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Abstract The sections in this article are: Pathogenesis of Type I Diabetes Effect of Type I Diabetes on Carbohydrate Metabolism Insulin Secretion and Action Postabsorptive and Postprandial Carbohydrate Metabolism Effects of Type I Diabetes and Its Treatment on Fatty Acid Metabolism Adipose Tissue Postabsorptive FFA Metabolism Postprandial FFA Availability Effects of Exercise on Adipose Tissue Lipolysis Regulation of Lipolysis During Hypoglycemia Effects Of Type I Diabetes on Protein Metabolism Regulation of Body Protein Mass, Amino Acid Levels and Nitrogen Balance Effect of Insulin on Protein Balance and Interaction of Insulin with Other Hormones and Substrates Effects of Insulin on Whole‐Body Protein Dynamics Effect of Insulin on Amino Acid Transamination Effect of Insulin on Regional Protein Dynamics Effect of Insulin on the Synthesis Rates of Specific Proteins Impact of Type I Diabetes on Protein Metabolism

Intermuscular adipose tissue (IMAT) accumulates in the lower leg musculature of healthy older adults. IMAT was negatively associated with the rate of glucose infusion during a hyperinsulinemic-euglycemic clamp and muscle oxidative capacity. Exercise training decreased IMAT to a greater extent in young compared with older adults. Together these data support the implication that IMAT accumulation is linked with metabolic derangements in older adults but the restorative potential of exercise in older adults needs further evaluation.

Candida krusei empyema is a rare but serious manifestation of invasive candidiasis, characterized by intrinsic resistance to fluconazole, biofilm formation, and high mortality, with limited case-level data to inform management. This review aims to systematically identify and synthesize all reported English-language cases of Candida krusei empyema from January 2005 to June 2025 using PubMed, ScienceDirect, OVID MEDLINE, and Gale OneFile and perform descriptive analysis on them. Screening, data extraction, and eligibility assessment were performed, and those articles not clearly meeting eligibility criteria were reviewed by additional reviewers with consensus resolution. Seven publications (six individual cases and two cohorts) were included. We additionally describe the clinical course, management, and outcome of a 70-year-old bilateral lung transplant patient who developed persistent C. krusei empyema despite optimized antifungal therapy. Patients ranged from 11 to 74 years of age (median 62.5 years). Predisposing factors included esophageal perforation (n = 4), post-transplant hemorrhage (n = 1), community-acquired empyema (n = 1), and thoracic surgery (n = 1). Empiric fluconazole was switched to caspofungin (3/4), with others receiving amphotericin B, voriconazole, or combination therapy. Source control varied: chest tube drainage (n = 3), percutaneous catheter (n = 3), and surgical decortication (n = 2). Mortality was 14.3% (1/7). In the absence of clear guidelines and robust literature, the management approach remains heterogeneous. Optimal care requires early recognition, aggressive multimodal antifungal therapy, and effective source control tailored to patient risk. Standardized antifungal protocols and larger case series are needed to guide clinicians in managing this challenging infection.

Abstract Background Vitamin D supplementation by human individuals has significantly increased in the world. In US the total stored 25-OH-Vitamin D3 and 25-OH-Vitamin D2 has significantly increased for both in summers and winters. Under sunlight exposure, 7 dehydrocholesterol is converted to Vitamin D3 and is endogenous source in mammals. However, most of the exogenous source for Vitamin D used to be Vitamin D2 which used to be extracted only from mushrooms but is now manufactured by supplement industry as well. In last decade most of the supplementation has been due to chemically synthesized Vitamin D3. Food is now supplemented by both D2 and D3. It is not clear what is the prevalence of D2 supplementation/consumption in American population. Competitive immunoassays do not consistently recover 25-OH-D2 compared to 25-OH-D3 and some antibodies used have variable or no cross reactivity with 25-OH-D2. LC-MS/MS method can easily distinguish the two and can help in providing the precise and accurate results for 25-OH-D2 and 25-OH-D3. Here we present what is the prevalence of Vitamin D2 consumption and toxicity in American population based on our LC-MS/MS methods. Methods The study measured vitamin 25-OH-D levels (total, D2, and D3) in 148,654 patients from Mayo Clinic as well as from other medical centers within the U.S. Patients age ranging from new-born babies to over 100 years, and represents Male, Female and Neutral genders. Samples were analyzed for 25-OH-Vitamin D by LC-MS/MS as published earlier. Unlike immunoassays, LC-MS/MS gave us separate results for 25-OH-D3 and 25-OH-D2 with 100 percent specificity. Results 25-OH-Vitamin D2 levels of greater than 10 was present in at least 10,358 and ranged from 10 to 205 ng/mL. Of 10,358, 51 percent had 20-50 ng/mL, 10 percent had 51-80 ng/mL, and 1.3 percent had >80 ng/mL, ranging from 81-205 ng/mL with a median of 92 ng/mL. Of the patients found at Total Vitamin D >80 ng/mL, toxic levels of both D2 and D3 were found more in females than males. There was no significant gender difference for Vitamin D3 consumption but for D2 consumption, mean and median levels were different in males and females. Conclusion Clinical lab testing should accurately measure both 25-OH-D3 and 25-OH-D2, otherwise the patient total Vitamin D values in circulation will be underestimated.

Abstract Insulin resistance (IR) is a modifiable risk factor for dementia, yet its effects on brain metabolism and function remain unclear. In older adults, greater IR was associated with reduced cerebral glucose uptake (indicating impaired mitochondrial metabolism), atrophy, and weakened connectivity between brain regions critical for cognition. In neuron-specific insulin receptor knockout mice, brain IR produced deficits in hippocampal- and prefrontal-dependent tasks accompanied by reduced brain mitochondrial ATP and elevated reactive oxygen species. To evaluate reversibility of IR-induced brain deficits, forty older adults with IR were randomized to 40-weeks of metformin or placebo. Metformin improved insulin sensitivity, increased brain glucose uptake, strengthened cognitive network connectivity, and preserved whole-brain and regional volumes implicated in decision-making and learning. Metformin also improved processing speed and working memory. Collectively, these findings highlight IR as a driver of brain metabolism and support the concept that insulin sensitization can prevent neurobiological deficits in older people with IR.

The indications for immune checkpoint inhibitor (ICI) use in cancer treatment continue to expand. This is attributable to their proven anticancer activity in addition to their tolerability and favorable toxicity profile as compared to conventional chemotherapeutic agents. ICIs work by blocking the inhibitory signals between tumor cells and T-cells, thereby enhancing the T-cell cytotoxic activity to inhibit tumor growth. Because of their immune-stimulating effect, ICIs are linked to adverse renal outcomes in both native and transplanted kidneys. The risk of kidney allograft rejection in the setting of ICI use has been reported to be around 40%, leading to an increased risk of graft loss. In this report, we review the literature examining outcomes in kidney transplant recipients receiving ICIs for various oncologic indications.

AbstractSkeletal muscle atrophy was a characteristic of type 1 diabetes (T1DM) prior to insulin discovery and replacement. Indirect calorimetry during the post‐absorptive state demonstrated that increased fuel oxidation during transient insulin deprivation in T1DM caused depletion of energy stores. Further, insulin has a critical role in preserving muscle mitochondrial content and function by enhancing mitochondrial biogenesis and proteostasis. Insulin deficiency not only inhibits mitochondrial biogenesis but also accelerates the degradation of mitochondrial proteins, causing a decline in mitochondrial content and efficiency. Inefficient mitochondrial respiration, reflected by the uncoupling of oxidative phosphorylation and consequent decline in ATP production, adversely affects many cellular functions and causes high oxidative stress. Oxidative stress adversely affects cardiovascular functions and damages many skeletal muscle proteins, accelerating their degradation and explaining muscle atrophy. Increased degradation of muscle proteins increases amino acid efflux that stimulates the liver to synthesize many non‐insulin‐dependent proteins, potentially contributing to macrovascular complications. This phenomenon explains a paradoxical increase in whole‐body protein synthesis during insulin deficiency. Further, the mitochondrial biology of brain regions rich in insulin receptors concurrent with accelerated transport of ketones and lactate across the blood–brain barrier during insulin deficiency seems to protect the brain from oxidative stress. In contrast, insulin resistance associated with less ketone and lactate production renders the brain susceptible to protein oxidative damage. Oxidative damage and reduced ATP production potentially explain the higher prevalence of dementia in insulin‐resistant people. Enhancement of insulin sensitivity by aerobic exercise and metformin in pre‐clinical studies prevents mitochondrial dysfunction and oxidative damage to the brain.

ABSTRACTIn Functional Magnetic Resonance Imaging (fMRI), the primary contrast is Blood Oxygen Level Dependent (BOLD) signal. Systemic Low Frequency Oscillations (sLFO) are BOLD signals between 0.01 and 0.1 Hz originating from systemic physiological processes. While sLFO signals in the brain have been shown to travel with blood in numerous studies, their behavior in the spinal cord (SC) remains unexplored. This study characterizes the coupling between brain‐sLFO and SC‐sLFO signals. Understanding brain‐SC‐coupling is pivotal for unraveling the vascular continuity of the central nervous system, which plays a crucial role in SC‐injury pathophysiology. BOLD signal extraction involved registering structural masks to fMRI space to obtain average time series from the brain, SC, and superior sagittal sinus. The sLFOs of the time series were cross‐correlated to determine vascular delays and analyzed for band power. It is found that the SC‐sLFO signal comprises two components relative to the brain, showing opposite correlation polarity and varying delays. These findings suggest that highly oxygenated blood arrives at the spinal cord before arriving at the brain, and some component of the brain's venous output circulates to or near to the spinal cord later, likely due to unique arterial and venous pathways connecting the central nervous system. This insight offers a valuable imaging marker for future studies on the effects of SC injury on brain‐SC interconnectivity.

Importance Tau positron emission tomography (PET) allows in vivo detection of neurofibrillary tangles, a core neuropathologic feature of Alzheimer disease (AD). Objective To provide estimates of the frequency of tau PET positivity and its associated risk of clinical outcomes. Design, Setting, and Participants Longitudinal study using data pooled from 21 cohorts, comprising a convenience sample of 6514 participants from 13 countries, collected between January 2013 and June 2024. Cognitively unimpaired individuals and patients with a clinical diagnosis of mild cognitive impairment (MCI), AD dementia, or other neurodegenerative disorders were included. Exposures Tau PET with flortaucipir F 18, amyloid-β (Aβ) PET, and clinical examinations. Tau PET scans were visually rated as positive according to a US Food and Drug Administration– and European Medicines Agency–approved method, designed to indicate the presence of advanced neurofibrillary tangle pathology (Braak stages V-VI). Main Outcomes and Measures Frequency of tau PET positivity and absolute risk of clinical progression (eg, progression to MCI or dementia). Results Among the 6514 participants (mean age, 69.5 years; 50.5% female), median follow-up time ranged from 1.5 to 4.0 years. Of 3487 cognitively unimpaired participants, 349 (9.8%) were tau PET positive; the estimated frequency of tau PET positivity was less than 1% in those aged younger than 50 years, and increased from 3% (95% CI, 2%-4%) at 60 years to 19% (95% CI, 16%-24%) at 90 years. Tau PET positivity frequency estimates increased across MCI and AD dementia clinical diagnoses (43% [95% CI, 41%-46%] and 79% [95% CI, 77%-82%] at 75 years, respectively). Most tau PET–positive individuals (92%) were also Aβ PET positive. Cognitively unimpaired participants who were positive for both Aβ PET and tau PET had a higher absolute risk of progression to MCI or dementia over the following 5 years (57% [95% CI, 45%-71%]) compared with both Aβ PET–positive/tau PET–negative (17% [95% CI, 13%-22%]) and Aβ PET–negative/tau PET–negative (6% [95% CI, 5%-8%]) individuals. Among participants with MCI at the time of the tau PET scan, an Aβ PET–positive/tau PET–positive profile was associated with a 5-year absolute risk of progression to dementia of 70% (95% CI, 59%-81%). Conclusions and Relevance In a large convenience sample, a positive tau PET scan occurred at a nonnegligible rate among cognitively unimpaired individuals, and the combination of Aβ PET positivity and tau PET positivity was associated with a high risk of clinical progression in both preclinical and symptomatic stages of AD. These findings underscore the potential of tau PET as a biomarker for staging AD pathology.

Abstract Rationale A subset of patients with group 1 pulmonary hypertension (PH) have superimposed left heart abnormalities with unclear metabolic implications. Objectives To compare serum/transpulmonary metabolome between group 1 PH stratified by heart failure with preserved ejection fraction (HFpEF) probability. Methods Patients with group 1 PH were stratified into low (<25%) and high (⩾75%) HFpEF-ABA (age, body mass index, and atrial fibrillation) probability, with healthy control subjects and subjects with clinical HFpEF used for comparison of venous and transpulmonary metabolomics. Measurements and Main Results Group 1 PH + high HFpEF probability (n = 131) was associated with a significant increase in 207 metabolites (false discovery rate [FDR] P < 0.05 and fold change >1) (n = 193, t test) and a significant decrease in 231 metabolites (FDR P < 0.05 and fold change <1) (n = 193, t test) compared with group 1 PH + low HFpEF probability (n = 62). Group 1 PH + high HFpEF probability was associated with enhanced tryptophan metabolism with higher downstream kynurenine metabolite concentrations and lower serotonin concentrations (FDR P < 0.002 for all, n = 193, t test). Linoleate (precursor to arachidonic acid and prostaglandins) and arginine and homoarginine (precursors to nitric oxide) were all lower in group 1 PH + high HFpEF probability (FDR P < 0.03 for all, n = 193, t test). Metabolome changes in group 1 PH + high HFpEF probability overlapped with clinical HFpEF (n = 240) but were abnormal relative to control subjects (n = 85) (P < 0.0001 for all, n = 456, t test). There was no evidence of differential transpulmonary uptake/release of most metabolites, suggesting probable nonpulmonary origin (except for serotonin, interaction P = 0.04; and kynurenine, interaction P = 0.03; n = 433, mixed model). Conclusions Patients with group 1 PH + high HFpEF probability have a unique metabolome characterized by enhanced tryptophan-kynurenine pathway breakdown, deficiency of amino acids (such as glycine and serine), lower serotonin, and decreased prostaglandin and nitric oxide precursors. Despite fulfilling clinical criteria for group 1 PH, these metabolome changes were comparable with clinical HFpEF, supporting biological overlap between these two forms of PH.