SGLT2 Inhibitors Decrease Overhydration and Proteasuria in Patients with Chronic Kidney Disease: A Longitudinal Observational Study.

INTRODUCTION: SGLT2 inhibitors are used to reduce the risk of progression of chronic kidney disease (CKD). In patients with type 2 diabetes, they have been found to reduce extracellular volume. Given the high prevalence of extracellular volume expansion and overhydration (OH) in CKD, we investigated whether SGLT2 inhibitors might correct these disturbances in CKD patients. METHODS: CKD patients who started treatment with an SGLT2 inhibitor were investigated in this prospective observational study for 6 months. Body composition and fluid status were measured by bioimpedance spectroscopy. In addition, spot urine samples were analyzed for albuminuria, glucosuria, and urinary aprotinin-sensitive serine protease activity. RESULTS: Forty-two patients (29% with diabetic/hypertensive CKD, 31% with IgA nephropathy; 88% dapagliflozin 10 mg, 10% dapagliflozin 5 mg, 2% empagliflozin 20 mg; median eGFR 46 mL/min/1.73 m2 and albuminuria 1,911 mg/g creatinine) participated in the study. Median glucosuria increased to 14 (10-19) g/g creatinine. At baseline, patients displayed OH with +0.4 (-0.2 to 2.2) L/1.73 m2, which decreased by 0.5 (0.1-1.2) L/1.73 m2 after 6 months. Decrease of OH correlated with higher OH at BL, decrease of albuminuria, glucosuria, and urinary aprotinin-sensitive protease activity. Adipose tissue mass was not significantly reduced after 6 months. CONCLUSION: SGLT2 inhibitors reduce OH in patients with CKD, which is pronounced in the presence of high albuminuria, glucosuria, and urinary aprotinin-sensitive protease activity.

Amiloride versus furosemide for the treatment of edema in patients with nephrotic syndrome: A pilot study (AMILOR).

AIM: In rodent models of nephrotic syndrome (NS), edema formation was prevented by blockade of the epithelial sodium channel ENaC with amiloride. However, apart from case reports, there is no evidence favoring ENaC blockade in patients with NS. METHODS: The monocentric randomized controlled AMILOR study investigated the antiedematous effect of amiloride (starting dose 5 mg/day, max. 15 mg/day) in comparison to standard therapy with the loop diuretic furosemide (40 mg/day, max. 120 mg/day) over 16 days. Overhydration (OH) was measured by bioimpedance spectroscopy (BCM, Fresenius). Depending on the OH response, diuretic dose was adjusted on days 2, 5, 8 and 12, and if necessary, hydrochlorothiazide (HCT) was added from d8 (12.5 mg/day, max. 25 mg/day). The primary endpoint was the decrease in OH on d8. The study was terminated prematurely due to insufficient recruitment and a low statistical power due to a low actual effect size. RESULTS: Median baseline OH was +26.4 (interquartile range 15.5-35.1)% extracellular water (ECW) in the amiloride arm and + 27.9 (24.1-29.4)% ECW in the furosemide arm and decreased by 1.95 (0.80-6.40) and 5.15 (0.90-8.30)% ECW after 8 days, respectively, and by 10.10 (1.30-14.40) and 7.40 (2.80-10.10)% ECW after 16 days, respectively. OH decrease on d8 and d16 was not significantly different between both arms. CONCLUSION: The AMILOR study is the first randomized controlled pilot study suggesting a similar antiedematous effect as furosemide. Further studies are required to better define the role of amiloride in NS (EudraCT 2019-002607-18).

Australia's Tinderbox Drought: An extreme natural event likely worsened by human-caused climate change.

We examine the characteristics and causes of southeast Australia's Tinderbox Drought (2017 to 2019) that preceded the Black Summer fire disaster. The Tinderbox Drought was characterized by cool season rainfall deficits of around -50% in three consecutive years, which was exceptionally unlikely in the context of natural variability alone. The precipitation deficits were initiated and sustained by an anomalous atmospheric circulation that diverted oceanic moisture away from the region, despite traditional indicators of drought risk in southeast Australia generally being in neutral states. Moisture deficits were intensified by unusually high temperatures, high vapor pressure deficits, and sustained reductions in terrestrial water availability. Anthropogenic forcing intensified the rainfall deficits of the Tinderbox Drought by around 18% with an interquartile range of 34.9 to -13.3% highlighting the considerable uncertainty in attributing droughts of this kind to human activity. Skillful predictability of this drought was possible by incorporating multiple remote and local predictors through machine learning, providing prospects for improving forecasting of droughts.

The global effect of extreme weather events on nutrient supply: a superposed epoch analysis.

BACKGROUND: To date, the effects of extreme weather events on nutrient supply within the population have not been quantified. In this study, we investigated micronutrient, macronutrient, and fibre supply changes during 175 extreme weather events within 87 countries in the year that a major extreme weather event occurred, with a targeted focus on low-income settings. METHODS: We collected data from the International Disasters Database and the Global Expanded Nutrient Supply model for the period 1961-2010, and applied superposed epoch analysis to calculate the percentage change in nutrient supply during the year of an extreme weather event relative to its historical context. We composited globally and by subgroup (EU, landlocked developing countries, least developed countries, low-income food deficit countries, and net food-importing developing countries). Lastly, we reported nutrient supply changes in terms of recommended dietary allowance for children aged 1-3 years. FINDINGS: Globally, all micronutrient supplies had a modest negative percentage change during the year of an extreme weather event; of these effects, those that reached an α=0·05 significance level included calcium, folate, thiamin, vitamin B6, and vitamin C, with nutrient supply changes ranging from -0·40 to -1·73% of the average supply. The effect of an extreme weather event was especially magnified among landlocked developing countries and low-income food deficit countries, with significant nutrient supply changes ranging from -1·61 to -7·57% of the average supply. Furthermore, the observed nutrient supply deficits in landlocked developing countries constituted a large percentage (ranging from 1·95 to 39·19%) of what a healthy child's sufficient average dietary intake should be. INTERPRETATION: The global effects of extreme weather events on nutrient supply found in this study are modest in isolation; however, in the context of nutrient needs for healthy child development in low-income settings, the effects observed are substantial. FUNDING: Australian-American Fulbright Commission.

Structural and Functional Remodeling of Amygdala GABAergic Synapses in Associative Fear Learning.

Associative learning is thought to involve different forms of activity-dependent synaptic plasticity. Although previous studies have mostly focused on learning-related changes occurring at excitatory glutamatergic synapses, we found that associative learning, such as fear conditioning, also entails long-lasting functional and structural plasticity of GABAergic synapses onto pyramidal neurons of the murine basal amygdala. Fear conditioning-mediated structural remodeling of GABAergic synapses was associated with a change in mIPSC kinetics and an increase in the fraction of synaptic benzodiazepine-sensitive (BZD) GABAA receptors containing the α2 subunit without altering the intrasynaptic distribution and overall amount of BZD-GABAA receptors. These structural and functional synaptic changes were partly reversed by extinction training. These findings provide evidence that associative learning, such as Pavlovian fear conditioning and extinction, sculpts inhibitory synapses to regulate inhibition of active neuronal networks, a process that may tune amygdala circuit responses to threats.

Suicidal ideation among Viennese high school students.

OBJECTIVE: Suicidality spans a spectrum ranging from suicidal thoughts to suicidal acts, and suicidal ideation is more prevalent in youth populations, suggesting important developmental issues. We assessed the prevalence of lifetime suicidal ideation and associated psychosocial factors among Viennese high school students. METHOD: An anonymous self-report survey assessing demographic characteristics and the major psychiatric risk factors of teenage suicide was completed by students at three Viennese high schools (n = 214; mean age 15.4 years). RESULTS: Eighty-one (37.9%) high school students reported having had suicidal thoughts at some point in their lives, girls significantly more often than boys (48.5% vs. 29.1%, P = 0.004). Furthermore, lifetime suicidal ideation in Viennese high school students was associated with living in broken-home families, cigarette smoking, substance problems (alcohol/drugs), self-reported depression, and high school type (the highest prevalence was in grammar school). After adjusting for confounders, we found that female gender, substance problems, school type and cigarette smoking were significantly associated with lifetime suicidal ideation in Viennese high school students. CONCLUSIONS: The psychosocial factors associated with adolescent suicidal ideation require attention in the contexts of suicide prevention and mental health promotion.

Projection-Specific Dynamic Regulation of Inhibition in Amygdala Micro-Circuits.

Cannabinoid receptor type 1 (CB1R)-expressing CCK interneurons are key regulators of cortical circuits. Here we report that retrograde endocannabinoid signaling and CB1R-mediated regulation of inhibitory synaptic transmission onto basal amygdala principal neurons strongly depend on principal neuron projection target. Projection-specific asymmetries in the regulation of local inhibitory micro-circuits may contribute to the selective activation of distinct amygdala output pathways during behavioral changes.

Effect of Trigger Sensitivity on Redistribution of Ventilation During Pressure Support Ventilation Detected by Electrical Impedance Tomography.

BACKGROUND: In supine position, pressure support ventilation causes a redistribution of ventilation towards the ventral regions of the lung. Theoretically, a less sensitive support trigger would cause the patient to breathe more actively, potentially attenuating the effect of positive pressure ventilation. OBJECTIVES: To quantify the effect of trigger setting, we assessed redistribution of ventilation during pressure support ventilation (PSV) using electrical impedance tomography (EIT). PATIENTS AND METHODS: With approval from the local ethics committee, six orthopedic patients were enrolled. All patients had general anesthesia with a laryngeal mask airway and a standardized anesthetic regimen (sufentanil, propofol and sevoflurane). Pressure support trigger settings varied between 2 and 15 L/minute and compared to unassisted spontaneous breathing. From EIT data, the center of ventilation (COV), the fraction of the total ventilation per region of interest (ROI) and intratidal gas distribution were calculated. RESULTS: At all trigger settings, pressure support ventilation caused a significant ventral shift of the center of ventilation compared with during spontaneous breathing, confirmed by the analysis by regions of interest. During spontaneous breathing, COV was not different from baseline values obtained before induction of anesthesia. During PSV, the intratidal regional gas distribution (ITV-analysis) revealed subtle changes during the early inspiratory phase not detected by the COV-analysis. CONCLUSIONS: Pressure support ventilation, but not spontaneous breathing, induces a significant redistribution of ventilation towards the ventral region. The sensitivity of the support trigger appears to influence the distribution of ventilation only during the early phase of inspiration.

The point mutation gamma 2F77I changes the potency and efficacy of benzodiazepine site ligands in different GABAA receptor subtypes.

Benzodiazepine site agonists or inverse agonists enhance or reduce gamma-aminobutyric acid(A) (GABA(A)) receptor-mediated inhibition of neurons, respectively. Recently, it was demonstrated that the point mutation gamma 2F77I causes a drastic change in the affinity of a variety of benzodiazepine agonists or inverse agonists in receptor binding studies. Here we investigated the potency and efficacy of 10 benzodiazepine site ligands from 6 structural classes in wild-type and gamma 2F77I point mutated recombinant GABA(A) receptors composed of alpha 1 beta 3 gamma 2, alpha 2 beta 3 gamma 2, alpha 3 beta 3 gamma 2, alpha 4 beta 3 gamma 2, alpha 5 beta 3 gamma 2, and alpha 6 beta 3 gamma 2 subunits. Results indicate that the effects of the benzodiazepine site ligands zolpidem, zopiclone, Cl218872, L-655,708 and DMCM were nearly completely eliminated in all mutated receptors up to a 1 microM concentration. The effects of bretazenil, Ro15-1788 or abecarnil were eliminated in some, but not all mutated receptors, suggesting that the gamma 2F77I mutation differentially influences the actions of these ligands in different receptor subtypes. In addition, this point mutation also influences the efficacy of diazepam for enhancing GABA-induced chloride flux, suggesting that the amino acid residue gamma 2F77 might also be involved in the transduction of the effect of benzodiazepines from binding to gating. The application of these drugs in a novel mouse model is discussed.