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Food insecurity is highly prevalent and linked to poorer diet and worse metabolic outcomes. Food insecurity can be stressful, and could elicit chronic psychological and physiological stress. In this study, we tested whether stress could be used to identify those at highest risk for worse diet and metabolic measures from food insecurity. Specifically, we hypothesized that cortisol (a physiological marker of stress) and perceived psychological stress would amplify the link between food insecurity and hyperpalatable food intake as well as metabolic measures. In a sample of 624 Black and White women aged 36-43 who participated in the NHLBI Growth and Health Study's midlife assessment, we assessed associations between food insecurity with hyperpalatable food intake (high fat + high sodium foods; high fat + high sugar foods; and high carbohydrate + high sodium foods), and metabolic measures (fasting glucose, insulin resistance, and waist circumference). We found that food insecurity was associated with higher levels of perceived stress (R2 = 0.09), and greater intake of high fat + high sugar (hyperpalatable) foods (R2 = 0.03). In those with higher cumulative cortisol (as indexed by hair cortisol), food insecurity was associated with higher levels of fasting glucose. Neither cortisol nor perceived stress moderated any other relationships, and neither variable functioned as a mediator in sensitivity analyses. Given these largely null findings, further research is needed to understand the role stress plays in the chronic health burdens of food insecurity.

The Na+-Ca2+ exchanger (NCX1) is the dominant Ca2+ extrusion mechanism in cardiac myocytes. NCX1 activity is inhibited by intracellular Na+ via a process known as Na+-dependent inactivation. A central question is whether this inactivation plays a physiological role in heart function. Using CRISPR/Cas9, we inserted the K229Q mutation in the gene (Slc8a1) encoding for NCX1. This mutation removes the Na+-dependent inactivation while preserving transport properties and other allosteric regulations. NCX1 mRNA levels, protein expression, and protein localization are unchanged in K229Q male mice. However, they exhibit reduced left ventricular ejection fraction and fractional shortening, while displaying a prolonged QT interval. K229Q ventricular myocytes show enhanced NCX1 activity, resulting in action potential prolongation, higher incidence of aberrant action potentials, a faster decline of Ca2+ transients, and depressed cell shortening. The results demonstrate that NCX1 Na+-dependent inactivation plays an essential role in heart function by affecting both cardiac excitability and contractility.

There is a bidirectional pathophysiological interaction between the heart and the kidneys, and prolonged physiological stress to the heart and/or the kidneys can cause adverse cardiorenal complications, including but not limited to subclinical cardiomyopathy, heart failure and chronic kidney disease. Whilst more common in individuals with Type 2 diabetes, cardiorenal complications also occur in the absence of diabetes. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were initially approved to reduce hyperglycaemia in patients with Type 2 diabetes. Recently, these agents have been shown to significantly improve cardiovascular and renal outcomes in patients with and without Type 2 diabetes, demonstrating a robust reduction in hospitalisation for heart failure and reduced risk of progression of chronic kidney disease, thus gaining approval for use in treatment of heart failure and chronic kidney disease. Numerous potential mechanisms have been proposed to explain the cardiorenal effects of SGLT2i. This review provides a simplified summary of key potential cardiac and renal mechanisms underlying the cardiorenal benefits of SGT2i and explains these mechanisms in the clinical context. Key mechanisms related to the clinical effects of SGLT2i on the heart and kidneys explained in this publication include their impact on (1) tissue oxygen delivery, hypoxia and resultant ischaemic injury, (2) vascular health and function, (3) substrate utilisation and metabolic health and (4) cardiac remodelling. Knowing the mechanisms responsible for SGLT2i-imparted cardiorenal benefits in the clinical outcomes will help healthcare practitioners to identify more patients that can benefit from the use of SGLT2i.

BACKGROUND & AIMS: Acute diarrheal diseases are the second most common cause of infant mortality in developing countries. This is contributed to by lack of effective drug therapy that shortens the duration or lessens the volume of diarrhea. The epithelial brush border sodium (Na+)/hydrogen (H+) exchanger 3 (NHE3) accounts for a major component of intestinal Na+ absorption and is inhibited in most diarrheas. Because increased intestinal Na+ absorption can rehydrate patients with diarrhea, NHE3 has been suggested as a potential druggable target for drug therapy for diarrhea. METHODS: A peptide (sodium-hydrogen exchanger 3 stimulatory peptide [N3SP]) was synthesized to mimic the part of the NHE3 C-terminus that forms a multiprotein complex that inhibits NHE3 activity. The effect of N3SP on NHE3 activity was evaluated in NHE3-transfected fibroblasts null for other plasma membrane NHEs, a human colon cancer cell line that models intestinal absorptive enterocytes (Caco-2/BBe), human enteroids, and mouse intestine in vitro and in vivo. N3SP was delivered into cells via a hydrophobic fluorescent maleimide or nanoparticles. RESULTS: N3SP uptake stimulated NHE3 activity at nmol/L concentrations under basal conditions and partially reversed the reduced NHE3 activity caused by elevated adenosine 3,5-cyclic monophosphate, guanosine 3,5-cyclic monophosphate, and Ca2+ in cell lines and in in vitro mouse intestine. N3SP also stimulated intestinal fluid absorption in the mouse small intestine in vivo and prevented cholera toxin-, Escherichia coli heat-stable enterotoxin-, and cluster of differentiation 3 inflammation-induced fluid secretion in a live mouse intestinal loop model. CONCLUSIONS: These findings suggest pharmacologic stimulation of NHE3 activity as an efficacious approach for the treatment of moderate/severe diarrheal diseases.

People with diabetes and chronic kidney disease (CKD) are at high risk for kidney failure, atherosclerotic cardiovascular disease, heart failure, and premature mortality. Recent clinical trials support new approaches to treat diabetes and CKD. The 2022 American Diabetes Association (ADA) Standards of Medical Care in Diabetes and the Kidney Disease: Improving Global Outcomes (KDIGO) 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease each provide evidence-based recommendations for management. A joint group of ADA and KDIGO representatives reviewed and developed a series of consensus statements to guide clinical care from the ADA and KDIGO guidelines. The published guidelines are aligned in the areas of CKD screening and diagnosis, glycemia monitoring, lifestyle therapies, treatment goals, and pharmacologic management. Recommendations include comprehensive care in which pharmacotherapy that is proven to improve kidney and cardiovascular outcomes is layered on a foundation of healthy lifestyle. Consensus statements provide specific guidance on use of renin-angiotensin system inhibitors, metformin, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, and a nonsteroidal mineralocorticoid receptor antagonist. These areas of consensus provide clear direction for implementation of care to improve clinical outcomes of people with diabetes and CKD.

The burden of early hospitalization (within 6 months) following simultaneous liver-kidney transplant (SLKT) is not known. We examined risk factors associated with early hospitalization after SLKT and their impact on patient mortality conditional on 6-month survival. We used data from the US Multicenter SLKT Consortium cohort study of all adult SLKT recipients between 2002 and 2017 who were discharged alive following SLKT. We used Poisson regression to model rates of early hospitalizations after SLKT. Cox regression was used to identify risk factors associated with mortality conditional on survival at 6 months after SLKT. Median age (N = 549) was 57.7 years (interquartile range [IQR], 50.6-63.9) with 63% males and 76% Whites; 33% had hepatitis C virus, 20% had non-alcohol-associated fatty liver disease, 23% alcohol-associated liver disease, and 24% other etiologies. Median body mass index (BMI) and Model for End-Stage Liver Disease-sodium scores were 27.2 kg/m2 (IQR, 23.6-32.2 kg/m2 ) and 28 (IQR, 23-34), respectively. Two-thirds of the cohort had at least one hospitalization within the first 6 months of SLKT. Age, race, hospitalization at SLKT, diabetes mellitus, BMI, and discharge to subacute rehabilitation (SAR) facility after SLKT were independently associated with a high incidence rate ratio of early hospitalization. Number of hospitalizations within the first 6 months did not affect conditional survival. Early hospitalizations after SLKT were very common but did not affect conditional survival. Although most of the risk factors for early hospitalization were nonmodifiable, discharge to SAR after initial SLKT was associated with a significantly higher incidence rate of early hospitalization. Efforts and resources should be focused on identifying SLKT recipients at high risk for early hospitalization to optimize their predischarge care, discharge planning, and long-term follow-up.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a recent addition to the pillars of medical therapy for heart failure (HF) with reduced ejection fraction, all of which improve quality of life, morbidity, and mortality. These benefits are evident within the first 30 days of initiation. This review discusses the rationale for SGLT2i initiation in simultaneous or in rapid sequence with other guideline-directed medical therapy (GDMT). We also discuss SGLT2i use and early benefits in HF patients with an ejection fraction greater than 40%.

It has been demonstrated experimentally that slow and fast conduction waves with distinct conduction velocities can occur in the same nerve system depending on the strength or the form of the stimulus, which give rise to two modes of nerve functions. However, the mechanisms remain to be elucidated. In this study, we use computer simulations of the cable equation with modified Hodgkin-Huxley kinetics and analytical solutions of a simplified model to show that stimulus-dependent slow and fast waves recapitulating the experimental observations can occur in the cable, which are the two stable conduction states of a bistable conduction behavior. The bistable conduction is caused by a positive feedback loop of the wavefront upstroke speed, mediated by the sodium channel inactivation properties. Although the occurrence of bistable conduction only requires the presence of the sodium current, adding a calcium current to the model further promotes bistable conduction by potentiating the slow wave. We also show that the bistable conduction is robust, occurring for sodium and calcium activation thresholds well within the experimentally determined ones of the known sodium and calcium channel families. Since bistable conduction can occur in the cable equation of Hodgkin-Huxley kinetics with a single inward current, i.e., the sodium current, it can be a generic mechanism applicable to stimulus-dependent fast and slow conduction not only in the nerve systems but also in other electrically excitable systems, such as cardiac muscles.

Background and aimsWe investigated the impact of the inclusion of kidney dysfunction type on the discrimination and calibration of the Model for End-Stage Liver Disease with sodium (MELD-Na-KT) score.Approach and resultsWe included all adults listed for ≥90 days without exception points from January 1, 2008, through December 31, 2018. We defined kidney dysfunction types as follows: acute kidney disease (AKD; an increase of ≥0.3 mg/dL or ≥50% in serum creatinine in the last 7 days or fewer than 72 days of hemodialysis), chronic kidney disease (CKD; an estimated glomerular filtration rate

Genetic variants in SCN2A, encoding the NaV1.2 voltage-gated sodium channel, are associated with a range of neurodevelopmental disorders with overlapping phenotypes. Some variants fit into a framework wherein gain-of-function missense variants that increase neuronal excitability lead to developmental and epileptic encephalopathy, while loss-of-function variants that reduce neuronal excitability lead to intellectual disability and/or autism spectrum disorder (ASD) with or without co-morbid seizures. One unique case less easily classified using this framework is the de novo missense variant SCN2A-p.K1422E, associated with infant-onset developmental delay, infantile spasms and features of ASD. Prior structure-function studies demonstrated that K1422E substitution alters ion selectivity of NaV1.2, conferring Ca2+ permeability, lowering overall conductance and conferring resistance to tetrodotoxin (TTX). Based on heterologous expression of K1422E, we developed a compartmental neuron model incorporating variant channels that predicted reductions in peak action potential (AP) speed. We generated Scn2aK1422E mice and characterized effects on neurons and neurological/neurobehavioral phenotypes. Cultured cortical neurons from heterozygous Scn2aK1422E/+ mice exhibited lower current density with a TTX-resistant component and reversal potential consistent with mixed ion permeation. Recordings from Scn2aK1442E/+ cortical slices demonstrated impaired AP initiation and larger Ca2+ transients at the axon initial segment during the rising phase of the AP, suggesting complex effects on channel function. Scn2aK1422E/+ mice exhibited rare spontaneous seizures, interictal electroencephalogram abnormalities, altered induced seizure thresholds, reduced anxiety-like behavior and alterations in olfactory-guided social behavior. Overall, Scn2aK1422E/+ mice present with phenotypes similar yet distinct from other Scn2a models, consistent with complex effects of K1422E on NaV1.2 channel function.

BackgroundSalt sensitivity of blood pressure is an independent predictor of cardiovascular morbidity and mortality. The exact mechanism by which salt intake increases blood pressure and cardiovascular risk is unknown. We previously found that sodium entry into antigen-presenting cells (APCs) via the amiloride-sensitive epithelial sodium channel EnaC (epithelial sodium channel) leads to the formation of IsoLGs (isolevuglandins) and release of proinflammatory cytokines to activate T cells and modulate salt-sensitive hypertension. In the current study, we hypothesized that ENaC-dependent entry of sodium into APCs activates the NLRP3 (NOD [nucleotide-binding and oligomerization domain]-like receptor family pyrin domain containing 3) inflammasome via IsoLG formation leading to salt-sensitive hypertension.MethodsWe performed RNA sequencing on human monocytes treated with elevated sodium in vitro and Cellular Indexing of Transcriptomes and Epitopes by Sequencing analysis of peripheral blood mononuclear cells from participants rigorously phenotyped for salt sensitivity of blood pressure using an established inpatient protocol. To determine mechanisms, we analyzed inflammasome activation in mouse models of deoxycorticosterone acetate salt-induced hypertension as well as salt-sensitive mice with ENaC inhibition or expression, IsoLG scavenging, and adoptive transfer of wild-type dendritic cells into NLRP3 deficient mice.ResultsWe found that high levels of salt exposure upregulates the NLRP3 inflammasome, pyroptotic and apoptotic caspases, and IL (interleukin)-1β transcription in human monocytes. Cellular Indexing of Transcriptomes and Epitopes by Sequencing revealed that components of the NLRP3 inflammasome and activation marker IL-1β dynamically vary with changes in salt loading/depletion. Mechanistically, we found that sodium-induced activation of the NLRP3 inflammasome is ENaC and IsoLG dependent. NLRP3 deficient mice develop a blunted hypertensive response to elevated sodium, and this is restored by the adoptive transfer of NLRP3 replete APCs.ConclusionsThese findings reveal a mechanistic link between ENaC, inflammation, and salt-sensitive hypertension involving NLRP3 inflammasome activation in APCs. APC activation via the NLRP3 inflammasome can serve as a potential diagnostic biomarker for salt sensitivity of blood pressure.

Recent advances in type 2 diabetes (T2D) research have highlighted the benefits of sodium-glucose co-transporter-2 (SGLT-2) inhibitors, including cardiovascular and renal protection. However, uptake rates of these drugs remain low in patients with T2D, particularly in subpopulations most likely to benefit from them. This review considers the potential barriers to prescribing SGLT-2 inhibitors in T2D in clinical practice and outlines potential multidisciplinary recommendations to overcome these barriers. Safety concerns and a lack of clarity in and divergence of guidelines around the introduction of SGLT-2 inhibitors into treatment regimens may represent a barrier to uptake from the clinicians perspective, including a general lack of understanding of the benefits associated with SGLT-2 inhibitors. Patient characteristics, such as socioeconomic status, may influence uptake because of the cost of SGLT-2 inhibitors, especially in the United States, where health insurance coverage could be a concern. SGLT-2 inhibitor prescription rates vary between clinical specialty (endocrinology, primary care, cardiology, and nephrology) and country, with cardiologists the lowest prescribers, and endocrinologists the highest. Primary care practitioners may experience more challenges in following SGLT-2 inhibitor-related guidelines than diabetes specialists as there may be fewer opportunities for education on how this drug class improves cardiovascular and renal outcomes in patients with T2D. Uptake rates appear to vary between countries because of differences in guidelines and health insurance systems. The amendment of SGLT-2 inhibitor-related guidelines for more multidisciplinary use and the implementation of patient and clinician education may encourage uptake of these drugs, potentially improving long-term health outcomes among patients with T2D.

AimsRecent trials have evaluated sodium-glucose co-transporter 2 inhibitors in patients with heart failure (HF). We sought to assess the robustness of findings from these trials using the fragility index (FI).Methods and resultsFragility index is defined as the minimum number of patients that must be moved from the 'non-event' to the 'event' group to turn a statistically significant result to non-significant. In addition to FI, fragility quotient [(FQ); FI divided by the sample size] was calculated to assess the proportion of events that must be moved to change the significance. For statistically non-significant outcomes, reverse fragility index (RFI) and reverse fragility quotient (RFQ) were calculated. Robustness of findings after pooling data from all three trials was also assessed. A robust reduction in first HF hospitalization or cardiovascular mortality was seen with dapagliflozin (FI = 62 and FQ = 0.013), empagliflozin (FI = 50 and FQ = 0.013), and sotagliflozin (FI = 60 and FQ = 0.049). Dapagliflozin nominally improved all-cause and cardiovascular mortality, with modest FI (n = 8 and 5) and FQ (0.002 and 0.001). Empagliflozin and sotagliflozin did not demonstrate statistically significant reductions in all-cause mortality, with modest RFI (empagliflozin: RFI = 26 and RFQ = 0.007; sotagliflozin: RFI = 6 and RFQ = 0.005). A similar trend was seen with cardiovascular mortality (empagliflozin: RFI = 24 and RFQ = 0.006; sotagliflozin: RFI = 7 and RFQ = 0.006). Upon meta-analysis, the result for first HF hospitalization or cardiovascular mortality was robust (FI = 95 and FQ = 0.010). The reductions in all-cause (FI = 12 and FQ = 0.001) and cardiovascular mortality (FI = 9 and FQ = 0.001), while statistically significant, were fragile.ConclusionImprovement in the composite outcome of first HF hospitalization or cardiovascular death was highly concordant and robust across sodium-glucose co-transporter 2 inhibitor trials. In contrast, secondary endpoints of all-cause and cardiovascular mortality were statistically fragile, underscoring the need to power trials for mortality to fully understand the benefit of therapies on fatal events.

BackgroundData on the stability of whole blood electrolytes is limited to small sample sizes. We sought to determine the stability of whole blood electrolytes under room temperature and slushed iced conditions in human patients at a major hospital center.MethodsWhole blood samples were obtained from 203 patients hospitalized for various pathophysiological conditions. Electrolyte concentrations of sodium, potassium [K+], ionized calcium, and chloride were measured at 5 different timepoints spanning 3 h. Samples were stored at room temperature (22-24 °C) or under slushed ice conditions (0.1-0.2 °C) before analysis.ResultsUnder both conditions, sodium, ionized calcium, and chloride did not show a measurable change up to 109 min compared to baseline; however, the mean increase in [K+] over 138 min of storage in slushed ice was 0.0032 (0.0021 [5th percentile] to 0.0047 [95th percentile]) mmol/L/min (adjusted R2 = 0.62, P

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have recently been recommended as a foundational therapy for patients with heart failure (HF) and reduced ejection fraction (HFrEF) because of their favourable effects on mortality, clinical events and quality of life. While clinical practice guidelines have recommended dapagliflozin or empagliflozin in all patients with HFrEF, or sotagliflozin in those with HFrEF and concomitant diabetes, the timing and practical integration of these drugs in clinical practice is less well defined. We propose that these drugs are candidates for early, upfront administration to patients with newly diagnosed HFrEF and for patients hospitalized with HF. Growing evidence has established early benefits, with clinically meaningful reductions in clinical events that reach statistical significance within days to weeks, following dapagliflozin, empagliflozin or, in diabetic patients, sotagliflozin initiation. Secondly, although major clinical trials have tested these drugs in patients already receiving background HF therapy, secondary analyses showed that their efficacy is independent of that. Third, SGLT2 inhibitors are generally safe and well tolerated, with clinical trial data reporting minimal effects on blood pressure, glycaemia-related adverse events, and no excess in acute kidney injury. Rather, they exert renal protective effects and reduce risk of hyperkalaemia, properties that favour initiation, tolerance and persistence of renin-angiotensin system inhibitors and mineralocorticoid receptor antagonists. This review supports the early initiation of dapagliflozin and empagliflozin (or sotagliflozin limited to patients with diabetes) to rapidly improve clinical outcome and quality of life of HFrEF patients.

BackgroundWe aimed to establish the observer repeatability and interscan reproducibility of coronary 18F-sodium-fluoride positron emission tomography (PET) uptake using a novel semi-automated approach, coronary microcalcification activity (CMA).MethodsPatients with multivessel coronary artery disease underwent repeated hybrid PET and computed tomography angiography (CTA) imaging (PET/CTA). CMA was defined as the integrated standardized uptake values (SUV) in the entire coronary tree exceeding 2 standard deviations above the background SUV. Coefficients of repeatability between the same observer (intraobserver repeatability), between 2 observers (interobserver repeatability) and coefficient of reproducibility between 2 scans (interscan reproducibility), were determined at vessel and patient level.ResultsIn 19 patients, CMA was assessed twice in 43 coronary vessels on two PET/CT scans performed 12 ± 5 days apart. There was excellent intraclass correlation for intraobserver and interobserver repeatability as well as interscan reproducibility (all ≥ 0.991). There was 100% intraobserver, interobserver and interscan agreement for the presence (CMA > 0) or absence (CMA = 0) of coronary18F-NaF uptake. Mean CMA was 3.12 ± 0.62 with coefficients of repeatability of ≤ 10% for all measures: intraobserver 0.24 and 0.22, interobserver 0.30 and 0.29 and interscan 0.33 and 0.32 at a per-vessel and per-patient level, respectively.ConclusionsCMA is a repeatable and reproducible global measure of coronary atherosclerotic activity.

Our global food system lacks the critically needed micronutrients to meet the daily requirements of the most at-risk populations. Diets also continue to shift toward unhealthy foods, including the increased intake of salt. While most countries exceed the WHO's recommended levels, sodium does play an essential physiological role. Table salt and other salt-containing condiments, such as bouillon, also have cultural importance, as they are used to enhance the flavor of foods cooked at home. Given their universal consumption across income classes and both urban and rural populations, these condiments are an integral part of the food system and should, therefore, be part of its transformation. Fortification of salt and salt-containing condiments can play a catalytic role in the delivery of population-wide nutritional and health benefits. With relatively consistent levels of intake across the population, these condiments hold high potential for delivering micronutrients beyond iodine while also reducing concerns related to high micronutrient intake, particularly so in countries where the industries are relatively consolidated. As a flexible and complementary strategy to an evolving food system, fortification levels can also be adjusted over time to ensure micronutrient delivery targets continue to be achieved as the system improves, whether through lower intakes of sodium in line with WHO recommendations, enhanced consumption of nutrient-dense foods, and/or broader adoption of biofortified crops. Future areas of innovation are required to realize this vision, including developing affordable salt substitutes to meet cost requirements of consumers in low-and middle-income countries, improving the stability and bioavailability of the micronutrients in condiments so that delivery targets can be reached without affecting sensory attributes, and the development of efficient systems for monitoring population intake and micronutrient status to inform fortification program design and management. Rather than being considered antithetical to the transformation, multiply-fortified salt and bouillon can strengthen our ability to meet the cultural, sensory, nutritional, and health needs of an evolving food system.

"Skin Sodium Accumulates in Psoriasis and Reflects Disease Severity" (Maifeld et al., 2021) showed that skin sodium ion (Na+) is increased in patients with a PASI > 5. Na+ concentration as well as its content were increased in these patients, supporting the proposed mechanism that increased Na+ concentrations enhance IL-17 expression from CD4+ cells. These data initially were generated using a noninvasive technique, sodium (23Na) magnetic resonance imaging, and then were verified using 23Na spectroscopy and atomic absorption spectrometry in ashed-skin biopsies in humans and also using mouse models of psoriasis. These findings suggest a novel pathologic mechanism for psoriasis development and target for treatment.

BackgroundGlucose galactose malabsorption (GGM) is a congenital diarrheal disorder of intestinal Na+/glucose cotransport (SGLT1/SLC5A1). The required glucose and galactose-restricted diet has been well described in infancy, but long-term nutrition follow-up is limited.AimTo perform a comprehensive nutritional assessment on a cohort of patients with GGM to gain insights into the consumption patterns within the population.MethodsA cross-sectional study examining dietary intake of a GGM cohort using prospective food records. The calories and nutrients of all foods, beverages, and condiments were analyzed with descriptive statistics and compared to intake patterns of age- and sex-matched NHANES groups.ResultsThe six patients were 0.7-26 years old. Whole foods and vegetable fats were major parts of the diet, while dairy and added sweeteners were restricted. Compared to typical US intakes, mean macronutrient distribution was 88th percentile from fat, 18th percentile from carbohydrates, and 78th percentile from protein. Fructose consumption, as a proportion of total sugar intake, decreased with age, from 86.1 to 50.4%. Meanwhile, glucose consumption increased with age, from 13.8 to 48.6% of sugar intake. However, the actual amount of glucose consumed remained low, equivalent to 4th percentile of US consumption level. Galactose intake was marginal throughout life.ConclusionsA GGM diet is a high-fat and high-protein/low-carbohydrate diet that is rich in fruits and vegetables but limited in dairy and added sugar. Relatively less fructose but more glucose is incorporated into the diet with age. Future studies should investigate the effects of the GGM diet on gut microbiome and long-term health.

BACKGROUND: Animal models implicate FGF-23 (fibroblast growth factor-23) as a direct contributor to adverse cardiorenal interactions such as sodium avidity, diuretic resistance, and neurohormonal activation, but this has not been conclusively demonstrated in humans. Therefore, we aimed to evaluate whether FGF-23 is associated with parameters of cardiorenal dysfunction in humans with heart failure, independent of confounding factors. METHODS: One hundred ninety-nine outpatients with heart failure undergoing diuretic treatment at the Yale Transitional Care Center were enrolled and underwent blood collection, and urine sampling before and after diuretics. RESULTS: FGF-23 was associated with several metrics of disease severity such as higher home loop diuretic dose and NT-proBNP (N-terminal pro-B-type natriuretic peptide), and lower estimated glomerular filtration rate, serum chloride, and serum albumin. Multivariable analysis demonstrated no statistically significant association between FGF-23 and sodium avidity measured by fractional excretion of sodium, or proximal or distal tubular sodium reabsorption, either before diuretic administration or at peak diuresis (P≥0.11 for all). Likewise, FGF-23 was not independently associated with parameters of diuretic resistance (diuretic excretion, cumulative urine and sodium output, and loop diuretic efficiency [P≥0.33 for all]) or neurohormonal activation (plasma or urine renin [P≥0.36 for all]). Moreover, the upper boundary of the 95% CI of all the partial correlations were ≤0.30, supporting the lack of meaningful correlations. FGF-23 was not associated with mortality in multivariable analysis (P=0.44). CONCLUSIONS: FGF-23 was not meaningfully associated with any cardiorenal parameter in patients with heart failure. While our methods cannot rule out a small effect, FGF-23 is unlikely to be a primary driver of cardiorenal interactions.

Sodium MR imaging has the potential to complement routine proton MR imaging examinations with the goal of improving diagnosis, disease characterization, and clinical monitoring in neurologic diseases. In the past, the utility and exploration of sodium MR imaging as a valuable clinical tool have been limited due to the extremely low MR signal, but with recent improvements in imaging techniques and hardware, sodium MR imaging is on the verge of becoming clinically realistic for conditions that include brain tumors, ischemic stroke, and epilepsy. In this review, we briefly describe the fundamental physics of sodium MR imaging tailored to the neuroradiologist, focusing on the basics necessary to understand factors that play into making sodium MR imaging feasible for clinical settings and describing current controversies in the field. We will also discuss the current state of the field and the potential future clinical uses of sodium MR imaging in the diagnosis, phenotyping, and therapeutic monitoring in neurologic diseases.

ObjectiveFluid replacement to correct dehydration, acidosis, and electrolyte abnormalities is the cornerstone of treatment for diabetic ketoacidosis (DKA), but little is known about optimal fluid infusion rates and electrolyte content. The objective of this study was to evaluate whether different fluid protocols affect the rate of normalization of biochemical derangements during DKA treatment.Research design and methodsThe current analysis involved moderate or severe DKA episodes (n = 714) in children age

Purpose of reviewThe dietary reference intake (DRI) for sodium has been highly debated with persuasive and elegant arguments made for both population sodium reduction and for maintenance of the status quo. After the 2015 Dietary Guidelines Advisory Committee (DGAC) report was published, controversy ensued, and by Congressional mandate, the sodium DRIs were updated in 2019. The 2019 DRIs defined adequate intake (AI) levels by age-sex groups that are largely consistent with the DRIs for sodium that were published in 2005. Given the overall similarities between the 2005 and 2019 DRIs, one may wonder how the recently published research on sodium and health outcomes was considered in determining the DRIs, particularly, the recent studies from very large observational cohort studies. We aim to address this concern and outline the major threats to ascertaining valid estimates of the relationship between dietary sodium and health outcomes in observational cohort studies. We use tools from modern epidemiology to demonstrate how unexpected and inconsistent findings in these relationships may emerge. We use directed acyclic graphs to illustrate specific examples in which biases may occur.Recent findingsWe identified the following key threats to internal validity: poorly defined target intervention, poorly measured sodium exposure, unmeasured or residual confounding, reverse causality, and selection bias. Researchers should consider these threats to internal validity while developing research questions and throughout the research process. For the DRIs to inform real-world interventions relating to sodium reduction, it is recommended that more specific research questions be asked that can clearly define potential interventions of interest.

Coagulation factor VIIa (FVIIa) consists of a γ-carboxyglutamic acid (GLA) domain, two epidermal growth factor-like (EGF) domains and a protease domain. FVIIa binds three Mg2+ ions and four Ca2+ ions in the GLA domain, one Ca2+ ion in the EGF1 domain and one Ca2+ ion in the protease domain. Further, FVIIa contains an Na+ site in the protease domain. Since Na+ and water share the same number of electrons, Na+ sites in proteins are difficult to distinguish from waters in X-ray structures. Here, to verify the Na+ site in FVIIa, the structure of the FVIIa-soluble tissue factor (TF) complex was solved at 1.8 Å resolution containing Mg2+, Ca2+ and Rb+ ions. In this structure, Rb+ replaced two Ca2+ sites in the GLA domain and occupied three non-metal sites in the protease domain. However, Rb+ was not detected at the expected Na+ site. In kinetic experiments, Na+ increased the amidolytic activity of FVIIa towards the synthetic substrate S-2288 (H-D-Ile-Pro-Arg-p-nitroanilide) by ∼20-fold; however, in the presence of Ca2+, Na+ had a negligible effect. Ca2+ increased the hydrolytic activity of FVIIa towards S-2288 by ∼60-fold in the absence of Na+ and by ∼82-fold in the presence of Na+. In molecular-dynamics simulations, Na+ stabilized the two Na+-binding loops (the 184-loop and 220-loop) and the TF-binding region spanning residues 163-180. Ca2+ stabilized the Ca2+-binding loop (the 70-loop) and Na+-binding loops but not the TF-binding region. Na+ and Ca2+ together stabilized both the Na+-binding and Ca2+-binding loops and the TF-binding region. Previously, Rb+ has been used to define the Na+ site in thrombin; however, it was unsuccessful in detecting the Na+ site in FVIIa. A conceivable explanation for this observation is provided.

PurposeTo implement an accelerated MR-acquisition method allowing to map T2∗ relaxation and absolute concentration of sodium within skeletal muscles at 3T.MethodsA fast-UTE-2D density-weighted concentric-ring-trajectory 23 Na-MRSI technique was used to acquire 64 time points of FID with a spectral bandwidth of 312.5 Hz with an in-plane resolution of 2.5 × 2.5 mm2 in ~15 min. The fast-relaxing 23 Na signal was localized with a single-shot, inversion-recovery-based, non-echo (SIRENE) outer volume suppression (OVS) method. The sequence was verified using simulation and phantom studies before implementing it in human calf muscles. To evaluate the 2D-SIRENE-MRSI (UTE = 0.55 ms) imaging performance, it was compared to a 3D-MRI (UTE = 0.3 ms) sequence. Both data sets were acquired within 2 same-day sessions to assess repeatability. The T2∗ values were fitted voxel-by-voxel using a biexponential model for the 2D-MRSI data. Finally, intra-subject coefficients of variation (CV) were estimated.ResultsThe MRSI-FID data allowed us to map the fast and slow components of T2∗ in the calf muscles. The spatial distributions of 23 Na concentration for both MRSI and 3D-MRI acquisitions were significantly correlated (P < .001). The test-retest analysis rendered high repeatability for MRSI with a CV of 5%. The mean T2Fast∗ in muscles was 0.7 ± 0.1 ms (contribution fraction = 37%), whereas T2Slow∗ was 13.2 ± 0.2 ms (63%). The mean absolute muscle 23 Na concentration calculated from the T2∗ -corrected data was 28.6 ± 3.3 mM.ConclusionThe proposed MRSI technique is a reliable technique to map sodium's absolute concentration and T2∗ within a clinically acceptable scan time at 3T.

BackgroundUromodulin modulates the sodium-potassium-two-chloride transporter in the thick ascending limb of the loop of Henle, and its overexpression in murine models leads to salt-induced hypertension. We hypothesized that individuals with higher baseline levels of urine uromodulin would have a greater increase in systolic blood pressure (SBP) for the same increase in sodium compared with those with lower uromodulin levels.MethodsWe used data from 157 subjects randomized to the control diet of the Dietary Approaches to Stop Hypertension (DASH)-Sodium trial who were assigned to 30 days of low (1,500 mg/d), medium (2,400 mg/d), and high salt (3,300 mg/d) diets in random order. Blood pressure was measured prerandomization and then weekly during each feeding period. We evaluated the association of prerandomization urine uromodulin with change in SBP between diets, as measured at the end of each feeding period, using multivariable linear regression.ResultsBaseline urine uromodulin stratified by tertiles was ≤17.64, 17.65-31.97, and ≥31.98 µg/ml. Across the tertiles, there were no significant differences in SBP at baseline, nor was there a differential effect of sodium diet on SBP across tertiles (low to high, P = 0.81). After adjusting for age, sex, body mass index, and race, uromodulin levels were not significantly associated with SBP change from low to high sodium diet (P = 0.42).ConclusionsIn a randomized trial of different levels of salt intake, higher urine uromodulin levels were not associated with a greater increase in blood pressure in response to high salt intake.

BackgroundPostdischarge mortality following hospitalization for heart failure with reduced ejection fraction (HFrEF) has remained high and unchanged over the past 2 decades, despite effective therapies for HFrEF. We aimed to explore whether these patterns could in part be explained by changes in longitudinal risk profile and HF severity over time.MethodsAmong patients hospitalized for HF in the GWTG-HF registry from January 2005 to December 2018 with available data, we evaluated GWTG-HF and ADHERE risk scores, observing in-hospital mortality per-year. The risk profiles and outcomes were described overall and by subgroups based on ejection fraction (EF), diabetes mellitus (DM), sex, and age.ResultsOverall, 335,735 patients were included (50% HFrEF, 46% DM, 48% female, mean age 74 years). In-hospital mortality increased by 2.0% per year from 2005 to 2018. There was no significant change in mean GWTG-HF risk score overall or when stratified by EF groups (P = 0.46 HFrEF, p = 0.26 HF mid-range EF [HFmrEF], and P = 0.72 HF preserved EF [HFpEF]), age, sex, or presence of DM. The observed/expected ratio based on the GWTG-HF risk score was 0.93 (0.91-0.96), 0.83 (0.77-0.90), 0.92 (0.89-95) for HFrEF, HFmrEF, and HFpEF, respectively. Similar findings were seen when risk was assessed using ADHERE risk score.ConclusionsThere were no significant changes in average risk profiles among hospitalized HF patients over the study duration. These data do not support the notion that worsening risk profile explains the lack of improved outcomes despite therapeutic advances, underscoring the importance of aggressive implementation of guideline-recommended therapies and investigation of novel treatments.

Avocados are a nutrient-dense plant-food, but limited trial-derived evidence exists about the effects of avocado intake on family nutritional status. We investigated the impact of two levels of avocado allotment, plus a standard nutrition education intervention on the nutritional status of Hispanic/Latino families. Seventy-two families consisting of at least three members of ≥5 years of age and residing in the same home, free of severe chronic disease, not on specific diets, and self-identified of Hispanic heritage, were randomized to one of two levels of avocado allotment (low = 3/week/family or high = 14/week/family) for 6 months plus 12 bi-weekly nutrition education sessions. The primary outcomes included change in a family's total energy and macro- and micronutrient intakes. Primary analysis was intention-to-treat with unpaired, two-sided t-tests to assess mean changes between groups at 6 months. At 6 months, the high avocado allotment group had a significant reduction in energy intake, carbohydrate, animal and vegetable protein, saturated and polyunsaturated fat, calcium, magnesium, sodium, potassium, iron, and vitamin D intakes (all p < 0.05). A high allotment of avocados significantly reduced self-reported energy intake by 29% kcal/family/day, compared to a 3% kcal/family/day reduction in families who received a low allotment. Culturally-appropriate plant-food interventions may alter the nutritional status of at-risk families.

BackgroundInterstitial fibrosis (IF) on kidney biopsy is one of the most potent risk factors for kidney disease progression. The furosemide stress test (FST) is a validated tool that predicts the severity of acute kidney injury (especially at 2 h) in critically ill patients. Since furosemide is secreted through the kidney tubules, the response to FST represents the tubular secretory capacity. To our knowledge there is no data on the correlation between functional tubular capacity assessed by the FST with IF on kidney biopsies from patients with chronic kidney disease (CKD). The aim of this study was to determine the association between urine output (UO), Furosemide Excreted Mass (FEM) and IF on kidney biopsies after a FST.MethodsThis study included 84 patients who underwent kidney biopsy for clinical indications and a FST. The percentage of fibrosis was determined by morphometry technique and reviewed by a nephropathologist. All patients underwent a FST prior to the biopsy. Urine volume and urinary sodium were measured in addition to urine concentrations of furosemide at different times (2, 4 and 6 h). We used an established equation to determine the FEM. Values were expressed as mean, standard deviation or percentage and Pearson Correlation.ResultsThe mean age of the participants was 38 years and 44% were male. The prevalence of diabetes mellitus, hypertension and diuretic use was significantly higher with more advanced degree of fibrosis. Nephrotic syndrome and acute kidney graft dysfunction were the most frequent indications for biopsy. eGFR was inversely related to the degree of fibrosis. Subjects with the highest degree of fibrosis (grade 3) showed a significant lower UO at first hour of the FST when compared to lower degrees of fibrosis (p = 0.015). Likewise, the total UO and the FEM was progressively lower with higher degrees of fibrosis. An inversely linear correlation between FEM and the degree of fibrosis (r = - 0.245, p = 0.02) was observed.ConclusionsOur findings indicate that interstitial fibrosis correlates with total urine output and FEM. Further studies are needed to determine if UO and FST could be a non-invasive tool to evaluate interstitial fibrosis.Trial registrationClinicalTrials.gov NCT02417883.

Sodium oxybate (SO), the sodium salt of γ-hydroxybutyric acid, is one of the primary pharmacologic agents used to treat excessive sleepiness, disturbed nighttime sleep, and cataplexy in narcolepsy. The sodium content of SO ranges from 550 to 1640 mg at 3-9 g, given in two equal nightly doses. Clinicians are advised to consider daily sodium intake in patients with narcolepsy who are treated with SO and have comorbid disorders associated with increased cardiovascular (CV) risk, in whom sodium intake may be a concern. It remains unclear whether all patients with narcolepsy treated with SO should modify or restrict their sodium intake. No data are currently available specific to the sodium content or threshold of SO at which patients might experience increased CV risk. To appraise attributable risk, critical evaluation of the literature was conducted to examine the relationship between CV risk and sodium intake, narcolepsy, and SO exposure. The findings suggest that increased CV risk is associated with extremes of daily sodium intake, and that narcolepsy is associated with comorbidities that may increase CV risk in some patients. However, data from studies regarding SO use in patients with narcolepsy have shown a very low frequency of CV side effects (eg, hypertension) and no overall association with CV risk. In the absence of data that specifically address CV risk with SO based on its sodium content, the clinical evidence to date suggests that SO treatment does not confer additional CV risk in patients with narcolepsy.

Background We compared the relationship of past and contemporary sodium (Na) intake with cardiometabolic biomarkers. Methods and Results A total of 1191 participants data from a randomized controlled trial in coastal Bangladesh were analyzed. Participants provided 24-hour urine Na (24UNa) data for 5 monthly visits. Their fasting blood glucose, total cholesterol, triglycerides, high-density lipoprotein, blood pressure, and 24-hour urine protein were measured at the fifth visit. Participants mean 24UNa over the first 4 visits was the past Na, and 24UNa of the fifth visit was the contemporary Na intake. We estimated the prevalence ratios of elevated cardiometabolic biomarkers and metabolic syndrome across 24UNa tertiles by multilevel logistic regression using participant-, household-, and community-level random intercepts. Models were adjusted for age, sex, body mass index, smoking, physical activity, alcohol consumption, sleep hours, religion, and household wealth. Compared with participants in tertile 1 of past urine Na, those in tertile 3 had 1.46 (95% CI, 1.08-1.99) times higher prevalence of prediabetes or diabetes mellitus, 5.49 (95% CI, 2.73-11.01) times higher prevalence of large waist circumference, and 1.60 (95% CI, 1.04-2.46) times higher prevalence of metabolic syndrome. Compared with participants in tertile 1 of contemporary urine Na, those in tertile 3 had 1.93 (95% CI, 1.24-3.00) times higher prevalence of prediabetes or diabetes mellitus, 3.14 (95% CI, 1.45-6.83) times higher prevalence of proteinuria, and 2.23 (95% CI, 1.34-3.71) times higher prevalence of large waist circumference. Conclusions Both past and contemporary Na intakes were associated with higher cardiometabolic disease risk.

BackgroundFalls and hip fractures among older people are associated with high morbidity and mortality. Hyponatraemia may be a risk for falls/hip fractures, but the effect of hyponatraemia duration is not well understood.AimsTo evaluate individuals with periods of sub-acute and chronic hyponatraemia on subsequent risk for serious falls and/or hip fractures.MethodsRetrospective cohort study in the period 1 January 1998 to 14 June 2016 within an integrated health system of individuals aged ≥55 years with ≥2 outpatient serum sodium measurements. Hyponatraemia was defined as sodium

We have used recent measurements of mammalian cone light responses and voltage-gated currents to calculate cone ATP utilization and compare it to that of rods. The largest expenditure of ATP results from ion transport, particularly from removal of Na+ entering outer segment light-dependent channels and inner segment hyperpolarization-activated cyclic nucleotide-gated channels, and from ATP-dependent pumping of Ca2+ entering voltage-gated channels at the synaptic terminal. Single cones expend nearly twice as much energy as single rods in darkness, largely because they make more synapses with second-order retinal cells and thus must extrude more Ca2+ In daylight, cone ATP utilization per cell remains high because cones never remain saturated and must continue to export Na+ and synaptic Ca2+ even in bright illumination. In mouse and human retina, rods greatly outnumber cones and consume more energy overall even in background light. In primates, however, the high density of cones in the fovea produces a pronounced peak of ATP utilization, which becomes particularly prominent in daylight and may make this part of the retina especially sensitive to changes in energy availability.

Background Several small-scale animal studies have suggested that gut microbiota and blood pressure (BP) are linked. However, results from human studies remain scarce and conflicting. We wanted to elucidate the multivariable-adjusted association between gut metagenome and BP in a large, representative, well-phenotyped population sample. We performed a focused analysis to examine the previously reported inverse associations between sodium intake and Lactobacillus abundance and between Lactobacillus abundance and BP. Methods and Results We studied a population sample of 6953 Finns aged 25 to 74 years (mean age, 49.2±12.9 years; 54.9% women). The participants underwent a health examination, which included BP measurement, stool collection, and 24-hour urine sampling (N=829). Gut microbiota was analyzed using shallow shotgun metagenome sequencing. In age- and sex-adjusted models, the α (within-sample) and β (between-sample) diversities of taxonomic composition were strongly related to BP indexes (P

Activation of mechanosensitive ion channels underlies a variety of fundamental physiological processes that require sensation of mechanical force. Different mechanosensitive channels adapt distinctive structures and mechanotransduction mechanisms to fit their biological roles. How mechanosensitive channels work, especially in animals, has been extensively studied in the past decade. Here we review key findings in the functional and structural characterizations of these channels and highlight the structural features relevant to the mechanotransduction mechanism of each specific channel.

Kidney size and glomerular filtration rate (GFR) often increase with the onset of diabetes, and elevated GFR is a risk factor for the development of diabetic kidney disease. Hyperfiltration mainly occurs in response to signals passed from the tubule to the glomerulus: high levels of glucose in the glomerular filtrate drive increased reabsorption of glucose and sodium by the sodium-glucose cotransporters SGLT2 and SGLT1 in the proximal tubule. Passive reabsorption of chloride and water also increases. The overall capacity for proximal reabsorption is augmented by growth of the proximal tubule, which (alongside sodium-glucose cotransport) further limits urinary glucose loss. Hyperreabsorption of sodium and chloride induces tubuloglomerular feedback from the macula densa to increase GFR. In addition, sodium-glucose cotransport by SGLT1 on macula densa cells triggers the production of nitric oxide, which also contributes to glomerular hyperfiltration. Although hyperfiltration restores sodium and chloride excretion it imposes added physical stress on the filtration barrier and increases the oxygen demand to drive reabsorption. Tubular growth is associated with the development of a senescence-like molecular signature that sets the stage for inflammation and fibrosis. SGLT2 inhibitors attenuate the proximal reabsorption of sodium and glucose, normalize tubuloglomerular feedback signals and mitigate hyperfiltration. This tubule-centred model of diabetic kidney physiology predicts the salutary effect of SGLT2 inhibitors on hard renal outcomes, as shown in large-scale clinical trials.

The Na+/I- symporter (NIS), the plasma membrane protein that actively transports I- (stoichiometry 2Na+:1I-) in thyroid physiology and radioiodide-based thyroid cancer treatment, also transports the environmental pollutant perchlorate (stoichiometry 1Na+:1ClO4-), which competes with I- for transport. Until now, the mechanism by which NIS transports different anion substrates with different stoichiometries has remained unelucidated. We carried out transport measurements and analyzed these using a statistical thermodynamics-based equation and electrophysiological experiments to show that the different stoichiometry of ClO4- transport is due to ClO4- binding to a high-affinity non-transport allosteric site that prevents Na+ from binding to one of its two sites. Furthermore, low concentrations of ClO4- inhibit I- transport not only by competition but also, critically, by changing the stoichiometry of I- transport to 1:1, which greatly reduces the driving force. The data reveal that ClO4- pollution in drinking water is more dangerous than previously thought.

Na/Ca exchange is the dominant calcium (Ca) efflux mechanism in cardiac myocytes. Although our knowledge of exchanger function (NCX1 in the heart) was originally established using biochemical and electrophysiological tools such as cardiac sarcolemmal vesicles and the giant patch technique [1-4], many advances in our understanding of the physiological/pathophysiological roles of NCX1 in the heart have been obtained using a suite of genetically modified mice. Early mouse studies focused on modification of expression levels of NCX1 in the ventricles, with transgenic overexpressors, global NCX1 knockout (KO) mice (which were embryonic lethal if homozygous), and finally ventricular-specific NCX1 KO [5-12]. We found, to our surprise, that ventricular cardiomyocytes lacking NCX1 can survive and function by engaging a clever set of adaptations to minimize Ca entry, while maintaining contractile function through an increase in excitation-contraction (EC) coupling gain [5,6,13]. Having studied ventricular NCX1 ablation in detail, we more recently focused on elucidating the role of NCX1 in the atria through altering NCX1 expression. Using a novel atrial-specific NCX1 KO mouse, we found unexpected changes in atrial cell morphology and calcium handling, together with dramatic alterations in the function of sinoatrial node (SAN) pacemaker activity. In this review, we will discuss these findings and their implications for cardiac disease.

RationaleHypokalemia occurs in up to 20% of hospitalized patients and is associated with increased incidence of ventricular and atrial fibrillation. It is unclear whether these differing types of arrhythmia result from direct and perhaps distinct effects of hypokalemia on cardiomyocytes.ObjectiveTo investigate proarrhythmic mechanisms of hypokalemia in ventricular and atrial myocytes.Methods and resultsExperiments were performed in isolated rat myocytes exposed to simulated hypokalemia conditions (reduction of extracellular [K+] from 5.0 to 2.7 mmol/L) and supported by mathematical modeling studies. Ventricular cells subjected to hypokalemia exhibited Ca2+ overload and increased generation of both spontaneous Ca2+ waves and delayed afterdepolarizations. However, similar Ca2+-dependent spontaneous activity during hypokalemia was only observed in a minority of atrial cells that were observed to contain t-tubules. This effect was attributed to close functional pairing of the Na+-K+ ATPase and Na+-Ca2+ exchanger proteins within these structures, as reduction in Na+ pump activity locally inhibited Ca2+ extrusion. Ventricular myocytes and tubulated atrial myocytes additionally exhibited early afterdepolarizations during hypokalemia, associated with Ca2+ overload. However, early afterdepolarizations also occurred in untubulated atrial cells, despite Ca2+ quiescence. These phase-3 early afterdepolarizations were rather linked to reactivation of nonequilibrium Na+ current, as they were rapidly blocked by tetrodotoxin. Na+ current-driven early afterdepolarizations in untubulated atrial cells were enabled by membrane hyperpolarization during hypokalemia and short action potential configurations. Brief action potentials were in turn maintained by ultra-rapid K+ current (IKur); a current which was found to be absent in tubulated atrial myocytes and ventricular myocytes.ConclusionsDistinct mechanisms underlie hypokalemia-induced arrhythmia in the ventricle and atrium but also vary between atrial myocytes depending on subcellular structure and electrophysiology.

Acute cardiac hypoxia produces life-threatening elevations in late sodium current (ILATE) in the human heart. Here, we show the underlying mechanism: hypoxia induces rapid SUMOylation of NaV1.5 channels so they reopen when normally inactive, late in the action potential. NaV1.5 is SUMOylated only on lysine 442, and the mutation of that residue, or application of a deSUMOylating enzyme, prevents hypoxic reopenings. The time course of SUMOylation of single channels in response to hypoxia coincides with the increase in ILATE, a reaction that is complete in under 100 s. In human cardiac myocytes derived from pluripotent stem cells, hypoxia-induced ILATE is confirmed to be SUMO-dependent and to produce action potential prolongation, the pro-arrhythmic change observed in patients.

Voltage-gated ion channels endow membranes with excitability and the means to propagate action potentials that form the basis of all neuronal signaling. We determined the structure of a voltage-gated sodium channel, two-pore channel 3 (TPC3), which generates ultralong action potentials. TPC3 is distinguished by activation only at extreme membrane depolarization (V50 ∼ +75 mV), in contrast to other TPCs and NaV channels that activate between -20 and 0 mV. We present electrophysiological evidence that TPC3 voltage activation depends only on voltage sensing domain 2 (VSD2) and that each of the three gating arginines in VSD2 reduces the activation threshold. The structure presents a chemical basis for sodium selectivity, and a constricted gate suggests a closed pore consistent with extreme voltage dependence. The structure, confirmed by our electrophysiology, illustrates the configuration of a bona fide resting state voltage sensor, observed without the need for any inhibitory ligand, and independent of any chemical or mutagenic alteration.

Sweat sensors introduced in recent years have targeted a variety of sweat features and biomarkers for non-invasive health monitoring. Amongst these targets, reliable monitoring of sweat rate is crucial due to its modulation of sweat analyte concentrations and its intrinsic significance to numerous medical and physiological health conditions. Here we present a sweat rate sensor structure comprising of electrodes with interdigitated fingers in a microfluidic channel. Each time the accumulating sweat impinges on an electrode finger, the sensor reports a jump in admittance that can be simply and efficiently counted to estimate sweat rate, overcoming selectivity limitations of previously reported sweat rate sensors. We further integrate an impedimetric sensor for measuring total ionic charge concentration and an electrochemical Na+ sensor, together creating a multi-modal system for analyzing fluid and electrolyte secretion. We demonstrate how low analyte diffusion rates through this microfluidic device allow for multi-purpose sensor function, including utilizing the sweat rate sensor signal to corroborate total ionic sensor measurements. This cross-verification capability ensures data integrity in real time, satisfying a vital consideration for personalized healthcare technologies. We use the presented patch for continuous analysis of sweat rate, total ionic charge concentration, and Na+ concentration during exercise, while demonstrating how multi-modal cross-verification brings new trust to sensor readings.

Sweat sensors introduced in recent years have targeted a variety of sweat features and biomarkers for non-invasive health monitoring. Amongst these targets, reliable monitoring of sweat rate is crucial due to its modulation of sweat analyte concentrations and its intrinsic significance to numerous medical and physiological health conditions. Here we present a sweat rate sensor structure comprising of electrodes with interdigitated fingers in a microfluidic channel. Each time the accumulating sweat impinges on an electrode finger, the sensor reports a jump in admittance that can be simply and efficiently counted to estimate sweat rate, overcoming selectivity limitations of previously reported sweat rate sensors. We further integrate an impedimetric sensor for measuring total ionic charge concentration and an electrochemical Na+ sensor, together creating a multi-modal system for analyzing fluid and electrolyte secretion. We demonstrate how low analyte diffusion rates through this microfluidic device allow for multi-purpose sensor function, including utilizing the sweat rate sensor signal to corroborate total ionic sensor measurements. This cross-verification capability ensures data integrity in real time, satisfying a vital consideration for personalized healthcare technologies. We use the presented patch for continuous analysis of sweat rate, total ionic charge concentration, and Na+ concentration during exercise, while demonstrating how multi-modal cross-verification brings new trust to sensor readings.

Poor vitamin D status is associated with a higher relapse rate and earlier disability in multiple sclerosis. Based on these associations, patients with multiple sclerosis are frequently supplemented with the vitamin D precursor cholecalciferol, although it is unclear whether this regimen is of therapeutic benefit. To model consequences of this common practice, mice were fed for more than 3 months with a low, medium or high dose of cholecalciferol, representative of vitamin D deficiency, modest and disproportionally high supplementation, respectively, in patients with multiple sclerosis. Compared to vitamin D-deprived mice, its moderate supplementation reduced the severity of subsequent experimental autoimmune encephalomyelitis, which was associated with an expansion of regulatory T cells. Direct exposure of murine or human T cells to vitamin D metabolites inhibited their activation. In contrast, mice with 25-(OH) vitamin D levels above 200 nmol/l developed fulminant experimental autoimmune encephalomyelitis with massive CNS infiltration of activated myeloid cells, Th1 and Th17 cells. When dissecting this unexpected outcome, we observed that high, but not medium dose vitamin D had caused mild hypercalcaemia, which rendered T cells more prone to pro-inflammatory activation. Exposing murine or human T cells to equivalent calcium concentrations in vitro enhanced its influx, triggering activation, upregulation of pro-inflammatory gene products and enhanced transmigration across a blood-brain barrier model. These findings suggest that vitamin D at moderate levels may exert a direct regulatory effect, while continuous high dose vitamin D treatment could trigger multiple sclerosis disease activity by raising mean levels of T-cell excitatory calcium.

Recent technological advancements in wearable sensors have made it easier to detect sweat components, but our limited understanding of sweat restricts its application. A critical bottleneck for temporal and regional sweat analysis is achieving uniform, high-throughput fabrication of sweat sensor components, including microfluidic chip and sensing electrodes. To overcome this challenge, we introduce microfluidic sensing patches mass fabricated via roll-to-roll (R2R) processes. The patch allows sweat capture within a spiral microfluidic for real-time measurement of sweat parameters including [Na+], [K+], [glucose], and sweat rate in exercise and chemically induced sweat. The patch is demonstrated for investigating regional sweat composition, predicting whole-body fluid/electrolyte loss during exercise, uncovering relationships between sweat metrics, and tracking glucose dynamics to explore sweat-to-blood correlations in healthy and diabetic individuals. By enabling a comprehensive sweat analysis, the presented device is a crucial tool for advancing sweat testing beyond the research stage for point-of-care medical and athletic applications.

Sodium-glucose cotransporter (SGLT) inhibitors are new oral antidiabetes medications shown to effectively reduce glycated hemoglobin (A1C) and glycemic variability, blood pressure, and body weight without intrinsic properties to cause hypoglycemia in people with type 1 diabetes. However, recent studies, particularly in individuals with type 1 diabetes, have demonstrated increases in the absolute risk of diabetic ketoacidosis (DKA). Some cases presented with near-normal blood glucose levels or mild hyperglycemia, complicating the recognition/diagnosis of DKA and potentially delaying treatment. Several SGLT inhibitors are currently under review by the U.S. Food and Drug Administration and European regulatory agencies as adjuncts to insulin therapy in people with type 1 diabetes. Strategies must be developed and disseminated to the medical community to mitigate the associated DKA risk. This Consensus Report reviews current data regarding SGLT inhibitor use and provides recommendations to enhance the safety of SGLT inhibitors in people with type 1 diabetes.