 14 out of 382 respondents confirmed via HealthTracker. Receiver operating characteristics identified HealthTracker as an excellent indicator of surgical site infection. HealthTracker is a feasible mHealth option for monitoring post-discharge surgical site infection post-caesarean section. In addition, by providing alerts, advising women to monitor their symptoms and seek treatment if necessary, HealthTracker has the potential to enhance self-efficacy for surgical wound monitoring at home.

Excised leaves show limited and species-specific effects on photosynthetic parameters across crop functional types.

Photosynthesis is increasingly becoming a recognized target for crop improvement. Phenotyping photosynthesis-related traits on field-grown material is a key bottleneck to progress here due to logistical barriers and short measurement days. Many studies attempt to overcome these challenges by phenotyping excised leaf material in the laboratory. To date there are no demonstrated examples of the representative nature of photosynthesis measurements performed on excised leaves relative to attached leaves in crops. Here, we tested whether standardized leaf excision on the day prior to phenotyping affected a range of common photosynthesis-related traits across crop functional types using tomato (C3 dicot), barley (C3 monocot), and maize (C4 monocot). Potentially constraining aspects of leaf physiology that could be predicted to impair photosynthesis in excised leaves, namely leaf water potential and abscisic acid accumulation, were not different between attached and excised leaves. We also observed non-significant differences in spectral reflectance and chlorophyll fluorescence traits between the treatments across the three species. However, we did observe some significant differences between traits associated with gas exchange and photosynthetic capacity across all three species. This study represents a useful reference for those who perform measurements of this nature and the differences reported should be considered in associated experimental design and statistical analyses.

Chlorophyll fluorescence-based high-throughput phenotyping facilitates the genetic dissection of photosynthetic heat tolerance in African (Oryza glaberrima) and Asian (Oryza sativa) rice.

Rising temperatures and extreme heat events threaten rice production. Half of the global population relies on rice for basic nutrition, and therefore developing heat-tolerant rice is essential. During vegetative development, reduced photosynthetic rates can limit growth and the capacity to store soluble carbohydrates. The photosystem II (PSII) complex is a particularly heat-labile component of photosynthesis. We have developed a high-throughput chlorophyll fluorescence-based screen for photosynthetic heat tolerance capable of screening hundreds of plants daily. Through measuring the response of maximum PSII efficiency to increasing temperature, this platform generates data for modelling the PSII-temperature relationship in large populations in a small amount of time. Coefficients from these models (photosynthetic heat tolerance traits) demonstrated high heritabilities across African (Oryza glaberrima) and Asian (Oryza sativa, Bengal Assam Aus Panel) rice diversity sets, highlighting valuable genetic variation accessible for breeding. Genome-wide association studies were performed across both species for these traits, representing the first documented attempt to characterize the genetic basis of photosynthetic heat tolerance in any species to date. A total of 133 candidate genes were highlighted. These were significantly enriched with genes whose predicted roles suggested influence on PSII activity and the response to stress. We discuss the most promising candidates for improving photosynthetic heat tolerance in rice.

Major disparities in patient-reported adherence compared to objective assessment of adherence using mass spectrometry: A prospective study in a tertiary-referral hypertension clinic.

AIM: Many challenges exist in determining true rates of adherence to antihypertensive medications among individuals in a clinic setting. For the first time, we aimed to compare patient-reported antihypertensive adherence with objective evidence using mass spectrometry spot urinalysis in a tertiary referral clinic setting. METHODS: A prospective observational single-centre cohort study was performed in a tertiary referral hypertension clinic, encompassing antihypertensive initiation and persistence. Patients were referred with apparent treatment-resistant hypertension or for suspected secondary causes. Participants completed a self-reported assessment of antihypertensive adherence and provided a spot urine sample. The presence of antihypertensive medications and/or their respective metabolites was evaluated using high-performance liquid chromatography tandem mass spectrometry. Patients were determined to be adherent if they demonstrated both self-reported adherence and objective mass spectrometry evidence. RESULTS: Of all 105 eligible participants initially recruited, 73 (69.5%) met the eligibility criteria. Only 27.4% (95% confidence interval 0.2-0.4) of participants demonstrated true adherence to their self-reported antihypertensives, despite 75.3% (0.6-0.8) reporting adherence. Greatest medication adherence was achieved with angiotensin II receptor blockers (61%), with calcium-channel blockers and mineralocorticoid antagonists demonstrating least adherence (38%). CONCLUSION: In patients attending a tertiary hypertension clinic, the combined use of spot urine mass spectrometry and self-reporting identifies higher rates of nonadherence when compared to either modality alone. Both techniques should be combined for more accurate detection of medication adherence.

Global mean potassium intake: a systematic review and Bayesian meta-analysis.

PURPOSE: Increasing potassium intake, especially in populations with low potassium intake and high sodium intake, has emerged as an important population-level intervention to reduce cardiovascular events. Current guideline recommendations, such as those made by the World Health Organisation, recommend a potassium intake of  > 3.5 g/day. We sought to determine summary estimates for mean potassium intake and sodium/potassium (Na/K) ratio in different regions of the world. METHODS: We performed a systematic review and meta-analysis. We identified 104 studies, that included 98 nationally representative surveys and 6 multi-national studies. To account for missingness and incomparability of data, a Bayesian hierarchical imputation model was applied to estimating summary estimates of mean dietary potassium intake (primary outcome) and sodium/potassium ratio. RESULTS: Overall, 104 studies from 52 countries were included (n = 1,640,664). Mean global potassium intake was 2.25 g/day (57 mmol/day) (95% credible interval (CI) 2.05-2.44 g/day), with highest intakes in Eastern and Western Europe (mean intake 3.53g/day, 95% CI 3.05-4.01 g/day and 3.29 g/day, 95% CI 3.13-3.47 g/day, respectively) and lowest intakes in East Asia (mean intake 1.89 g/day; 95% CI 1.55-2.25 g/day). Approximately 31% (95% CI, 30-41%) of global population included have an estimated potassium intake  > 2.5 g/day, with 14% (95% CI 11-17%) above 3.5 g/day. CONCLUSION: Global mean potassium intake (2.25 g/day) falls below current guideline recommended intake level of  > 3.5 g/day, with only 14% (95% CI 11-17%) of the global population achieving guideline-target mean intake. There was considerable regional variation, with lowest mean potassium intake reported in Asia, and highest intake in Eastern and Western Europe.

Randomised controlled trials of antihypertensive therapy: does exclusion of orthostatic hypotension alter treatment effect? A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Management of antihypertensive therapy is challenging in patients with symptomatic orthostatic hypotension, a population often excluded from randomised controlled trials of antihypertensive therapy. In this systematic review and meta-analysis, we sought to determine whether the association of antihypertensive therapy and adverse events (e.g. falls, syncope), differed among trials that included or excluded patients with orthostatic hypotension. METHODS: We performed a systematic review and meta-analysis of randomised controlled trials comparing blood pressure lowering medications to placebo, or different blood pressure targets on falls or syncope outcomes and cardiovascular events. A random-effects meta-analysis was used to estimate a pooled treatment-effect overall in subgroups of trials that excluded patients with orthostatic hypotension and trials that did not exclude patients with orthostatic hypotension, and tested P for interaction. The primary outcome was fall events. RESULTS: 46 trials were included, of which 18 trials excluded orthostatic hypotension and 28 trials did not. The incidence of hypotension was significantly lower in trials that excluded participants with orthostatic hypotension (1.3% versus 6.2%, P < 0.001) but not incidences of falls (4.8% versus 8.8%; P = 0.40) or syncope (1.5% versus 1.8%; P = 0.67). Antihypertensive therapy was not associated with an increased risk of falls in trials that excluded (OR 1.00, 95% CI; 0.89-1.13) or included (OR 1.02, 95% CI; 0.88-1.18) participants with orthostatic hypotension (P for interaction = 0.90). CONCLUSIONS: The exclusion of patients with orthostatic hypotension does not appear to affect the relative risk estimates for falls and syncope in antihypertensive trials.

Antiplatelet therapy and incident cognitive impairment or dementia-a systematic review and meta-analysis of randomised clinical trials.

OBJECTIVE: The benefit of antiplatelet therapy in preventing cognitive impairment or dementia is uncertain. We investigated the association between antiplatelet therapy and incident cognitive impairment or dementia in randomised clinical trials. METHODS: We searched PubMed, EMBASE and CENTRAL for randomised clinical trials published from database inception through 1 February 2023. Trials that evaluated the association of antiplatelet therapy with incident cognitive impairment or dementia were included. For single-agent antiplatelet, the control group was placebo. For dual agent antiplatelet therapy, the control group was single-agent monotherapy. A random-effects meta-analysis model was used to report pooled treatment effects and 95% confidence intervals (CIs). The primary outcome was incident cognitive impairment or dementia. Secondary outcomes included change in cognitive test scores. RESULTS: A total of 11 randomised clinical trials were included (109,860 participants). All reported the incidence of cognitive impairment or dementia on follow-up. The mean (SD) age of trial participants was 66.2 (7.9) years. Antiplatelet therapy was not significantly associated with a reduced risk of cognitive impairment or dementia (11 trials; 109,860 participants) (3.49% versus 4.18% of patients over a mean trial follow-up of 5.8 years; odds ratio [OR], 0.94 [95% CI, 0.88-1.00]; absolute risk reduction, 0.2% [95% CI, -0.4% to 0.009%]; I2 = 0.0%). Antiplatelet therapy was not significantly associated with mean change in cognitive test scores. CONCLUSION: In this meta-analysis, antiplatelet therapy was not significantly associated with a lower risk of incident cognitive impairment or dementia, but the CIs around this outcome do not exclude a modest preventative effect.

Early Metformin in Gestational Diabetes: A Randomized Clinical Trial.

Importance: Gestational diabetes is a common complication of pregnancy and the optimal management is uncertain. Objective: To test whether early initiation of metformin reduces insulin initiation or improves fasting hyperglycemia at gestation weeks 32 or 38. Design, Setting, and Participants: Double-blind, placebo-controlled trial conducted in 2 centers in Ireland (one tertiary hospital and one smaller regional hospital). Participants were enrolled from June 2017 through September 2022 and followed up until 12 weeks' postpartum. Participants comprised 510 individuals (535 pregnancies) diagnosed with gestational diabetes based on World Health Organization 2013 criteria. Interventions: Randomized 1:1 to either placebo or metformin (maximum dose, 2500 mg) in addition to usual care. Main Outcomes And Measures: The primary outcome was a composite of insulin initiation or a fasting glucose level of 5.1 mmol/L or greater at gestation weeks 32 or 38. Results: Among 510 participants (mean age, 34.3 years), 535 pregnancies were randomized. The primary composite outcome was not significantly different between groups and occurred in 150 pregnancies (56.8%) in the metformin group and 167 pregnancies (63.7%) in the placebo group (between-group difference, -6.9% [95% CI, -15.1% to 1.4%]; relative risk, 0.89 [95% CI, 0.78-1.02]; P = .13). Of 6 prespecified secondary maternal outcomes, 3 favored the metformin group, including time to insulin initiation, self-reported capillary glycemic control, and gestational weight gain. Secondary neonatal outcomes differed by group, with smaller neonates (lower mean birth weights, a lower proportion weighing >4 kg, a lower proportion in the >90% percentile, and smaller crown-heel length) in the metformin group without differences in neonatal intensive care needs, respiratory distress requiring respiratory support, jaundice requiring phototherapy, major congenital anomalies, neonatal hypoglycemia, or proportion with 5-minute Apgar scores less than 7. Conclusion and relevance: Early treatment with metformin was not superior to placebo for the composite primary outcome. Prespecified secondary outcome data support further investigation of metformin in larger clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02980276; EudraCT: 2016-001644-19.

Machine learning-enabled phenotyping for GWAS and TWAS of WUE traits in 869 field-grown sorghum accessions.

Sorghum (Sorghum bicolor) is a model C4 crop made experimentally tractable by extensive genomic and genetic resources. Biomass sorghum is studied as a feedstock for biofuel and forage. Mechanistic modeling suggests that reducing stomatal conductance (gs) could improve sorghum intrinsic water use efficiency (iWUE) and biomass production. Phenotyping to discover genotype-to-phenotype associations remains a bottleneck in understanding the mechanistic basis for natural variation in gs and iWUE. This study addressed multiple methodological limitations. Optical tomography and a machine learning tool were combined to measure stomatal density (SD). This was combined with rapid measurements of leaf photosynthetic gas exchange and specific leaf area (SLA). These traits were the subject of genome-wide association study and transcriptome-wide association study across 869 field-grown biomass sorghum accessions. The ratio of intracellular to ambient CO2 was genetically correlated with SD, SLA, gs, and biomass production. Plasticity in SD and SLA was interrelated with each other and with productivity across wet and dry growing seasons. Moderate-to-high heritability of traits studied across the large mapping population validated associations between DNA sequence variation or RNA transcript abundance and trait variation. A total of 394 unique genes underpinning variation in WUE-related traits are described with higher confidence because they were identified in multiple independent tests. This list was enriched in genes whose Arabidopsis (Arabidopsis thaliana) putative orthologs have functions related to stomatal or leaf development and leaf gas exchange, as well as genes with nonsynonymous/missense variants. These advances in methodology and knowledge will facilitate improving C4 crop WUE.

The leaf economics spectrum of triploid and tetraploid C4 grass Miscanthus x giganteus.

The leaf economics spectrum (LES) describes multivariate correlations in leaf structural, physiological and chemical traits, originally based on diverse C3 species grown under natural ecosystems. However, the specific contribution of C4 species to the global LES is studied less widely. C4 species have a CO2 concentrating mechanism which drives high rates of photosynthesis and improves resource use efficiency, thus potentially pushing them towards the edge of the LES. Here, we measured foliage morphology, structure, photosynthesis, and nutrient content for hundreds of genotypes of the C4 grass Miscanthus× giganteus grown in two common gardens over two seasons. We show substantial trait variations across M.× giganteus genotypes and robust genotypic trait relationships. Compared to the global LES, M.× giganteus genotypes had higher photosynthetic rates, lower stomatal conductance, and less nitrogen content, indicating greater water and photosynthetic nitrogen use efficiency in the C4 species. Additionally, tetraploid genotypes produced thicker leaves with greater leaf mass per area and lower leaf density than triploid genotypes. By expanding the LES relationships across C3 species to include C4 crops, these findings highlight that M.× giganteus occupies the boundary of the global LES and suggest the potential for ploidy to alter LES traits.

Out of Africa: characterizing the natural variation in dynamic photosynthetic traits in a diverse population of African rice (Oryza glaberrima).

African rice (Oryza glaberrima) has adapted to challenging environments and is a promising source of genetic variation. We analysed dynamics of photosynthesis and morphology in a reference set of 155 O. glaberrima accessions. Plants were grown in an agronomy glasshouse to late tillering stage. Photosynthesis induction from darkness and the decrease in low light was measured by gas exchange and chlorophyll fluorescence along with root and shoot biomass, stomatal density, and leaf area. Steady-state and kinetic responses were modelled. We describe extensive natural variation in O. glaberrima for steady-state, induction, and reduction responses of photosynthesis that has value for gene discovery and crop improvement. Principal component analyses indicated key clusters of plant biomass, kinetics of photosynthesis (CO2 assimilation, A), and photoprotection induction and reduction (measured by non-photochemical quenching, NPQ), consistent with diverse adaptation. Accessions also clustered according to countries with differing water availability, stomatal conductance (gs), A, and NPQ, indicating that dynamic photosynthesis has adaptive value in O. glaberrima. Kinetics of NPQ, A, and gs showed high correlation with biomass and leaf area. We conclude that dynamic photosynthetic traits and NPQ are important within O. glaberrima, and we highlight NPQ kinetics and NPQ under low light.

Age Predicts Older Adults' Driving Self-Regulation but Not Dangerous Driving Behaviors after Controlling for Executive Function.

OBJECTIVES: The aim of the study was to examine the unique contributions of age to objectively measure driving frequency and dangerous driving behaviors in healthy older adults after adjusting for executive function (EF). METHOD: A total of 28 community-dwelling older adults (mean age = 82.0 years, standard deviation [SD] = 7.5) without dementia who were in good physical health and enrolled in a longitudinal aging study completed several EF and clinical self-report measures at baseline. Participants subsequently had a sensor installed in their vehicle for a mean of 208 (SD = 38, range = 127-257) days. RESULTS: Participants drove for an average of 54 min per day. Mixed-effects models indicated that after controlling for EF, older age was associated with less time driving per day, decreased number of trips, and less nighttime driving. Age was not associated with hard brakes or hard accelerations. DISCUSSION: After accounting for EF, greater age is associated with higher driving self-regulation but not dangerous driving behaviors in healthy older adults. Future studies should recruit larger samples and collect sensor-measured driving data over a more extended time frame to better determine how and why these self-regulation changes take place.

Rapid temperature responses of photosystem II efficiency forecast genotypic variation in rice vegetative heat tolerance.

A key target for the improvement of Oryza sativa (rice) is the development of heat-tolerant varieties. This necessitates the development of high-throughput methodologies for the screening of heat tolerance. Progress has been made to this end via visual scoring and chlorophyll fluorescence; however, these approaches demand large infrastructural investments to expose large populations of adult plants to heat stress. To address this bottleneck, we investigated the response of the maximum quantum efficiency of photosystem II (PSII) to rapidly increasing temperatures in excised leaf segments of juvenile rice plants. Segmented models explained the majority of the observed variation in response. Coefficients from these models, i.e. critical temperature (Tcrit ) and the initial response (m1 ), were evaluated for their usability for forecasting adult heat tolerance, measured as the vegetative heat tolerance of adult rice plants through visual (stay-green) and chlorophyll fluorescence (ɸPSII) approaches. We detected substantial variation in heat tolerance of a randomly selected set of indica rice varieties. Both Tcrit and m1 were associated with measured heat tolerance in adult plants, highlighting their usability as high-throughput proxies. Variation in heat tolerance was associated with daytime respiration but not with photosynthetic capacity, highlighting a role for the non-photorespiratory release of CO2 in heat tolerance. To date, this represents the first published instance of genetic variation in these key gas-exchange traits being quantified in response to heat stress in a diverse set of rice accessions. These results outline an efficient strategy for screening heat tolerance and accentuate the need to focus on reduced rates of respiration to improve heat tolerance in rice.

Association of Oral Anticoagulation With Stroke in Atrial Fibrillation or Heart Failure: A Comparative Meta-Analysis.

Background and Purpose: Atrial fibrillation and heart failure with reduced ejection fraction (HFrEF) are common sources of cardioembolism. While oral anticoagulation is strongly recommended for atrial fibrillation, there are marked variations in guideline recommendations for HFrEF due to uncertainty about net clinical benefit. This systematic review and meta-analysis evaluates the comparative association of oral anticoagulation with stroke and other cardiovascular risk in populations with atrial fibrillation or HFrEF in sinus rhythm and identify factors mediating different estimates of net clinical benefit. Methods: PubMed and Embase were searched from database inception to November 20, 2019 for randomized clinical trials comparing oral anticoagulation to control. A random-effects meta-analysis was used to estimate a pooled treatment-effect overall and within atrial fibrillation and HFrEF trials. Differences in treatment effect were assessed by estimating I2 among all trials and testing the between-trial-population P-interaction. The primary outcome measure was all stroke. Secondary outcome measures were ischemic stroke, hemorrhagic stroke, mortality, myocardial infarction, and major hemorrhage. Results: Twenty-one trials were eligible for inclusion, 15 (n=19 332) in atrial fibrillation (mean follow-up: 23.1 months), and 6 (n=9866) in HFrEF (mean follow-up: 23.9 months). There were differences in primary outcomes between trial populations, with all-cause mortality included for 95.2% of HFrEF trial population versus 0.38% for atrial fibrillation. Mortality was higher in controls groups of HFrEF populations (19.0% versus 9.6%) but rates of stroke lower (3.1% versus 7.0%) compared with atrial fibrillation. The association of oral anticoagulation with all stroke was consistent for atrial fibrillation (odds ratio, 0.51 [95% CI, 0.42­0.63]) and HFrEF (odds ratio, 0.61 [95% CI, 0.47­0.79]; I2=12.4%; P interaction=0.31). There were no statistically significant differences in the association of oral anticoagulation with cardiovascular events, mortality or bleeding between populations. Conclusions: The relative association of oral anticoagulation with stroke risk, and other cardiovascular outcomes, is similar for patients with atrial fibrillation and HFrEF. Differences in the primary outcomes employed by trials in HFrEF, compared with atrial fibrillation, may have contributed to differing conclusions of the relative efficacy of oral anticoagulation.