Alzheimer's disease (AD) is a leading cause of death and disability, and treatment options for Alzheimer's disease and related dementias (ADRD) remain limited. We applied a data-driven, mechanism-agnostic Medication-Wide Association Study Plus (MWAS+) framework to identify candidate medications associated with ADRD using longitudinal electronic health record data and explainable artificial intelligence (AI).

Diuretic resistance in worsening heart failure (HF) is associated with poorer outcomes and, although common, can be challenging to identify. The recently developed BAN-ADHF score can potentially identify patients with worsening HF at risk of diuretic resistance. We externally validated the BAN-ADHF diuretic-resistance score in a multicentre randomized trial comparing adjunctive dapagliflozin to metolazone in patients with HF and diuretic resistance. We calculated a seven-variable modified BAN-ADHF score at baseline and dichotomised patients by the median BAN-ADHF score (8). We assessed loop diuretic efficiency (kg weight change per 40-mg furosemide) and decongestion (weight, eight-zone lung ultrasound B-lines, clinical congestion score) over 96 h. A baseline score ≥8 identified lower loop diuretic efficiency (pooled difference -0.12 kg/40 mg, 95% CI -0.18 to -0.06; p < 0.001) despite similar congestion markers at baseline. The BAN-ADHF score may be useful clinically to identify patients at risk of diminished response to diuretics.

The global rise of antimicrobial resistance necessitates innovative strategies to combat persistent infections, including those caused by Helicobacter pylori. This study investigates potential inhibitors of the H. pylori urease enzyme, a key virulence factor that enables survival in the highly acidic gastric environment. A virtual screening of 1773 FDA-approved drugs was performed, followed by molecular dynamics simulations. Among the top candidates, Natamycin, Zavegepant, Midostaurin, Avacopan, and Metolazone displayed significant binding affinities towards urease. Further simulations confirmed the stability and favorable interaction profiles of these drug-enzyme complexes, with the Avacopan-urease complex exhibiting the highest stability based on RMSD and binding free energy analyses. Natamycin and Avacopan were subsequently selected for in vitro validation, where both significantly inhibited urease activity and demonstrated antibacterial effects against clinical isolates and the reference strain H. pylori B128. Avacopan exhibited inhibition ranging from 30.0% in strain CL2 to 99.7% in B128, whereas Natamycin showed consistently stronger inhibition across all clinical strains, ranging from 89.2% in CL4 to 99.9% in CL1, and exceeding 90% in CL1, CL2, CL3, and B128. Both inhibitors were effective against cag-positive and cag-negative clinical isolates, indicating broad-spectrum urease inhibition. However, the bactericidal activities of these compounds were more strain-specific with increased efficacies observed in cag- isolates. Therefore, further studies are warranted to fully explore the specific mechanisms and selectivity of their individual inhibitory activities. These findings highlight Avacopan and Natamycin as promising urease-targeted drug repurposing candidates for future therapeutic development against H. pylori.

Gastric cancer (GC) is a common malignant tumour and a leading cause of cancer-related deaths worldwide. Although the OAS gene family has been implicated in various tumour-related biological processes, its specific role in GC remains unclear. This study integrated bioinformatics analysis of public datasets with experimental validation using clinical GC specimens to investigate the function of the OAS gene family in GC. We found that OAS family members were significantly upregulated in GC and associated with poor patient prognosis. Furthermore, OAS expression levels correlated with genomic mutation profiles and showed positive associations with neutrophil and dendritic cell infiltration in the tumour microenvironment, but negative correlation with B cell infiltration. In vitro functional experiments demonstrated that knockdown of OAS3 or OASL inhibited GC cell proliferation and migration, while overexpression of OASL enhanced these malignant behaviors. RNA-seq analysis revealed upregulation of SFRP4 and JUN and downregulation of ACTA2. KEGG pathway analysis indicated significant enrichment in necroptosis, MAPK signaling, PI3K-Akt signaling, cAMP signaling, viral carcinogenesis, cancer pathways, neutrophil extracellular trap formation, and IL-17 signaling pathways. Additionally, OASL may regulate DNA damage response and metabolic reprogramming. Drug prediction and molecular docking identified chlorendic acid, idarubicin, PHA-848,125, and tosedostat as potential activators of the OAS family due to their strong binding affinity. Conversely, GW842166, NSC 23,766, and metolazone showed high binding affinity for OASL and may inhibit its expression. In summary, The OAS gene family, associated with poor prognosis in gastric cancer, promotes tumour progression and represents a promising therapeutic target.

Acute heart failure is frequently encountered in acute medicine wards. Even without randomized placebo-controlled clinical studies, intravenous furosemide remains the diuretic treatment of choice. However, it sometimes proves insufficiently effective. The arsenal of diuretic treatments has significantly evolved over the past years, with an increasing amount of evidence supporting the use of both novel and older molecules for treating patients with cardiac decompensation. These include thiazides, acetazolamide, and sodium-glucose cotransporter-2 inhibitors.

The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update (CPU) is to summarize the available evidence and offer expert Best Practice Advice (BPA) on the management of ascites, hepatic hydrothorax, volume overload, and hyponatremia in patients with cirrhosis.

Background: Adherence to current clinical guidelines is crucial for ensuring optimal therapy in patients with heart failure (HF). This study aims to explore how cardiologists, as specialists in heart failure, approach the clinical scenarios encountered in the management of HF patients, in line with the recommended guidelines. A heart failure-focused meeting was organized, during which participating cardiologists engaged actively. During HF meetings in which cardiologists participated, 108 questionnaires were distributed electronically. In total, 57 men and 51 women expressed their opinions regarding the Delphi analysis. Results: A strong consensus on the benefits of beta-blockers in improving prognoses for, and reducing mortality in, patients with HF and reduced systolic function emerged. The majority of cardiologists continue to prefer intravenous therapy with continuous loop-diuretic administration in combination with thiazide diuretics. The use of metolazone elicits fewer preferences, probably due to concerns about side effects. Certainly, SGLT2i is useful in reducing hospitalizations and reducing congestion; however, there is no full consensus on whether MRAi should be discontinued in favor of SGLT2i alone. The majority of participants would discontinue MRAs in the presence of hyperkalemia and worsening renal function, maintaining sacubitril/valsartan, and indicating a priority for renal safety. There was near-unanimous agreement on the early initiation of sacubitril/valsartan after the stabilization of patients hospitalized for heart failure. Conclusions: A significant majority (97%) of cardiologists expressed a preference for utilizing all of the guideline-recommended drug classes in the management of heart failure, even if this meant not always reaching the maximum tolerated dose for each medication. This approach underscores the importance of comprehensive therapy, targeting multiple pathophysiological mechanisms in heart failure. Cardiologists emphasized that while achieving optimal dosing is ideal, flexibility in treatment regimens is often necessary to accommodate individual patient characteristics, tolerance, and clinical status. The findings highlight the need for personalized treatment strategies that align with current guidelines, while also recognizing the challenges and variability in patient responses to therapy.

Heart failure is one of the common reasons for presentations to emergency departments. Heart failure, which has an increasing prevalence and high mortality rate, significantly affects the health system. Therefore, it is important to predict mortality in emergency department. This study investigated the performance of the Emergency Heart Failure Mortality Risk Grade (EHMRG) score. In this study, we retrospectively examined the data of patients who presented to our emergency department with heart failure symptoms and were diagnosed with decompensated heart failure. The ability of the EHMRG score to determine hospitalization/discharge status and predict 7- and 30-day mortality was investigated. The study included 469 patients with a mean age of 73.09 ± 11.82 years. Patients admitted to the hospital and those who died within 7 or 30 days had higher EHMRG scores compared to those who were discharged and those who survived beyond these timeframes (P < .05). The score had a sensitivity of 69.48% and a specificity of 53.91% for making hospitalization/discharge decisions; a sensitivity and specificity of 50% and 88.96%, respectively, for the prediction of 7-day mortality; and a sensitivity and specificity of 60.98% and 74.53%, respectively, for the prediction of 30-day mortality. The EHMRG score is a useful tool for assessing disease severity, making hospital admission decisions, and predicting 7- and 30-day mortality. However, it is not a discriminatory scoring system for determining whether admitted patients require ward or intensive care. The EHMRG score can be utilized without any reservations in countries where metolazone is not available.

Methylglyoxal (MGO), a byproduct produced in the process of glycolysis, has cytotoxicity and forms advanced glycation endproducts (AGEs), which cause cell failure in several tissues. Because MGO is mainly removed by the action of glyoxalase I (GLO1), the activity of this enzyme contributes to the accumulation of MGO. We recently found that quinetazone, a diuretic pharmaceutical agent, has the potential to inhibit GLO1 activity. Therefore, we explored whether diuretics that have a similar structure to quinetazone inhibit GLO1. The inhibitory characteristics of diuretics with recombinant GLO1 were spectrophotometrically determined. Cell proliferation and accumulation of MGO-derived AGEs were evaluated by MTT assay and Western blotting. Among the thiazide, thiazide-like, and loop diuretics, metolazone and azosemide were found to inhibit GLO1 activity by 97% at 100 µM. Furthermore, we examined whether the substructures of these diuretics have inhibitory activity, quinazolinone or phenyltetrazole were determined to be the minimal structures of metolazone or azosemide required for inhibition of GLO1, respectively. In proximal renal tubule-like HK-2 and vascular endothelial cell-like EA.hy926 cells, these diuretics were shown to inhibit cell proliferation and induce accumulation of MGO-derived AGEs. In contrast, the substructures of these diuretics that did not affect GLO1 activity did not cause these changes. Metolazone and azosemide have inhibitory effects against GLO1. Considering that these diuretics are clinically employed as pharmaceutical agents, high or prolonged dosages may contribute to pathogenesis through GLO1 inhibition, followed by MGO and/or AGE accumulation.