Assessing heat tolerance in potatoes: Responses to stressful Texas field locations and controlled contrasting greenhouse conditions.

In recent years, heat stress has affected potato production more frequently, resulting in lower marketable yields and reduced tuber quality. In order to develop heat-tolerant potatoes, it is necessary to select under heat-stress conditions and consider traits affected by heat stress. The Texas A&M Potato Breeding Program has selected potatoes under high-temperature stress for several decades. Ten potato cultivars, representing heat tolerant and sensitive clones based on past performance in Texas, were included in field trials for three years at the two main locations used by the Texas Breeding Program (Dalhart and Springlake, TX) to assess if the Texas field locations are suitable for heat tolerance screening. Both locations were confirmed as appropriate for heat stress screening. However, Springlake was a more stressful location since it had significantly lower yields of marketable tubers and increased percentages of tuber defects. Planting time did not have a significant effect at the most stressful location. The same ten potato clones were included in greenhouse experiments with contrasting temperatures (normal versus heat stress). There was confirmation that heat stress conditions resulted in significantly lower marketable yields, specific gravity, dormancy, and significantly higher percentages of tuber defects; however, significant differences existed between potato clones. Under heat stress conditions, Russet Burbank had a high percent of tubers with external defects, whereas Atlantic showed the highest percentage of internal defects (mainly internal heat necrosis). Vanguard Russet produced the highest marketable yield while maintaining a low percentage of external and internal defects. Russet Burbank and Atlantic were heat-sensitive controls for external and internal tuber defects, respectively. In contrast, Vanguard Russet can be used as a reliable heat-tolerant control. Including appropriate controls in heat stress studies will help identify clones with heat tolerance.

Microstructural neural correlates of maximal grip strength in autistic children: the role of the cortico-cerebellar network and attention-deficit/hyperactivity disorder features.

Introduction: Maximal grip strength, a measure of how much force a person's hand can generate when squeezing an object, may be an effective method for understanding potential neurobiological differences during motor tasks. Grip strength in autistic individuals may be of particular interest due to its unique developmental trajectory. While autism-specific differences in grip-brain relationships have been found in adult populations, it is possible that such differences in grip-brain relationships may be present at earlier ages when grip strength is behaviorally similar in autistic and non-autistic groups. Further, such neural differences may lead to the later emergence of diagnostic-group grip differences in adolescence. The present study sought to examine this possibility, while also examining if grip strength could elucidate the neuro-motor sources of phenotypic heterogeneity commonly observed within autism. Methods: Using high resolution, multi-shell diffusion, and quantitative R1 relaxometry imaging, this study examined how variations in key sensorimotor-related white matter pathways of the proprioception input, lateral grasping, cortico-cerebellar, and corticospinal networks were associated with individual variations in grip strength in 68 autistic children and 70 non-autistic (neurotypical) children (6-11 years-old). Results: In both groups, results indicated that stronger grip strength was associated with higher proprioceptive input, lateral grasping, and corticospinal (but not cortico-cerebellar modification) fractional anisotropy and R1, indirect measures concordant with stronger microstructural coherence and increased myelination. Diagnostic group differences in these grip-brain relationships were not observed, but the autistic group exhibited more variability particularly in the cortico-cerebellar modification indices. An examination into the variability within the autistic group revealed that attention-deficit/hyperactivity disorder (ADHD) features moderated the relationships between grip strength and both fractional anisotropy and R1 relaxometry in the premotor-primary motor tract of the lateral grasping network and the cortico-cerebellar network tracts. Specifically, in autistic children with elevated ADHD features (60% of the autistic group) stronger grip strength was related to higher fractional anisotropy and R1 of the cerebellar modification network (stronger microstructural coherence and more myelin), whereas the opposite relationship was observed in autistic children with reduced ADHD features. Discussion: Together, this work suggests that while the foundational elements of grip strength are similar across school-aged autistic and non-autistic children, neural mechanisms of grip strength within autistic children may additionally depend on the presence of ADHD features. Specifically, stronger, more coherent connections of the cerebellar modification network, which is thought to play a role in refining and optimizing motor commands, may lead to stronger grip in children with more ADHD features, weaker grip in children with fewer ADHD features, and no difference in grip in non-autistic children. While future research is needed to understand if these findings extend to other motor tasks beyond grip strength, these results have implications for understanding the biological basis of neuromotor control in autistic children and emphasize the importance of assessing co-occurring conditions when evaluating brain-behavior relationships in autism.

Infrared Photodissociation Spectroscopy of Water-Tagged Ions with a Widely Tunable Quantum Cascade Laser for Planetary Science Applications.

This work presents a benchtop method for collecting the room temperature gas phase infrared (IR) action spectra of protonated amino acids and their isomers. The adopted setup uses a minimally modified commercial electrospray ionization linear ion trap mass spectrometer (ESI-LIT-MS) coupled to a broadband continuous wave (cw) quantum cascade laser (QCL) source. This approach leverages messenger assisted action spectroscopic techniques using water-tagged molecular ions with complex formation, irradiation, and subsequent analysis, all taking place within a single linear ion trap stage. This configuration thus circumvents the use of multiple mass selection and analysis stages, cryogenic buffer cells, and complex high-power laser systems typically called upon to execute these techniques. The benchtop action spectrometer is used to collect the 935-1600 cm-1 (6.2-10.7 µm) IR action spectrum of a collection of amino acids and a dipeptide with results cross referenced against literature examples obtained with a free electron laser source. Recorded IR spectra are used for the analysis of binary mixture samples composed of constitutional isomers α-alanine and ß-alanine with ratios determined to ∼4% measurement uncertainty without the aid of a front-end separation stage. This turn-key QCL-based approach is a major step in showing the viability of tag-based action spectroscopic techniques for use in future in situ planetary science sensors and general analytical applications.

Pre-treatment bone mineral density (BMD) and the benefit of pharmacologic treatment on fracture risk and BMD change: analysis from the FNIH-ASBMR SABRE project.

Some osteoporosis drug trials have suggested that treatment is more effective in those with low bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA). This study used data from a large set of randomised controlled trials (RCTs) to determine whether the anti-fracture efficacy of treatments differs according to baseline BMD. We used individual patient data from 25 RCTs (103 086 subjects) of osteoporosis medications collected as part of the FNIH-ASBMR SABRE project. Participants were stratified into femoral neck (FN) BMD T-score subgroups (≤ -2.5, > -2.5). We used Cox proportional hazard regression to estimate treatment effect for clinical fracture outcomes and logistic regression for the radiographic vertebral fracture outcome. We also performed analyses based on BMD quintiles. Overall, 42% had a FN BMD T-score ≤ -2.5. Treatment with anti-osteoporosis drugs led to significant reductions in fractures in both T-score ≤ -2.5 and > -2.5 subgroups. Compared to those with FN BMD T-score > -2.5, the risk reduction for each fracture outcome was greater in those with T-score ≤ -2.5, but only the all fracture outcome reached statistical significance (interaction p = 0.001). Results were similar when limited to bisphosphonate trials. In the quintile analysis, there was significant anti-fracture efficacy across all quintiles for vertebral fractures and with greater effects on fracture risk reduction for non-vertebral, all and all clinical fractures in the lower BMD quintiles (all interaction p ≤ 0.03). In summary, anti-osteoporotic medications reduced the risk of fractures regardless of baseline BMD. Significant fracture risk reduction with treatment for 4 of the 5 fracture endpoints was seen in participants with T-scores above -2.5, though effects tended to be larger and more significant in those with baseline T-scores <-2.5.

It is important to know whether our treatments for osteoporosis are effective at reducing the risk of fracture no matter what the bone mineral density (BMD) before starting treatment. This study used data from many clinical trials to determine whether the anti-fracture efficacy of treatments differs according to baseline BMD. We found that anti-osteoporotic medications reduced the risk of fractures regardless of baseline BMD, though effects tended to be larger and more significant in those with lower BMD scores.

Analysis of early intermediate states of the nitrogenase reaction by regularization of EPR spectra.

Due to the complexity of the catalytic FeMo cofactor site in nitrogenases that mediates the reduction of molecular nitrogen to ammonium, mechanistic details of this reaction remain under debate. In this study, selenium- and sulfur-incorporated FeMo cofactors of the catalytic MoFe protein component from Azotobacter vinelandii are prepared under turnover conditions and investigated by using different EPR methods. Complex signal patterns are observed in the continuous wave EPR spectra of selenium-incorporated samples, which are analyzed by Tikhonov regularization, a method that has not yet been applied to high spin systems of transition metal cofactors, and by an already established grid-of-error approach. Both methods yield similar probability distributions that reveal the presence of at least four other species with different electronic structures in addition to the ground state E0. Two of these species were preliminary assigned to hydrogenated E2 states. In addition, advanced pulsed-EPR experiments are utilized to verify the incorporation of sulfur and selenium into the FeMo cofactor, and to assign hyperfine couplings of 33S and 77Se that directly couple to the FeMo cluster. With this analysis, we report selenium incorporation under turnover conditions as a straightforward approach to stabilize and analyze early intermediate states of the FeMo cofactor.

Characterization of innate lymphoid cell subsets infiltrating melanoma and epithelial ovarian tumors.

The innate lymphoid cell (ILC) family is composed of heterogeneous innate effector and helper immune cells that preferentially reside in tissues where they promote tissue homeostasis. In cancer, they have been implicated in driving both pro- and anti-tumor responses. This apparent dichotomy highlights the need to better understand differences in the ILC composition and phenotype within different tumor types that could drive seemingly opposite anti-tumor responses. Here, we characterized the frequency and phenotype of various ILC subsets in melanoma metastases and primary epithelial ovarian tumors. We observed high PD-1 expression on ILC subsets isolated from epithelial ovarian tumor samples, while ILC populations in melanoma samples express higher levels of LAG-3. In addition, we found that the frequency of cytotoxic ILCs and NKp46+ILC3 in tumors positively correlates with monocytic cells and conventional type 2 dendritic cells, revealing potentially new interconnected immune cell subsets in the tumor microenvironment. Consequently, these observations may have direct relevance to tumor microenvironment composition and how ILC subset may influence anti-tumor immunity.

Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men : Individual Participant Data Meta-analyses.

BACKGROUND: Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial. PURPOSE: To clarify associations of sex hormones with these outcomes. DATA SOURCES: Systematic literature review to July 2019, with bridge searches to March 2024. STUDY SELECTION: Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up. DATA EXTRACTION: Independent variables were testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use. DATA SYNTHESIS: Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates (n = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events. LIMITATIONS: Observational study design, heterogeneity among studies, and imputation of missing data. CONCLUSION: Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies.

Splicing factor mutations are common in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but how they alter cellular functions is unclear. We show that the pathogenic SRSF2P95H/+ mutation disrupts the splicing of mitochondrial mRNAs, impairs mitochondrial complex I function, and robustly increases mitophagy. We also identified a mitochondrial surveillance mechanism by which mitochondrial dysfunction modifies splicing of the mitophagy activator PINK1 to remove a poison intron, increasing the stability and abundance of PINK1 mRNA and protein. SRSF2P95H-induced mitochondrial dysfunction increased PINK1 expression through this mechanism, which is essential for survival of SRSF2P95H/+ cells. Inhibition of splicing with a glycogen synthase kinase 3 inhibitor promoted retention of the poison intron, impairing mitophagy and activating apoptosis in SRSF2P95H/+ cells. These data reveal a homeostatic mechanism for sensing mitochondrial stress through PINK1 splicing and identify increased mitophagy as a disease marker and a therapeutic vulnerability in SRSF2P95H mutant MDS and AML.

A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies.

Splicing factor mutations are common in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but how they alter cellular functions is unclear. We show that the pathogenic SRSF2P95H/+ mutation disrupts the splicing of mitochondrial mRNAs, impairs mitochondrial complex I function, and robustly increases mitophagy. We also identified a mitochondrial surveillance mechanism by which mitochondrial dysfunction modifies splicing of the mitophagy activator PINK1 to remove a poison intron, increasing the stability and abundance of PINK1 mRNA and protein. SRSF2P95H-induced mitochondrial dysfunction increased PINK1 expression through this mechanism, which is essential for survival of SRSF2P95H/+ cells. Inhibition of splicing with a glycogen synthase kinase 3 inhibitor promoted retention of the poison intron, impairing mitophagy and activating apoptosis in SRSF2P95H/+ cells. These data reveal a homeostatic mechanism for sensing mitochondrial stress through PINK1 splicing and identify increased mitophagy as a disease marker and a therapeutic vulnerability in SRSF2P95H mutant MDS and AML.

Mosquito Microbiomes of Rwanda: Characterizing Mosquito Host and Microbial Communities in the Land of a Thousand Hills.

Mosquitoes are a complex nuisance around the world and tropical countries bear the brunt of the burden of mosquito-borne diseases. Rwanda has had success in reducing malaria and some arboviral diseases over the last few years, but still faces challenges to elimination. By building our understanding of in situ mosquito communities in Rwanda at a disturbed, human-occupied site and at a natural, preserved site, we can build our understanding of natural mosquito microbiomes toward the goal of implementing novel microbial control methods. Here, we examined the composition of collected mosquitoes and their microbiomes at two diverse sites using Cytochrome c Oxidase I sequencing and 16S V4 high-throughput sequencing. The majority (36 of 40 species) of mosquitoes captured and characterized in this study are the first-known record of their species for Rwanda but have been characterized in other nations in East Africa. We found significant differences among mosquito genera and among species, but not between mosquito sexes or catch method. Bacteria of interest for arbovirus control, Asaia, Serratia, and Wolbachia, were found in abundance at both sites and varied greatly by species.

A Novel Approach to Integrate Human Biomonitoring Data with Model Predicted Dietary Exposures: A Crop Protection Chemical Case Study Using Lambda-Cyhalothrin.

The appropriate use of human biomonitoring data to model population chemical exposures is challenging, especially for rapidly metabolized chemicals, such as agricultural chemicals. The objective of this study is to demonstrate a novel approach integrating model predicted dietary exposures and biomonitoring data to potentially inform regulatory risk assessments. We use lambda-cyhalothrin as a case study, and for the same representative U.S. population in the National Health and Nutrition Examination Survey (NHANES), an integrated exposure and pharmacokinetic model predicted exposures are calibrated to measurements of the urinary metabolite 3-phenoxybenzoic acid (3PBA), using an approximate Bayesian computing (ABC) methodology. We demonstrate that the correlation between modeled urinary 3PBA and the NHANES 3PBA measurements more than doubled as ABC thresholding narrowed the acceptable tolerance range for predicted versus observed urinary measurements. The median predicted urinary concentrations were closer to the median measured value using ABC than using current regulatory Monte Carlo methods.

Revision Strategy for Proximal Junctional Failure: Combined Effect of Proximal Extension and Focal Correction.

STUDY DESIGN: Retrospective review of a prospectively-collected multicenter database. OBJECTIVES: The objective of this study was to determine optimal strategies in terms of focal angular correction and length of proximal extension during revision for PJF. METHODS: 134 patients requiring proximal extension for PJF were analyzed in this study. The correlation between amount of proximal junctional angle (PJA) reduction and recurrence of proximal junctional kyphosis (PJK) and/or PJF was investigated. Following stratification by the degree of PJK correction and the numbers of levels extended proximally, rates of radiographic PJK (PJA >28° & ΔPJA >22°), and recurrent surgery for PJF were reported. RESULTS: Before revision, mean PJA was 27.6° ± 14.6°. Mean number of levels extended was 6.0 ± 3.3. Average PJA reduction was 18.8° ± 18.9°. A correlation between the degree of PJA reduction and rate of recurrent PJK was observed (r = -.222). Recurrent radiographic PJK (0%) and clinical PJF (4.5%) were rare in patients undergoing extension ≥8 levels, regardless of angular correction. Patients with small reductions (<5°) and small extensions (<4 levels) experienced moderate rates of recurrent PJK (19.1%) and PJF (9.5%). Patients with large reductions (>30°) and extensions <8 levels had the highest rate of recurrent PJK (31.8%) and PJF (16.0%). CONCLUSION: While the degree of focal PJK correction must be determined by the treating surgeon based upon clinical goals, recurrent PJK may be minimized by limiting reduction to <30°. If larger PJA correction is required, more extensive proximal fusion constructs may mitigate recurrent PJK/PJF rates.

Sciatic and tibial neuropathies.

The sciatic nerve is the body's largest peripheral nerve. Along with their two terminal divisions (tibial and fibular), their anatomic location makes them particularly vulnerable to trauma and iatrogenic injuries. A thorough understanding of the functional anatomy is required to adequately localize lesions in this lengthy neural pathway. Proximal disorders of the nerve can be challenging to precisely localize among a range of possibilities including lumbosacral pathology, radiculopathy, or piriformis syndrome. A correct diagnosis is based upon a thorough history and physical examination, which will then appropriately direct adjunctive investigations such as imaging and electrodiagnostic testing. Disorders of the sciatic nerve and its terminal branches are disabling for patients, and expert assessment by rehabilitation professionals is important in limiting their impact. Applying techniques established in the upper extremity, surgical reconstruction of lower extremity nerve dysfunction is rapidly improving and evolving. These new techniques, such as nerve transfers, require electrodiagnostic assessment of both the injured nerve(s) as well as healthy, potential donor nerves as part of a complete neurophysiological examination.

Elevated fish densities extend kilometres from oil and gas platforms.

Thousands of offshore oil and gas platforms have been installed throughout the world's oceans and more structures are being installed as part of the transition to renewable energy. These structures increase the availability of ecological niches by providing hard substrate in midwater and complex 3D habitat on the seafloor. This can lead to 'hotspots' of biodiversity, or increased densities of flora and fauna, which potentially spill over into the local area. However, the distances over which these higher densities extend (the 'range of influence') can be highly variable. Fish aggregate at such structures, but the range of influence and any implications for wider fish populations, are unclear. We investigated the relationship between fish and platform areal densities using high resolution fisheries acoustic data. Data were collected in the waters surrounding the vessel exclusions zones around 16 oil and gas platforms in the North Sea, and throughout the wider area. We estimated densities of schooling fish using echo-integration, and densities of non-schooling fish using echo-counting. At 10 platforms, non-schooling fish densities were elevated near the platform relative to background levels in the equivalent wider area. The range of influence, defined here as the range to which fish densities were elevated above background, varied from 0.8 to 23 km. In areas of high platform density, fish schools were encountered more often, and non-schooling fish densities were higher, when controlling for other sources of environmental variation. This is the first time such long-range effects have been identified; previously, ranges of influence have been reported in the order of just 10s-100s of metres. These findings suggest that the environmental impact of these structures may extend further than previously thought, which may be relevant in the context of upcoming management decisions around the decommissioning of these structures.

Lessons learned from using wild-caught and captive-reared lesser scaup (Aythya affinis) in captive experiments.

Waterfowl are housed in captivity for research studies that are infeasible in the wild. Accommodating the unique requirements of semi-aquatic species in captivity while meeting experimental design criteria for research questions can be challenging and may have unknown effects on animal health. Thus, testing and standardizing best husbandry and care practices for waterfowl is necessary to facilitate proper husbandry and humane care while ensuring reliable and repeatable research results. To inform husbandry practices for captive-reared and wild-caught lesser scaup (Aythya affinis; hereafter, scaup), we assessed body mass and fat composition across two different aspects of husbandry, source population (captive-reared or wild caught), and housing densities (birds/m2). Our results suggest that housing scaup at low densities (≤0.6 m2/bird, P = 0.049) relative to other species can minimize negative health effects. Captive-reared scaup were heavier (P = 0.027) with greater body fat (P < 0.001) and exhibited fewer signs of stress during handling than wild-caught scaup. In our experience, scaup which are captive-reared from eggs collected in the wild were better for long-term captivity studies as they maintained body mass between and recovered lost body mass following trials. Researchers would benefit from carefully evaluating the tradeoffs of using short- and long-term captive methods on their research question before designing projects, husbandry practices, and housing facilities for waterfowl.

Impact of Self-Reported Loss of Balance and Gait Disturbance on Outcomes following Adult Spinal Deformity Surgery.

Background: The objective of this study was to evaluate if imbalance influences complication rates, radiological outcomes, and patient-reported outcomes (PROMs) following adult spinal deformity (ASD) surgery. Methods: ASD patients with baseline and 2-year radiographic and PROMs were included. Patients were grouped according to whether they answered yes or no to a recent history of pre-operative loss of balance. The groups were propensity-matched by age, pelvic incidence-lumbar lordosis (PI-LL), and surgical invasiveness score. Results: In total, 212 patients were examined (106 in each group). Patients with gait imbalance had worse baseline PROM measures, including Oswestry disability index (45.2 vs. 36.6), SF-36 mental component score (44 vs. 51.8), and SF-36 physical component score (p < 0.001 for all). After 2 years, patients with gait imbalance had less pelvic tilt correction (-1.2 vs. -3.6°, p = 0.039) for a comparable PI-LL correction (-11.9 vs. -15.1°, p = 0.144). Gait imbalance patients had higher rates of radiographic proximal junctional kyphosis (PJK) (26.4% vs. 14.2%) and implant-related complications (47.2% vs. 34.0%). After controlling for age, baseline sagittal parameters, PI-LL correction, and comorbidities, patients with imbalance had 2.2-times-increased odds of PJK after 2 years. Conclusions: Patients with a self-reported loss of balance/unsteady gait have significantly worse PROMs and higher risk of PJK.

Impaired metabolic flexibility to fasting is associated with increased ad libitum energy intake in healthy adults.

OBJECTIVE: We investigated how changes in 24-h respiratory exchange ratio (RER) and substrate oxidation during fasting versus an energy balance condition influence subsequent ad libitum food intake. METHODS: Forty-four healthy, weight-stable volunteers (30 male and 14 female; mean [SD], age 39.3 [11.0] years; BMI 31.7 [8.3] kg/m2) underwent 24-h energy expenditure measurements in a respiratory chamber during energy balance (50% carbohydrate, 30% fat, and 20% protein) and 24-h fasting. Immediately after each chamber stay, participants were allowed 24-h ad libitum food intake from computerized vending machines. RESULTS: Twenty-four-hour RER decreased by 9.4% (95% CI: -10.4% to -8.5%; p < 0.0001) during fasting compared to energy balance, reflecting a decrease in carbohydrate oxidation (mean [SD], -2.6 [0.8] MJ/day; p < 0.0001) and an increase in lipid oxidation (2.3 [0.9] MJ/day; p < 0.0001). Changes in 24-h RER and carbohydrate oxidation in response to fasting were correlated with the subsequent energy intake such that smaller decreases in fasting 24-h RER and carbohydrate oxidation, but not lipid oxidation, were associated with greater energy intake after fasting (r = 0.31, p = 0.04; r = 0.40, p = 0.007; and r = -0.27, p = 0.07, respectively). CONCLUSIONS: Impaired metabolic flexibility to fasting, reflected by an inability to transition away from carbohydrate oxidation, is linked with increased energy intake.

SARS-CoV-2 mitochondrial metabolic and epigenomic reprogramming in COVID-19.

To determine the effects of SARS-CoV-2 infection on cellular metabolism, we conducted an exhaustive survey of the cellular metabolic pathways modulated by SARS-CoV-2 infection and confirmed their importance for SARS-CoV-2 propagation by cataloging the effects of specific pathway inhibitors. This revealed that SARS-CoV-2 strongly inhibits mitochondrial oxidative phosphorylation (OXPHOS) resulting in increased mitochondrial reactive oxygen species (mROS) production. The elevated mROS stabilizes HIF-1α which redirects carbon molecules from mitochondrial oxidation through glycolysis and the pentose phosphate pathway (PPP) to provide substrates for viral biogenesis. mROS also induces the release of mitochondrial DNA (mtDNA) which activates innate immunity. The restructuring of cellular energy metabolism is mediated in part by SARS-CoV-2 Orf8 and Orf10 whose expression restructures nuclear DNA (nDNA) and mtDNA OXPHOS gene expression. These viral proteins likely alter the epigenome, either by directly altering histone modifications or by modulating mitochondrial metabolite substrates of epigenome modification enzymes, potentially silencing OXPHOS gene expression and contributing to long-COVID.

Association Between Hemoglobin A1c and Development of Cardiovascular Disease in Canadian Men and Women Without Diabetes at Baseline: A Population-Based Study of 608 474 Adults.

BACKGROUND: We examined the association between hemoglobin A1c (HbA1c) and the development of cardiovascular disease (CVD) in men and women, without diabetes or CVD at baseline. METHODS AND RESULTS: This retrospective cohort study included adults aged 40 to <80 years in Alberta, Canada. Men and women were divided into categories based on a random HbA1c during a 3-year enrollment period. The primary outcome of CVD hospitalization and secondary outcome of combined CVD hospitalization/mortality were examined during a 5-year follow-up period until March 31, 2021. A total of 608 474 individuals (55.2% women) were included. Compared with HbA1c 5.0% to 5.4%, men with HbA1c of 5.5% to 5.9% had an increased risk of CVD hospitalization (adjusted hazard ratio [aHR], 1.12 [95% CI, 1.07-1.19]) whereas women did not (aHR, 1.01 [95% CI, 0.95-1.08]). Men and women with HbA1c of 6.0% to 6.4% had a 38% and 17% higher risk and men and women with HbA1c ≥6.5% had a 79% and 51% higher risk of CVD hospitalization, respectively. In addition, HbA1c of 6.0% to 6.4% and HbA1c ≥6.5% were associated with a higher risk (14% and 41%, respectively) of CVD hospitalization/death in men, but HbA1c ≥6.5% was associated with a 24% higher risk only among women. CONCLUSIONS: In both men and women, HbA1c ≥6.0% was associated with an increased risk of CVD and mortality outcomes. The association between CVD and HbA1c levels of 5.5% to 5.9%, considered to be in the "normal" range, highlights the importance of optimizing cardiovascular risk profiles at all levels of glycemia, especially in men.

Uptake of SGLT2i and Outcomes in Patients with Diabetes and Heart Failure: A Population-Based Cohort and a Specialized Clinic Cohort.

BACKGROUND: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are effective in adults with diabetes mellitus (DM) and heart failure (HF) based on randomized clinical trials. We compared SGLT2 inhibitor uptake and outcomes in two cohorts: a population-based cohort of all adults with DM and HF in Alberta, Canada and a specialized heart function clinic (HFC) cohort. METHODS: The population-based cohort was derived from linked provincial healthcare datasets. The specialized clinic cohort was created by chart review of consecutive patients prospectively enrolled in the HFC between February 2018 and August 2022. We examined the association between SGLT2 inhibitor use (modeled as a time-varying covariate) and all-cause mortality or deaths/cardiovascular hospitalizations. RESULTS: Of the 4,885 individuals from the population-based cohort, 64.2% met the eligibility criteria of the trials proving the effectiveness of SGLT2 inhibitors. Utilization of SGLT2 inhibitors increased from 1.2% in 2017 to 26.4% by January 2022. In comparison, of the 530 patients followed in the HFC, SGLT2 inhibitor use increased from 9.8% in 2019 to 49.1 % by March 2022. SGLT2 inhibitor use in the population-based cohort was associated with fewer all-cause mortality (aHR 0.51, 95%CI 0.41-0.63) and deaths/cardiovascular hospitalizations (aHR 0.65, 95%CI 0.54-0.77). However, SGLT2 inhibitor usage rates were far lower in HF patients without DM (3.5% by March 2022 in the HFC cohort). CONCLUSIONS: Despite robust randomized trial evidence of clinical benefit, the uptake of SGLT2 inhibitors in patients with HF and DM remains low, even in the specialized HFC. Clinical care strategies are needed to enhance the use of SGLT2 inhibitors and improve implementation.