SGLT2 Inhibitor-Associated Ketoacidosis vs Type 1 Diabetes-Associated Ketoacidosis.

This cohort study examines the natural history and response to treatment of sodium glucose cotransporter 2 (SGLT2) inhibitor­associated ketoacidosis compared with that of type 1 diabetes­associated ketoacidosis.

Approach the Patient With Obstructive Sleep Apnea and Obesity.

Obstructive sleep apnea (OSA) and obesity are highly prevalent and bidirectionally associated. OSA is underrecognized, however, particularly in women. By mechanisms that overlap with those of obesity, OSA increases the risk of developing, or having poor outcomes from, comorbid chronic disorders and impairs quality of life. Using 2 illustrative cases, we discuss the relationships between OSA and obesity with type 2 diabetes, dyslipidemia, cardiovascular disease, cognitive disturbance, mood disorders, lower urinary tract symptoms, sexual function, and reproductive disorders. The differences in OSA between men and women, the phenotypic variability of OSA, and comorbid sleep disorders are highlighted. When the probability of OSA is high due to consistent symptoms, comorbidities, or both, a diagnostic sleep study is advisable. Continuous positive airway pressure or mandibular advancement splints improve symptoms. Benefits for comorbidities are variable depending on nightly duration of use. By contrast, weight loss and optimization of lifestyle behaviors are consistently beneficial.

Tonabersat Significantly Reduces Disease Progression in an Experimental Mouse Model of Multiple Sclerosis.

Multiple sclerosis (MS) is a neurodegenerative disease marked by chronic neuroinflammation thought to be mediated by the inflammasome pathway. Connexin 43 (Cx43) hemichannels contribute to the activation of the inflammasome through the release of adenosine triphosphate (ATP) inflammasome activation signals. The objective of the study was to evaluate if the Cx43 hemichannel blocker, tonabersat, is effective in modulating the inflammatory response and reducing disability in the myelin oligodendrocyte glycoprotein 35-55-induced experimental autoimmune encephalomyelitis (MOG35-55 EAE) model of MS. Here, we show that the Cx43 hemichannel blocking drug, tonabersat, significantly reduced expression of neuroinflammatory markers for microglial activation (ionized calcium-binding adapter molecule 1 (Iba1)) and astrogliosis (glial fibrillary acidic protein (GFAP)) while preserving myelin basic protein (MBP) expression levels in the corpus callosum, motor cortex, and striatum regions of the brain in MOG35-55 EAE mice. Reduced NOD-like receptor protein 3 (NLRP3) inflammasome complex assembly and Caspase-1 activation confirmed the drug's mode of action. MOG35-55 EAE mice showed clinical signs of MS, but MOG35-55 EAE mice treated with tonabersat retained behavior closer to normal. These data suggest that clinical trial phase IIb-ready tonabersat may merit further investigation as a promising candidate for MS treatment.

Additional challenges in reaching hepatitis C elimination goals in Germany due to the COVID-19 pandemic - descriptive analysis of drug prescription data from January 2018 to June 2021.

Effectively treating hepatitis C viral (HCV) infections prevents sequelae and onward transmission. In Germany, HCV drug prescriptions have declined since 2015. During the COVID-19 pandemic, lockdowns impacted the access to HCV care services and HCV treatment. We assessed if the COVID-19 pandemic further decreased treatment prescriptions in Germany. We built log-linear models with monthly HCV drug prescription data from pharmacies from January 2018 - February 2020 (pre-pandemic) to calculate expected prescriptions for March 2020-June 2021 and different pandemic phases. We calculated monthly prescription trends per pandemic phase using log-linear models. Further, we scanned all data for breakpoints. We stratified all data by geographic region and clinical settings. The number of DAA prescriptions in 2020 (n = 16,496, -21%) fell below those of 2019 (n = 20,864) and 2018 (n = 24,947), continuing the declining trend from previous years. The drop in prescriptions was stronger from 2019 to 2020 (-21%) than from 2018 to 2020 (-16%). Observed prescriptions met predictions from March 2020 to June 2021, but not during the first COVID-19 wave (March 2020-May 2020). Prescriptions increased during summer 2020 (June 2020-September 2020) and fell below the pre-pandemic numbers during the following pandemic waves (October 2020 - February 2021 and March 2021 - June 2021). Breakpoints during the first wave indicate that prescriptions plummeted overall, in all clinical settings and in four of six geographic regions. Both, outpatient clinics and private practices prescribed overall as predicted. However, outpatient hospital clinics prescribed 17-39% less than predicted during the first pandemic wave. HCV treatment prescriptions declined but stayed within the lower realms of predicted counts. The strongest decline during the first pandemic wave indicates a temporary HCV treatment gap. Later, prescriptions matched predictions despite of pronounced decreases during the second and third waves. In future pandemics, clinics and private practices need to adapt more rapidly to maintain a continuous access to care. In addition, political strategies should focus more on continuously providing essential medical care during periods of restricted access due to infectious disease outbreaks. The observed decrease in HCV treatment may challenge reaching the HCV elimination goals in Germany by 2030.

COVID-19 Mortality and Progress Toward Vaccinating Older Adults - World Health Organization, Worldwide, 2020-2022.

After the emergence of SARS-CoV-2 in late 2019, transmission expanded globally, and on January 30, 2020, COVID-19 was declared a public health emergency of international concern.* Analysis of the early Wuhan, China outbreak (1), subsequently confirmed by multiple other studies (2,3), found that 80% of deaths occurred among persons aged ≥60 years. In anticipation of the time needed for the global vaccine supply to meet all needs, the World Health Organization (WHO) published the Strategic Advisory Group of Experts on Immunization (SAGE) Values Framework and a roadmap for prioritizing use of COVID-19 vaccines in late 2020 (4,5), followed by a strategy brief to outline urgent actions in October 2021.† WHO described the general principles, objectives, and priorities needed to support country planning of vaccine rollout to minimize severe disease and death. A July 2022 update to the strategy brief§ prioritized vaccination of populations at increased risk, including older adults,¶ with the goal of 100% coverage with a complete COVID-19 vaccination series** for at-risk populations. Using available public data on COVID-19 mortality (reported deaths and model estimates) for 2020 and 2021 and the most recent reported COVID-19 vaccination coverage data from WHO, investigators performed descriptive analyses to examine age-specific mortality and global vaccination rollout among older adults (as defined by each country), stratified by country World Bank income status. Data quality and COVID-19 death reporting frequency varied by data source; however, persons aged ≥60 years accounted for >80% of the overall COVID-19 mortality across all income groups, with upper- and lower-middle-income countries accounting for 80% of the overall estimated excess mortality. Effective COVID-19 vaccines were authorized for use in December 2020, with global supply scaled up sufficiently to meet country needs by late 2021 (6). COVID-19 vaccines are safe and highly effective in reducing severe COVID-19, hospitalizations, and mortality (7,8); nevertheless, country-reported median completed primary series coverage among adults aged ≥60 years only reached 76% by the end of 2022, substantially below the WHO goal, especially in middle- and low-income countries. Increased efforts are needed to increase primary series and booster dose coverage among all older adults as recommended by WHO and national health authorities.

Peri-colonoscopy Implications of Sodium-Glucose Cotransporter-2 Inhibitor Therapy: A Mini-review of Available Evidence.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a class of oral glucose-lowering agents commonly used for the treatment of type 2 diabetes. With increased use, there has been an increase in the incidence of the rare but life-threatening complication of euglycemic diabetic ketoacidosis. A common but underappreciated precipitant is colonoscopy. In this work, we outline the pathophysiology of the interaction between colonoscopy and SGLT2i use, the evidence regarding SGLT2i use in the periprocedural setting and Australian Diabetes Society guidelines.

Corticosteroid-binding globulin (CBG): spatiotemporal distribution of cortisol in sepsis.

Corticosteroid-binding globulin (CBG) is a 50-60 kDa circulating glycoprotein with high affinity for cortisol. CBG is adapted for sepsis; its cortisol binding is reduced reversibly by pyrexia and acidaemia, and reduced irreversibly by neutrophil elastase (NE) cleavage, converting high cortisol-binding affinity CBG to a low affinity form. These characteristics allow for the targeted delivery of immunomodulatory cortisol to tissues at the time and body site where cortisol is required in sepsis and septic shock. In addition, high titer inflammatory cytokines in sepsis suppress CBG hepatic synthesis, increasing the serum free cortisol fraction. Recent clinical studies have highlighted the importance of CBG in septic shock, with CBG deficiency independently associated with mortality.

Measuring Emotion Regulation Skill Use During Treatment: A Promising Methodological Approach.

Emotion regulation has become ubiquitous in the study of psychopathology and a growing number of treatment outcome studies are collecting data on emotion regulation skill use. However, traditional measures of emotion regulation fail to capture important nuances in emotion regulation processes, their relationship to psychopathology, and how individuals use emotion regulation skills over time and across contexts. Novel methodologies are particularly needed for measuring emotion regulation in the context of treatment studies. In this article, we discuss a proposed methodology, the combination of ecological momentary assessment (EMA), and single-case experimental design (SCED), for measuring emotion regulation strategy use in the context of treatment outcome studies. To inform this discussion, we provide a brief overview of common approaches to assessing emotion regulation skill use in the context of treatment outcome research. We then describe the utility of intensive data capture (EMA) in the context of idiographic treatment studies (SCED), present a case study to illustrate the different uses of data collected through EMA in the context of a SCED study, and discuss considerations for implementing this method in clinical practice.

BNT162b2 vaccination reduced infections and transmission in a COVID-19 outbreak in a nursing home in Germany, 2021.

BACKGROUND: A SARS-CoV-2 outbreak was detected in a nursing home in February 2021 after residents and staff had received two doses of BNT162b2 vaccine in January 2021. METHODS: Nursing home staff, long-term residents and day-care receivers were included in a retrospective cohort study. We calculated attack rates (AR), secondary AR (SAR) and their 95% binomial confidence interval (CI), and we compared them using Fisher's exact test or chi-squared test, depending on the sample size. We used Poisson regression with robust error estimates to calculate vaccine effectiveness against SARS-COV-2 infections. We selected variables based on directed acyclic graphs. As a proxy for viral load at diagnosis, we compared the mean Ct values at diagnosis using t tests or Mann-Whitney U tests. RESULTS: The adjusted vaccine effectiveness against infection was 56% (95% CI: 15-77%, p = 0.04). Ct values at diagnosis were higher when intervals after receiving the second vaccination were longer (>21 vs. ≤21 days: 4.48 cycles, p = 0.08). The SAR was 67% lower in households of vaccinated (2/9 [22.2%]) than of unvaccinated infected staff (12/18 [66.7%]; p = 0.046). Vaccination rates were lowest among staff with close physical contact to care-receivers (46%). The highest AR in vaccinated staff had those working on wards (14%). CONCLUSIONS: Vaccination reduced the risk for SARS-CoV-2 infection, viral load and transmission; however, non-pharmaceutical interventions remain essential to reduce transmission of SARS-CoV-2 infections, even for vaccinated individuals. Vaccination coverage of staff ought to increase reduction of infections among themselves, their household members and residents.

Corticosteroid-Binding Globulin Deficiency Independently Predicts Mortality in Septic Shock.

CONTEXT: Hydrocortisone administration in septic shock remains controversial. Corticosteroid-binding globulin (CBG) transports cortisol to inflammatory sites and is depleted in septic shock. OBJECTIVE: To determine whether severely deficient serum CBG < 200 nmol/L (reference range 269-641 nmol/L) independently predicts septic shock mortality. METHODS: A prospective observational study in patients with septic shock. Patients were categorized into 2 groups: mean plasma CBG concentrations <200 nmol/L and ≥200 nmol/L (day 1/2), with additional categorization by nadir CBG. Primary outcome was intensive care unit (ICU) mortality. Secondary outcomes were 28- and 90-day mortality, norepinephrine requirements, renal replacement therapy, and clinician-instituted hydrocortisone. RESULTS: 135 patients were included. Mortality rates in ICU were higher in the CBG < 200 nmol/L vs the CBG ≥ 200 nmol/L group: 32.4% vs 13.9% [odds ratio (OR) 2.97 (95% CI 1.19, 7.41); P = 0.02] with 28-day mortality OR 2.25 (95% CI 0.99, 5.11) and 90-day mortality OR 2.21 (95% CI 0.99, 4.91). Multivariate analysis revealed 4 factors independently associated with ICU mortality: CBG < 200 nmol/L (adjusted OR 3.23, 95% CI 1.06, 9.88), Acute Physiology and Chronic Health Evaluation II > 25 (adjusted OR 3.58, 95% CI 1.20, 10.68), Sequential Organ Failure Assessment (SOFA) liver score (adjusted OR 1.98, 95% CI 1.04, 3.72), and renal replacement therapy (adjusted OR 6.59, 95% CI 2.17, 20.01). Nadir CBG levels were associated with higher SOFA cardiovascular scores and norepinephrine total dose (µg; P < 0.01) and duration (days; P < 0.01). Plasma cortisol concentrations and hydrocortisone administration did not relate to ICU mortality. CONCLUSION: Septic shock patients with CBG < 200 nmol/L had higher norepinephrine requirements and 3.2-fold higher ICU mortality. CBG concentration was the only directly reversible independent mortality risk factor.

A comparison of the stress hyperglycemia ratio, glycemic gap, and glucose to assess the impact of stress-induced hyperglycemia on ischemic stroke outcome.

BACKGROUND: The aim of this study is to compare metrics specific for stress-induced hyperglycemia (SIH) with glucose for predicting ischemic stroke outcome. METHODS: This observational retrospective study (n = 300) included patients acutely hospitalized for ischemic stroke over a 3.8-year period. We assessed the association between acute ischemic stroke outcome with the stress hyperglycemia ratio (SHR, relative increase in glycemia) and glycemic gap (GG, absolute increase in glycemia) using admission values and 5-day maximum values, along with incidence of poor outcome above recognized clinical thresholds of glucose 10 mmol/L, SHR 1.14, and GG 2.5 mmol/L. RESULTS: At admission, only SHR was associated with outcome after adjustment for clinical covariates (odds ratio [OR] = 2.88; 95% CI: 1.05-7.91; P = .041), while glucose or GG were not. Admission SHR ≥ 1.14 was also an indicator of poor outcome (39.1% vs 23.4%, P = .016), but not glucose ≥10 mmol/L or GG ≥ 2.5 mmol/L. All 5-day maximum glucose metrics were associated with outcome, as was any SHR ≥ 1.14 (40.9% vs 20.1%, P < .001) or GG ≥ 2.5 mmol/L (42.9% vs 23.4%, P = .011), but not glucose ≥10 mmol/L. Increased comorbidity was strongly associated with worse outcome (P < .001) in all models. CONCLUSIONS: SHR provided the best prognostic insight at admission to assess the relationship between SIH and ischemic stroke outcome. Absolute glucose levels failed to account for natural interpatient variation in background glycemia and provided little prognostic insight. To assess the impact of SIH, future interventional studies need to be designed using designated markers of SIH such as SHR in preference to absolute glucose.

CBG Montevideo: A Clinically Novel SERPINA6 Mutation Leading to Haploinsufficiency of Corticosteroid-binding Globulin.

Corticosteroid-binding globulin (CBG) is the main transport protein for cortisol, binding up to 90% in a 1:1 ratio. CBG provides transport of cortisol within the circulation and targeted cortisol tissue delivery. Here, we describe the clinically novel "CBG Montevideo" a SERPINA6 pathogenic variant that results in a 50% reduction in plasma CBG levels. This was associated with low serum total cortisol and clinical features of hypoglycemia, exercise intolerance, chronic fatigue, and hypotension in the proband, a 7-year-old boy, and his affected mother. Previous reports of 9 human CBG genetic variants affecting either CBG concentrations or reduced CBG-cortisol binding properties have outlined symptoms consistent with attenuated features of hypocortisolism, fatigue, and hypotension. Here, however, the presence of hypoglycemia, despite normal circulating free cortisol, suggests a specific role for CBG in effecting glucocorticoid function, perhaps involving cortisol-mediated hepatic glucose homeostasis and cortisol-brain communication.

The Transcription Factor Shox2 Shapes Neuron Firing Properties and Suppresses Seizures by Regulation of Key Ion Channels in Thalamocortical Neurons.

Thalamocortical neurons (TCNs) play a critical role in the maintenance of thalamocortical oscillations, dysregulation of which can result in certain types of seizures. Precise control over firing rates of TCNs is foundational to these oscillations, yet the transcriptional mechanisms that constrain these firing rates remain elusive. We hypothesized that Shox2 is a transcriptional regulator of ion channels important for TCN function and that loss of Shox2 alters firing frequency and activity, ultimately perturbing thalamocortical oscillations into an epilepsy-prone state. In this study, we used RNA sequencing and quantitative PCR of control and Shox2 knockout mice to determine Shox2-affected genes and revealed a network of ion channel genes important for neuronal firing properties. Protein regulation was confirmed by Western blotting, and electrophysiological recordings showed that Shox2 KO impacted the firing properties of a subpopulation of TCNs. Computational modeling showed that disruption of these conductances in a manner similar to Shox2's effects modulated frequency of oscillations and could convert sleep spindles to near spike and wave activity, which are a hallmark for absence epilepsy. Finally, Shox2 KO mice were more susceptible to pilocarpine-induced seizures. Overall, these results reveal Shox2 as a transcription factor important for TCN function in adult mouse thalamus.

Dynamics of adrenergic signaling in cardiac myocytes and implications for pharmacological treatment.

Dense innervation of the heart by the sympathetic nervous system (SNS) allows cardiac output to respond appropriately to the needs of the body under varying conditions, but occasionally the abrupt onset of SNS activity can trigger cardiac arrhythmias. Sympathetic activity leads to the release of norepinephrine (NE) onto cardiomyocytes, activating ß1-adrenergic receptors (ß1-ARs) and leading to the production of the second messenger cyclic AMP (cAMP). Upon sudden activation of ß1-ARs in experiments, intracellular cAMP can transiently rise to a high concentration before converging to a steady state level. Although changes to cellular cAMP concentration are important in modulating the overall cardiovascular response to sympathetic tone, the underlying mechanisms of the cAMP transients and the parameters that control their magnitude are unclear. We reduce a detailed computational model of the ß1-adrenergic signaling cascade to a system of two differential equations by eliminating extraneous variables and applying quasi-steady state approximation. The structure of the reduced model reveals that the large cAMP transients associated with abrupt ß1-AR activation are generated by the interplay of production/degradation of cAMP and desensitization/resensitization of ß1-ARs. The reduced model is used to predict how the dynamics of intracellular cAMP depend on the concentrations of norepinephrine (NE), phosphodiesterases 3 and 4 (PDE3,4), G-protein coupled receptor kinase 2 (GRK2), and ß1-AR, in healthy conditions and a simple model of early stages of heart failure. The key findings of the study are as follows: 1) Applying a reduced model of the dynamics of cardiac sympathetic signaling we show that the concentrations of two variables, cAMP and non-desensitized ß1-AR, capture the overall dynamics of sympathetic signaling; 2) The key factors influencing cAMP production are AC activity and PDE3,4 activity, while those that directly impact ß1-AR phosphorylation are GRK2 and PKA1. Thus, disease states that affect sympathetic control of the heart can be thoroughly assessed by studying AC activity, PDE3,4, GRK2 and PKA activity, as these factors directly impact cAMP production/degradation and ß1-AR (de) phosphorylation and are therefore predicted to comprise the most effective pharmaceutical targets in diseases affecting cardiac ß1-adrenergic signaling.