GLP-1 metabolite GLP-1(9-36) is a systemic inhibitor of mouse and human pancreatic islet glucagon secretion.

AIMS/HYPOTHESIS: Diabetes mellitus is associated with impaired insulin secretion, often aggravated by oversecretion of glucagon. Therapeutic interventions should ideally correct both defects. Glucagon-like peptide 1 (GLP-1) has this capability but exactly how it exerts its glucagonostatic effect remains obscure. Following its release GLP-1 is rapidly degraded from GLP-1(7-36) to GLP-1(9-36). We hypothesised that the metabolite GLP-1(9-36) (previously believed to be biologically inactive) exerts a direct inhibitory effect on glucagon secretion and that this mechanism becomes impaired in diabetes. METHODS: We used a combination of glucagon secretion measurements in mouse and human islets (including islets from donors with type 2 diabetes), total internal reflection fluorescence microscopy imaging of secretory granule dynamics, recordings of cytoplasmic Ca2+ and measurements of protein kinase A activity, immunocytochemistry, in vivo physiology and GTP-binding protein dissociation studies to explore how GLP-1 exerts its inhibitory effect on glucagon secretion and the role of the metabolite GLP-1(9-36). RESULTS: GLP-1(7-36) inhibited glucagon secretion in isolated islets with an IC50 of 2.5 pmol/l. The effect was particularly strong at low glucose concentrations. The degradation product GLP-1(9-36) shared this capacity. GLP-1(9-36) retained its glucagonostatic effects after genetic/pharmacological inactivation of the GLP-1 receptor. GLP-1(9-36) also potently inhibited glucagon secretion evoked by ß-adrenergic stimulation, amino acids and membrane depolarisation. In islet alpha cells, GLP-1(9-36) led to inhibition of Ca2+ entry via voltage-gated Ca2+ channels sensitive to ω-agatoxin, with consequential pertussis-toxin-sensitive depletion of the docked pool of secretory granules, effects that were prevented by the glucagon receptor antagonists REMD2.59 and L-168049. The capacity of GLP-1(9-36) to inhibit glucagon secretion and reduce the number of docked granules was lost in alpha cells from human donors with type 2 diabetes. In vivo, high exogenous concentrations of GLP-1(9-36) (>100 pmol/l) resulted in a small (30%) lowering of circulating glucagon during insulin-induced hypoglycaemia. This effect was abolished by REMD2.59, which promptly increased circulating glucagon by >225% (adjusted for the change in plasma glucose) without affecting pancreatic glucagon content. CONCLUSIONS/INTERPRETATION: We conclude that the GLP-1 metabolite GLP-1(9-36) is a systemic inhibitor of glucagon secretion. We propose that the increase in circulating glucagon observed following genetic/pharmacological inactivation of glucagon signalling in mice and in people with type 2 diabetes reflects the removal of GLP-1(9-36)'s glucagonostatic action.

Quantitative Analysis of Characteristics Associated with Patient-Directed Discharges, Representations, and Readmissions: a Safety-Net Hospital Experience.

BACKGROUND: No clinical tools currently exist to stratify patients' risks of patient-directed discharge (PDD). OBJECTIVE: This study aims to identify trends and factors associated with PDD, representation, and readmission. DESIGN: This was an IRB-approved, single-centered, retrospective study. PARTICIPANTS: Patients aged > 18, admitted to medicine service, were included from January 1st through December 31st, 2019. Patients admitted to ICU or surgical services were excluded. MAIN MEASURES: Demographics, insurance information, medical history, social history, rates of events occurrences, and discharge disposition were obtained. KEY RESULTS: Of the 16,889 encounters, there were 776 (4.6%) PDDs, 4312 (25.5%) representations, and 2924 (17.3%) readmissions. Of those who completed PDDs, 42.1% represented and 26.4% were readmitted. Male sex, age ≤ 45, insurance type, homelessness, and substance use disorders had higher rates of PDD (OR = 2.0; 4.2; 4.5; 6.2; 5.2; p < 0.0001, respectively). Patients with homelessness, substance use disorders, mental health disorders, or prior history of PDD were more likely to represent (OR = 3.6; 2.0; 2.0; 1.5; p < 0.0001, respectively) and be readmitted (OR = 2.2; 1.6; 1.9; 1.5; p < 0.0001, respectively). Patients aged 30-35 had the highest PDD rate at 16%, but this was not associated with representations or readmissions. Between July and September, the PDD rate peaked at 5.5% and similarly representation and readmission rates followed. The rates of subsequent readmissions after PDDs were nearly two-fold compared to non-PDD patients in later half of the year. 51% of all subsequent readmissions occur within 7 days of PDD, compared to 34% in the non-PDD group (OR = 2.0; p < 0.0001). Patients with primary diagnosis of abscess had 16% PDDs. CONCLUSIONS: Factors associated with PDD include male, younger age, insurance type, substance use, homelessness, and primary diagnosis of abscess. Factors associated with representation and readmission are homelessness, substance use disorders, mental health disorders, and prior history of PDD. Further research is needed to develop a risk stratification tool to identify at-risk patients.

Discharge Outcomes of Hospitalized Patients with New Onset Decompensated Cirrhosis.

INTRODUCTION: There are a lack of data describing outcomes and follow-up after hospital discharge for patients with newly diagnosed cirrhosis with complication on index admission. This study examines factors that influence outcomes such as readmission, follow-up, and mortality for patients with newly diagnosed cirrhosis. METHODS: We conducted a single-center retrospective chart review study of 230 patients with newly diagnosed cirrhosis from January 1st, 2020 through December 31st, 2021. We obtained demographics, clinical diagnoses, admission, and discharge MELD-Na, disposition, mortality, appointment requests rate, appointment show rate, and readmission. RESULTS: The primary complications on admission were GI bleed (27%), ascites (25.7%), and hepatic encephalopathy (HE) (10.4%). Overall, the median length of stay (LOS) was 6 days, and the readmission rate was 27%. Out of 230 patients, 25 (10.9%) patients died while hospitalized while another 43 (18.6%) died after initial discharge within the two-year study period. Although there was a significant reduction of the MELD-Na from admission to discharge (p < 0.05), admission MELD-Na did not correlate with LOS and discharge MELD-Na did not predict readmission. Patients with HE had the highest median LOS, while patients with ascites had the highest readmission rate. The median time to an appointment was 32 days. When comparing discharge destinations, most patients were discharged to home (63%), to facilities (13.9%), or expired (10.9%). The average appointment show rate was 38.5%, although 70% of patients had appointment requests. Readmission rate and mortality did not differ based on appointment requests. No significant differences in outcomes were observed based on race, sex, or insurance status. CONCLUSION: New diagnosis of decompensated was found to have high mortality and high readmission rates. Higher MELD-Na score was seen in patients who died within 30 days. Routine appointment requests did not significantly improve readmission, mortality, increase appointment show rate, or decrease time to appointment. A comprehensive and specialized hepatology-specific program may have great benefits after cirrhotic decompensation, especially for those with newly diagnosed cirrhosis.

Water and Air Stable Copper(I) Complexes of Tetracationic Catenane Ligands for Oxidative C-C Cross-Coupling.

Aqueous soluble and stable Cu(I) molecular catalysts featuring a catenane ligand composed of two dicationic, mutually repelling but mechanically interlocked macrocycles are reported. The ligand interlocking not only fine-tunes the coordination sphere and kinetically stabilizes the Cu(I) against air oxidation and disproportionation, but also buries the hydrophobic portions of the ligands and prevents their dissociation which are necessary for their good water solubility and a sustained activity. These catenane Cu(I) complexes can catalyze the oxidative C-C coupling of indoles and tetrahydroisoquinolines in water, using H2O2 as a green oxidant with a good substrate scope. The successful use of catenane ligands in exploiting aqueous Cu(I) catalysis thus highlights the many unexplored potential of mechanical bond as a design element for exploring transition metal catalysis under challenging conditions.

Making Sense: Treating Patients with Opioid Use Disorder through the Lens of Game Theory.

The opioid epidemic continues to influence the field of medicine, creating new challenges and obstacles to quality care. Patients with injection drug use are marginalized individuals who received poor quality of care and often discharged without safe recovery plan. Cooperation between physicians and patients allow the best outcomes for the patient, the physician, and society, however we often see patient-directed discharges and inadequate care. We believe that this result is due to an incentive model in the decision-making process that ultimately makes cooperation difficult. We use different game theory models (assurance model, prisoner's dilemma, centipede model, conflicting interest coordination) in this paper to describe common scenarios within a hospitalization when caring for patient with opioid use disorder, from admission through discharge. When physician and patient are driven away from cooperation, the outcome is the worst and most harmful for society. In today's worsening opioid crisis, game theory can help physician provide high quality care to a complex high-risk population.

Cross-Sectional Melt Pool Geometry of Laser Scanned Tracks and Pads on Nickel Alloy 718 for the 2022 Additive Manufacturing Benchmark Challenges.

The Additive Manufacturing Benchmark Series (AM Bench) is a NIST-led organization that provides a continuing series of additive manufacturing benchmark measurements, challenge problems, and conferences with the primary goal of enabling modelers to test their simulations against rigorous, highly controlled additive manufacturing benchmark measurement data. To this end, single-track (1D) and pad (2D) scans on bare plate nickel alloy 718 were completed with thermography, cross-sectional grain orientation and local chemical composition maps, and cross-sectional melt pool size measurements. The laser power, scan speed, and laser spot size were varied for single tracks, and the scan direction was varied for pads. This article focuses on the cross-sectional melt pool size measurements and presents the predictions from challenge problems. Single-track depth correlated with volumetric energy density while width did not (within the studied parameters). The melt pool size for pad scans was greater than single tracks due to heat buildup. Pad scan melt pool depth was reduced when the laser scan direction and gas flow direction were parallel. The melt pool size in pad scans showed little to no trend against position within the pads. Uncertainty budgets for cross-sectional melt pool size from optical micrographs are provided for the purpose of model validation.

Digital health and medical technology for perioperative sarcopenia optimisation and prehabilitation - Where to go from here?

Sarcopenia has been shown to cause poorer outcomes in surgical oncology. With the advancement of artificial intelligence technology, body composition analysis can be obtained with ease. Given the lead time between cancer diagnosis and surgery, selected patients at risk of complications secondary to sarcopenia may be amenable to prehabilitation. The COVID-19 pandemic has led to the rapid adaptation of digital health and medical technology. Our perspective piece will review the current available evidence and propose innovative ways to incorporate technology into physical and nutritional prehabilitation.

Dynamic mechanostereochemical switching of a co-conformationally flexible [2]catenane controlled by specific ionic guests.

Responsive synthetic receptors for adaptive recognition of different ionic guests in a competitive environment are valuable molecular tools for not only ion sensing and transport, but also the development of ion-responsive smart materials and related technologies. By virtue of the mechanical chelation and ability to undergo large-amplitude co-conformational changes, described herein is the discovery of a chameleon-like [2]catenane that selectively binds copper(I) or sulfate ions and its associated co-conformational mechanostereochemical switching. This work highlights not only the advantages and versatility of catenane as a molecular skeleton in receptor design, but also its potential in constructing complex responsive systems with multiple inputs and outputs.

Venom-inspired somatostatin receptor 4 (SSTR4) agonists as new drug leads for peripheral pain conditions.

Persistent pain affects one in five people worldwide, often with severely debilitating consequences. Current treatment options, which can be effective for mild or acute pain, are ill-suited for moderate-to-severe persistent pain, resulting in an urgent need for new therapeutics. In recent years, the somatostatin receptor 4 (SSTR 4 ), which is expressed in sensory neurons of the peripheral nervous system, has emerged as a promising target for pain relief. However, the presence of several closely related receptors with similar ligand-binding surfaces complicates the design of receptor-specific agonists. In this study, we report the discovery of a potent and selective SSTR 4 peptide, consomatin Fj1, derived from extensive venom gene datasets from marine cone snails. Consomatin Fj1 is a mimetic of the endogenous hormone somatostatin and contains a minimized binding motif that provides stability and drives peptide selectivity. Peripheral administration of synthetic consomatin Fj1 provided analgesia in mouse models of postoperative and neuropathic pain. Using structure-activity studies, we designed and functionally evaluated several Fj1 analogs, resulting in compounds with improved potency and selectivity. Our findings present a novel avenue for addressing persistent pain through the design of venom-inspired SSTR 4 -selective pain therapeutics. One Sentence Summary: Venom peptides from predatory marine mollusks provide new leads for treating peripheral pain conditions through a non-opioid target.

Fish-hunting cone snail disrupts prey's glucose homeostasis with weaponized mimetics of somatostatin and insulin.

Venomous animals have evolved diverse molecular mechanisms to incapacitate prey and defend against predators. Most venom components disrupt nervous, locomotor, and cardiovascular systems or cause tissue damage. The discovery that certain fish-hunting cone snails use weaponized insulins to induce hypoglycemic shock in prey highlights a unique example of toxins targeting glucose homeostasis. Here, we show that, in addition to insulins, the deadly fish hunter, Conus geographus, uses a selective somatostatin receptor 2 (SSTR2) agonist that blocks the release of the insulin-counteracting hormone glucagon, thereby exacerbating insulin-induced hypoglycemia in prey. The native toxin, Consomatin nG1, exists in several proteoforms with a minimized vertebrate somatostatin-like core motif connected to a heavily glycosylated N-terminal region. We demonstrate that the toxin's N-terminal tail closely mimics a glycosylated somatostatin from fish pancreas and is crucial for activating the fish SSTR2. Collectively, these findings provide a stunning example of chemical mimicry, highlight the combinatorial nature of venom components, and establish glucose homeostasis as an effective target for prey capture.