The dopamine transporter is essential for dopamine homeostasis maintenance. Therefore, single amino acid changes in its gene can be sufficient to induce disease, such as dopamine transporter deficiency syndrome (DTDS). DTDS-associated variants may lead to DAT protein misfolding, retention in the endoplasmic reticulum, and reduced DAT surface expression. In turn, proper dopaminergic regulation is lost. Current treatments for DTDS are largely ineffective, necessitating better options. We developed a novel mouse model of DTDS harboring the A313V knock-in DAT variant, a proxy for the human A314V variant. The A313V mice are hyperactive, have decreased striatal tissue content of dopamine and increases in its metabolite HVA, and impaired dopamine uptake. FDA approved compounds alpha-methyl-para-tyrosine and amphetamine ameliorate the observed hyperactivity. Moreover, alpha-methyl-para-tyrosine may be a disease-modifying treatment by addressing the hyperdopaminergic tone underlying this hyperactivity. Noribogaine, a pharmacological chaperone for DAT, is unable to rescue DAT expression. These findings demonstrate that the A313V knock-in DAT variant mice recapitulate several defining phenotypes seen in patients with DTDS, and provide evidence for two novel treatments for the disease.

We previously identified Stromalin, a cohesin complex subunit, as a learning suppressor in Drosophila melanogaster that acts by limiting synaptic vesicle numbers in dopamine neurons. However, the mechanism by which Stromalin modulates synaptic vesicles remains unclear. We hypothesized that this occurred through the cohesin complex's function in developmental gene regulation. Through dopamine neuron-specific RNA-sequencing followed by RNAi screening, we identified Neprilysin 1 (Nep1), a zinc-dependent metallopeptidase, to be positively regulated by the cohesin complex and a key downstream effector of Stromalin. Nep1 knockdown phenocopies Stromalin knockdown effects, enhancing learning and memory and increasing synaptic vesicle markers in dopamine neurons. Like Stromalin, Nep1 suppresses synaptic strength between dopamine and mushroom body neurons. Finally, we show Nep1 overexpression rescues both memory and synaptic vesicle phenotypes caused by Stromalin reduction. Interestingly, while cohesin complex appears to set the expression levels for Nep1 during development, Nep1 function in adult flies supports its learning effects.

The Unani system of medicine, rooted in Greco-Arabic traditions, emphasizes prevention, holistic care, and community well-being. While its contributions to individualized healthcare and public hygiene are well-documented historically, attention to its contemporary applicability in addressing global health challenges has remained limited.

To explore the principles of preventive and social medicine (PSM) in the Unani framework, highlight their historical foundation, and assess their relevance in modern healthcare, particularly in relation to lifestyle disorders, mental health, and pandemics.

A narrative review was conducted by analyzing classical Unani texts, historical contributions, and contemporary research. Emphasis was placed on Asbāb Sitta Darūriyya (six essential factors), Mizāj (temperament), and collective health practices described in Unani literature.

Preventive measures in Unani medicine include dietary moderation, exercise-rest balance, Harakat-o-Sukūn Nafsānī (stress regulation), hygiene, and sanitation. Classical physicians such as Ibn Sina advocated quarantine during epidemics, while Galen emphasized sanitation and environmental health. These principles align with modern public health strategies. Recent AYUSH guidelines during the COVID-19 pandemic illustrate the potential of integrating Unani regimens and immunity-boosting interventions into mainstream healthcare.

Unani medicine offers a timeless perspective on PSM. Its holistic emphasis on individual well-being, community health, and environmental balance makes it highly relevant to current global healthcare challenges. Future directions include empirical validation of Unani interventions, standardization of practices, and integration into national and global health frameworks.

Unani Medicine, Preventive Health Services, Public Health, Lifestyle Diseases, Mental Health, Pandemics.

This study describes and evaluates the acceptance procedure for a ViewRay (VR) MRIdian 0.35T MR-Linac, emphasizing key challenges, limitations, and recommendations to enhance clinical performance and accuracy.

A comprehensive acceptance test was conducted at a single institution, following the manufacturer's protocols and aligned with established acceptance guidelines. Specific tools and phantoms were used to assess three primary components: mechanical, dosimetric, and Magnetic Resonance Imaging (MRI).

Overall, the test outcomes satisfied the manufacturer's specifications. However, certain issues were identified: high couch attenuation at specific gantry angles (leading to their exclusion from treatment), variations in magnetic field homogeneity at different gantry angles, and discrepancies between TPS calculations and measurements for field output factors smaller than 0.83 cm × 0.83 cm.

This work provides a detailed account of the acceptance testing procedure and establishes a QA baseline for 0.35T MR-Linac systems. In doing so, it also identifies key system limitations, such as couch attenuation, magnetic field inhomogeneity, and small-field output discrepancies, underscoring the need for careful gantry angle selection, field homogeneity optimization, and meticulous validation of very small fields.

Heart failure remains one of the leading causes of cardiovascular morbidity and mortality, impairing the quality of life. Based on randomized, controlled clinical trials, SGLT2 inhibitors significantly improve outcomes and reduce symptoms. However, real-world evidence is essential to better assess their effectiveness and safety in everyday clinical practice.

To evaluate the effects of empagliflozin therapy on the quality of life and functional status, as well as to assess its safety profile in the Hungarian cohort of the international Emp-Activity study, covering the full spectrum of heart failure.

This prospective, non-interventional, multicenter, observational study involved symptomatic heart failure patients enrolled from 11 Hungarian centers. A total of 106 patients were enrolled, of whom 101 were assigned to the empagliflozin cohort and 5 to the non-empagliflozin cohort. Patients received empagliflozin as part of routine heart failure therapy and completed the Kansas City Cardiomyopathy Questionnaire (KCCQ-12) at baseline and after 24 weeks. Functional status was assessed using the New York Heart Association (NYHA) classification.

101 patients were enrolled to the empagliflozin cohort (median age 69 years, 28.7% female), primarily in NYHA class II and III. Among them, 57% had HFrEF, 19% HFmrEF, and 22% HFpEF. The most frequent etiology was ischemic heart disease (42%). The most common comorbidities included hypertension (58%), atrial fibrillation (33%), diabetes mellitus (26%), and hyperlipidemia (25%). A significant improvement was observed in the KCCQ-12 overall score (74.3 ± 19.5 vs. 67.1 ± 19.5, p<0.01), with clinically meaningful improvement (≥5-point increment) in 53% of patients. The NYHA class improved significantly. Systolic blood pressure decreased (131 ± 16 mmHg vs. 127 ± 17 mmHg, p = 0.02), while diastolic blood pressure, serum creatinine, and potassium levels remained stable during the 24-week follow-up.

In Hungarian patients with heart failure, 24-week empagliflozin treatment resulted in significant improvements in the quality of life and functional capacity, while being well tolerated. These findings support the effectiveness and safety of empagliflozin in routine clinical practice across the full spectrum of heart failure. Orv Hetil. 2026; 167(7): 257-264.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have consistent nephroprotective effects across diverse patient populations, including those with glomerular disease without diabetes mellitus. These somehow unexpected benefits cannot be solely explained by glycosuria and intrarenal hemodynamic effects. Experimental evidence largely supports the effects of SGLT2 inhibitors on several pathways, many of them outside the kidneys. This review explores the mechanisms underlying these benefits, focusing on those of importance in primary and secondary glomerulonephritis. In addition to glucose homeostasis, SGLT2 inhibitors exert local and systemic effects that mimic nutrient deprivation, impacting inflammation, immunity, autophagy, hypoxia responses, ferroptosis, lipotoxicity, and energy metabolism. Sodium-glucose cotransporter 2 inhibitors modulate inflammatory pathways through suppression of cytokines and NLR family pyrin domain containing 3 inflammasome activity, mechanisms relevant to immunoglobulin A glomerulonephritis, lupus nephritis, and anti-neutrophil cytoplasmic antibody-associated vasculitis. They also influence immune cell metabolism, inhibit T-cell activation, and potentially modulate B-cell and macrophage polarization. There is evidence that autophagy may show a dual role in glomerular disease. It could activate innate and adaptive immunity, so triggering the disease, or may protect podocytes, so reducing proteinuria and the risk of progression. Sodium-glucose cotransporter 2 inhibition also modulates the hypoxia inducible factor axis and reduces ferroptosis, possibly contributing to attenuate hypoxia-induced kidney damage. The upregulation of ketogenesis and activation of nutrient-sensing pathways (adenosine monophosphate-activated protein kinase-activated protein kinase, sirtuins, and mammalian target of rapamycin) further supports their role in metabolic reprogramming. Finally, they contribute to preserve gerosuppressor functions by increasing kidney Klotho, a protein with anti-aging, and-inflammatory, and antifibrotic effects, and liver betaine. Although direct clinical evidence on the specific molecular pathways targeted by SGLT2 inhibitors in glomerulonephritis remains limited, preclinical data and emerging human observations suggest SGLT2 inhibitors may offer therapeutic advantages beyond non-specific kidney-cardiovascular protection.

Identify factors influencing audiological care for chemotherapy-induced ototoxicity from the perspectives of oncology providers in the Veterans Health Administration (VA), and quantify audiology service use among Veterans receiving ototoxic chemotherapies.

We surveyed VA oncology providers to identify barriers and facilitators to ototoxicity management (OtoM). We also conducted a VA-wide retrospective cohort analysis over a 5-year period to quantify audiology service use among Veterans who received cisplatin, carboplatin, or oxaliplatin chemotherapy.

A total of 30,643 Veterans received platinum-based chemotherapy from 2014 to 2019. Few of them (< 10% on cisplatin, < 5% on carboplatin or oxaliplatin) accessed audiology services within a year of treatment. Of the 8702 patients on cisplatin, only 9.6% had two or more audiology encounters. Thirty-six oncology providers completed our survey. Most providers believed OtoM should be routine for patients on cisplatin (97%) or carboplatin (70%), but they overestimated audiology service provision levels relative to our analysis. Most providers would consider giving a different chemotherapy drug (73%) or decrease the dose (56%) for patients with ototoxicity, yet only 36% routinely referred patients to audiology. Access, perceived need, and resources were major barriers to OtoM, while care coordination was a primary facilitator.

OtoM is a care-gap for Veterans with cancer, despite its perceived value to VA oncology providers. Cisplatin and carboplatin frequently add hearing loss and tinnitus to survivors' treatment burdens. This study offers insights into oncology providers' views on OtoM, guiding efforts to address the identified care gap.

To analyze the correlation between lipid levels and the severity of polycystic ovary syndrome (PCOS) and its predictive value for pregnancy outcome.

This retrospective study included 275 PCOS patients treated with ovulation induction therapy and 234 healthy controls (used only for baseline comparisons). Lipid levels were correlated with disease phenotype and sex hormones using Spearman/Pearson coefficients. Binary logistic regression and ROC curves assessed the predictive value of lipid levels for pregnancy failure.

There were statistically significant differences between the two groups in glycemic indexes (fasting blood glucose (FBG), fasting insulin (FINS), homeostatic model assessment for insulin resistance (HOMA-IR)) and sex hormone indexes (testosterone (T), luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), anti-Müllerian hormone (AMH)). The levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (Apo B) were significantly elevated in patients with PCOS and were closely correlated with the severity of the disease. In addition, these four lipid parameters were significantly positively correlated with T, LH, FSH, and AMH, and significantly negatively correlated with E2. Elevated levels of T, LH, TG, LDL-C, and Apo B were independent risk factors for pregnancy failure after ovulation induction treatment. TG assisted in predicting pregnancy failure after ovulation induction therapy in PCOS patients with an AUC of 0.861 (sensitivity 75.61%, specificity 85.53%); LDL-C assisted in predicting pregnancy failure after ovulation induction therapy in PCOS patients with an AUC of 0.868 (sensitivity 75.61%, specificity 83.55%); and Apo B assisted in predicting pregnancy failure after ovulation induction therapy in PCOS patients with an AUC of 0.836 (sensitivity 74.80%, specificity 86.84%).

Lipid levels were significantly correlated with the severity of disease in PCOS patients, and TG, LDL-C, and Apo B levels assisted in predicting the occurrence of pregnancy failure after ovulation induction therapy.

Although prostate magnetic resonance imaging (MRI) enhances the detection of high-grade prostate cancer (PCa), its predictive role in active surveillance (AS) of favorable risk PCa is unclear. We examined the association between baseline MRI Prostate Imaging-Reporting and Data System (PI-RADS) score and Gleason Grade Group (GG) upgrade risk among patients managed with AS.

We systematically searched eight databases to identify studies evaluating the association between baseline PI-RADS score and the risk of GG upgrade in patients managed with AS for PCa (PROSPERO: CRD42024567762). We pooled the hazard ratios (HR)using Hartung-Knapp random-effects meta-analysis models. We assessed the risk of bias using the ROBINS-I tool.

We included eleven studies (n = 6309) in the meta-analysis. The risk of bias was moderate, attributed to the retrospective and unblinded design of seven included studies. Among studies reporting baseline PI-RADS, 2,640 patients (52.1%) had PI-RADS 1-3 lesions, and 2,421 patients (47.9%) had PI-RADS 4-5 lesions. Baseline PI-RADS 4-5 was associated with an increased risk of upgrade compared to those with PI-RADS 1-3 lesions (HR:2.21, 95%CI: 1.66-2.93, p<.001). Compared to PI-RADS 1-2, the presence of PI-RADS 3 (HR:1.88, 95%CI: 1.29-2.74, p=.008), PI-RADS 4 (HR:2.73, 95%CI: 2.08-3.58, p<.001), or PI-RADS 5 (HR:3.69, 95%CI: 2.50-5.45, p<.001) lesions were associated with an increased risk of upgrade.

Baseline prostate MRI finding as assessed with PI-RADS is highly prognostic for GG upgrading among patients with favorable risk PCa managed with AS. These findings support further study of tailored surveillance strategies based on initial MRI findings.

Project Optimus has been reforming the dose selection and optimization paradigm in oncology. In this context, model-informed drug development (MIDD) approaches were utilized to validate the optimal dose selection of 6 mg/kg every 3 weeks (Q3W) for datopotamab deruxtecan (Dato-DXd) in patients with HR-positive/HER2-negative breast cancer (HR+/HER2- BC). A Tumor Growth Inhibition (TGI)-Progression-Free Survival (PFS) modeling framework was developed to assess the relationship between Dato-DXd PK exposure, tumor dynamics, and PFS, and support virtual trial simulations at different Dato-DXd dose levels. Simulations suggested that Dato-DXd at 6 mg/kg Q3W provide superior tumor control and improved PFS compared to a lower dose in patients with HR+/HER2- BC. This work underscores the importance of integrating advanced modeling techniques into the dose optimization paradigm.