Winthrop-University Hospital

The kidneys contribute to glucose homeostasis by gluconeogenesis and glucose reabsorption. Herein, we identified previously unknown fasting-induced, glucagon-mediated inhibitory effect of the circadian clock gene basic helix-loop-helix ARNT like 1 (Bmal1) on the expression of the main proximal tubule glucose transporter solute carrier family 5 member 2 (Sglt2) in mice. During fasting, glucagon induces Bmal1, which increases expression of nuclear receptor subfamily 1, group D, member 1 (Rev-erbα). Rev-erbα represses nuclear respiratory factor 1, a transcriptional activator of Sglt2, and diminishes Sglt2 expression and thereby kidney glucose reabsorption capacity. During refeeding (lower glucagon) this process is attenuated, thereby inducing glucose reabsorption. The physiological role of this mechanism appears to ensure optimal temporal retrieval of filtered glucose during fasting/refeeding. Thus, this study demonstrates that during fasting and refeeding, glucagon regulates renal glucose reabsorption by utilizing the local cellular circadian machinery.

Background: Mental health conditions are a growing public health concern among U.S. adolescents, particularly high school students. Emerging data show a strong link between exposure to neighborhood violence and increased risk of poor mental health outcomes, such as depression, anxiety, and persistent sadness. Objective: This study examined the relationship between neighborhood violence exposure and mental health outcomes among high school students. Method: This is a cross-sectional study using the 2023 Youth Risk Behavior Survey. The sample included 19,910 students in grades 9–12 across gender and race. Mental health status and exposure to neighborhood violence were analyzed using chi-square tests and logistic regression models. Results: Students exposed to neighborhood violence had significantly higher odds of reporting poor mental health outcomes (AOR = 1.789, 95% CI: 1.573–2.035, p < 0.001) than the unexposed. Additionally, female, Hispanic/Latino, and multiracial students reported higher rates of mental health disorders than the male students. Conclusions: Neighborhood violence exposure was significantly associated with poor mental health outcomes among high school students. These findings signify the need for targeted interventions to support affected students and reduce neighborhood violence exposure, particularly in marginalized communities. The findings will inform public health professionals, educators, and policymakers to make targeted school-based mental health interventions and community-centered policies addressing neighborhood safety and adolescent mental health.

Case Description: BRASH syndrome is characterized by the following: bradycardia, renal failure, atrioventricular blockade, shock, and hyperkalemia. Due to its overlapping features, it is often under-reported and misdiagnosed as isolated hyperkalemia. This case involves a 53-year-old male who presented with palpitations following a hemodialysis session. Upon arrival, the patient was tachycardic and found to be in atrial flutter (Figure 1). Initial treatment with diltiazem effectively controlled his heart rate. However, the following day, the patient received additional beta-blockers and developed hypotension (72/50 mmHg), bradycardia (39 bpm) (Figure 2), and hyperkalemia (K 7.3). Upon being upgraded to the cardiac care unit (CCU), his management included atropine, epinephrine, glucagon, and calcium gluconate. Ultimately, the patient was stabilized with urgent dialysis. Discussion: BRASH syndrome is a cyclical condition that includes the amalgamation of the following: bradycardia, renal failure, atrioventricular (AV) nodal blockade, shock, and hyperkalemia. Carries an in-hospital mortality of 5.7%. It is often underreported and mistaken for isolated hyperkalemia or AV blocker toxicity. One reason for this underreporting is the subtlety of its presentation, which can easily be confused with hyperkalemia alone, especially when patients present primarily with bradycardia and renal dysfunction. Unlike typical hyperkalemia, which generally needs to be severe to induce bradycardia, BRASH syndrome can cause significant bradycardia even with moderate potassium elevations due to the synergistic effect of AV nodal blockers and renal failure. This case of BRASH syndrome, triggered by both beta-blockers and calcium channel blockers, is rare. The combined use of both agents compounds the effects on AV node conduction and can severely depress heart rate, especially when renal impairment leads to reduced drug clearance. Management of BRASH syndrome requires addressing all components of the syndrome. Initial treatment often includes correction of hyperkalemia with calcium gluconate and insulin. Bradycardia may be managed with atropine, epinephrine, or pacing. Additionally, medications contributing to AV node blockade should be held, and hemodynamic support with vasopressors may be necessary if hypotension persists. In some cases, such as ours, dialysis may be required to manage hyperkalemia and improve renal clearance of medications.

Microangiopathy is a major complication of SARS-CoV-2 infection and contributes to the acute and chronic complications of the disease1. Endotheliopathy and dysregulated blood coagulation are prominent in COVID-19 and are considered to be major causes of microvascular obstruction1,2. Here we demonstrate extensive endothelial cell (EC) death in the microvasculature of COVID-19 organs. Notably, EC death was not associated with fibrin formation or platelet deposition, but was linked to microvascular red blood cell (RBC) haemolysis. Importantly, this RBC microangiopathy was associated with ischaemia-reperfusion injury, and was prominent in the microvasculature of humans with myocardial infarction, gut ischaemia, stroke, and septic and cardiogenic shock. Mechanistically, ischaemia induced MLKL-dependent EC necroptosis and complement-dependent RBC haemolysis. Deposition of haemolysed RBC membranes at sites of EC death resulted in the development of a previously unrecognized haemostatic mechanism preventing microvascular bleeding. Exaggeration of this haemolytic response promoted RBC aggregation and microvascular obstruction. Genetic deletion of Mlkl from ECs decreased RBC haemolysis, microvascular obstruction and reduced ischaemic organ injury. Our studies demonstrate the existence of a RBC haemostatic mechanism induced by dying ECs, functioning independently of platelets and fibrin. Therapeutic targeting of this haemolytic process may reduce microvascular obstruction in COVID-19, and other major human diseases associated with organ ischaemia.

Hyperattenuating contents detected in the gastrointestinal (GI) tract on CT scans are commonly seen and are almost always due to the purposeful ingestion of an oral contrast agent, usually barium- or iodine-based, used for evaluating the GI tract. Occasionally, other ingested material such as antacids or other medications, foreign objects, and medical devices can also be hyperattenuating. While these are usually correctly identified, these materials can potentially be misdiagnosed as a pathologic condition. Lokelma (sodium zirconium cyclosilicate (SZC)) is an increasingly used agent to treat hyperkalemia and has a hyperattenuating appearance on CT due to the presence of zirconium. However, this is not well known to the radiologic community. Here, we describe a case where SZC was seen in the GI tract on CT and misinterpreted as an acute GI bleed. A 72-year-old woman underwent single (portal venous) phase intravenous contrast-enhanced abdominal and pelvic CT after presenting to the ED with a lower GI bleed. The CT showed intraluminal hyperattenuation within the cecum, which was diagnosed prospectively as an active GI bleed. A CT angiogram of the abdomen and pelvis performed the following day for follow-up showed the hyperattenuating contents to be present on the non-IV contrast-enhanced series of the study, thereby proving that it was not due to active bleeding. Further investigation of the patient's medical record showed that the patient was being treated with SZC for hyperkalemia, accounting for the hyperattenuating cecal contents. Awareness of the hyperattenuating appearance of SZC on CT by radiologists and clinical staff can help avoid confusion and misdiagnosis.

to date, no standardized, evidence-based follow-up schemes exist for the monitoring of patients who underwent focal therapy (FT) and expert centers rely mainly on their own experience and/or institutional protocols. We aimed to perform a comprehensive review of the most advantageous follow-up strategies and their rationale after FT for prostate cancer (PCa). a narrative review of the literature was conducted to investigate different follow-up protocols of FT for PCa. Outcomes of interest were post-ablation oncological and functional outcomes and complications. Oncological success after FT was generally defined as the biopsy-confirmed absence of clinically significant PCa in the treated zone. De novo PCa in the untreated area usually reflects an inaccurate patient selection and should be treated as primary PCa. During follow-up, oncological outcomes should be evaluated with periodic PSA, multiparametric MRI and prostate biopsy. The use of PSA derivatives and new biomarkers is still controversial and therefore not recommended. The first MRI after FT should be performed between 6-12 months to avoid ablation-related artifacts and diagnostic delay in case of FT failure. Other imaging modalities, such as PSMA PET/CT scan, are promising but still need to be validated in the post-FT setting. A 12-month "for-protocol" prostate biopsy, including targeted and systematic biopsy, was generally considered the preferred biopsy method to rule out tumor persistence/recurrence. Subsequent mpMRIs and biopsies should follow a risk-adapted approach depending on the clinical scenario. Functional outcomes should be periodically assessed using validated questionnaires within the first year, when typically recover to a new baseline. Complications, despite uncommon, should be strictly monitored mainly in the first month. FT follow-up is a multifaceted process involving clinical, radiological, and histological assessment. Studies evaluating the impact of different follow-up strategies and ideal timings are needed to produce standardized protocols following FT.

Persistent mineralocorticoid receptor activation is a pathologic response in type 2 diabetes and chronic kidney disease. Whereas mineralocorticoid receptor antagonists are beneficial in reducing cardiovascular complications, direct mechanistic pathways for these effects in humans are lacking. The MAGMA trial (Mineralocorticoid Receptor Antagonism Clinical Evaluation in Atherosclerosis) was a randomized, double-blind, placebo-controlled trial in patients with high-risk type 2 diabetes with chronic kidney disease (not receiving dialysis) on maximum tolerated renin-angiotensin system blockade. The primary end point was change in thoracic aortic wall volume, expressed as absolute or percent value (ΔTWV or ΔPWV), using 3T magnetic resonance imaging at 12 months. Secondary end points were changes in left ventricle (LV) mass; LV fibrosis, measured as a change in myocardial native T1; and 24-hour ambulatory and central aortic blood pressures. Tertiary end points included plasma proteomic changes in 7596 plasma proteins using an aptamer-based assay. A total of 79 patients were randomized to placebo (n=42) or 25 mg of spironolactone daily (n=37). After a modified intent-to-treat, including available baseline data of study end points, patients who completed the trial protocol were included in the final analyses. At the 12-month follow-up, the average change in PWV was 7.1±10.7% in the placebo group and 0.87±10.0% in the spironolactone group (P=0.028), and ΔTWV was 1.2±1.7 cm3 in the placebo group and 0.037±1.9 cm3 in the spironolactone group (P=0.022). Change in LV mass was 3.1±8.4 g in the placebo group and -5.8±8.4 g in the spironolactone group (P=0.001). Changes in LV T1 values were significantly different between the placebo and spironolactone groups (26.0±41.9 ms in the placebo group versus a decrease of -10.1±36.3 ms in the spironolactone group; P=6.33×10-4). Mediation analysis revealed that the spironolactone effect on thoracic aortic wall volume and myocardial mass remained significant after adjustment for ambulatory and central blood pressures. Proteomic analysis revealed a dominant effect of spironolactone on pathways involving oxidative stress, inflammation, and leukocyte activation. Among patients with diabetes with moderate to severe chronic kidney disease at elevated cardiovascular risk, treatment with spironolactone prevented progression of aortic wall volume and resulted in regression of LV mass and favorable alterations in native T1, suggesting amelioration of left-ventricular fibrosis. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02169089.

ZusammenfassungKleinwüchsige Kinder mit einem Wachstumshormonmangel (GHD) können seit 1987 in Deutschland mit rekombinantem humanem Wachstumshormon (rhGH) behandelt werden, wobei rhGH täglich, einmal abends, als s.c.-Injektion verabreicht wird. Die Therapie hat sich über mehr als 4 Jahrzehnte als wirksam und sicher erwiesen. Langzeitbeobachtungen an Kindern mit GHD zeigten, dass ca. 10–20 % der Kinder keine Erwachsenengröße im Zielbereich der Eltern erreichen. Als vordringlicher Grund hierfür wird eine unzureichende Verordnungstreue (Adhärenz) wegen der notwendigen, aber unangenehmen, täglichen s.c.-Injektionen angenommen. Dies führte zur Entwicklung von lang wirksamem GH („long-acting GH“ [LAGH]), das nur einmal wöchentlich injiziert wird. Seit Ende 2023 stehen in Deutschland drei LAGH-Präparate für die Behandlung von Kindern und Jugendlichen ab einem Alter von 3 Jahren mit einer Wachstumsstörung durch eine unzureichende Ausschüttung von GH zur Verfügung. Die Präparate sind in ihrer chemischen Gesamtstruktur unterschiedlich. Das LAGH bindet wie rhGH an den GH-Rezeptor und initiiert die Signalkaskade, die zur Aktivierung des Wachstums und Stoffwechsels führt. Die LAGH-Präparate konnten in Phase-3-Studien zeigen, dass sie der täglichen s.c.-rhGH-Therapie nicht unterlegen sind und über ein vergleichbares Sicherheitsprofil verfügen. Aufgrund fehlender Langzeitdaten können mögliche Sicherheitsbedenken nicht vollständig ausgeräumt werden. Die LAGH-Präparate eröffnen eine neue Option bei der Behandlung von Kindern und Jugendlichen mit GHD. Langzeitwirksamkeit und -sicherheit müssen jedoch weiter evaluiert werden. Vor der Behandlung müssen Eltern und Patienten über alle relevanten Aspekte der neuen Behandlung aufgeklärt werden. In der Übersichtsarbeit werden die aktuell in Deutschland zugelassenen LAGH-Präparate zusammen mit den bisher dazu publizierten Daten aus pädiatrischer Sicht diskutiert.

Premature infants frequently face feeding challenges due to disrupted coordination of sucking, swallowing, and breathing, increasing their risk of dysphagia. There are few effective treatment options available for these infants. In adults experiencing dysphagia, consuming cold foods or liquids can be an effective strategy. This method stimulates the sensory receptors in the pharyngeal mucosa, promoting safer and more effective swallowing. We have previously demonstrated that short-duration feeding (5 swallows) with cold liquid significantly reduces dysphagia in preterm infants; however, the impact of extended cold milk feeding remains unexplored. This study aims to assess the safety of cold milk feedings in preterm infants diagnosed with uncoordinated feeding patterns and its effect on feeding performance. Preterm infants with uncoordinated feeding patterns (n=26) were randomized to be fed milk at either room or cold temperatures using an experimental, randomized crossover design. We monitored axillary and gastric content temperatures, mesenteric blood flow, and feeding performance. The findings suggest that preterm infants can safely tolerate cold milk without any clinically significant changes in temperature or mesenteric blood flow, and it may enhance certain aspects of feeding performance. These results suggest that cold milk feeding could be a safe therapeutic option for preterm infants. These results highlight the potential for further comprehensive studies to explore the use of cold milk as an effective therapeutic approach for addressing feeding and swallowing difficulties in preterm infants. Registered at clinicaltrials.org #NCT04421482.