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The management of Type-2 Diabetes Mellitus (T2DM) remains challenging in cases of poor glycemic control despite triple Oral Hypoglycemic Agent (OHA) therapy. This prospective cohort study aimed to assess the effectiveness of Empagliflozin as part of a quadruple OHA regimen over a 7-year follow-up period in 575 adult patients with uncontrolled T2DM on a triple OHA regimen and who were unwilling to initiate insulin therapy. Overall, 92.5% of patients achieved their target HbA1c levels. Significant reductions were observed in all glycemic parameters after 68 months (p < 0.001). Weight and BMI significantly decreased, whereas waist circumference remained unchanged. Lipid profiles showed significant improvements in total cholesterol, LDL, and triglycerides, while HDL levels did not change significantly. Blood pressure trends revealed significant reductions in both diastolic blood pressure (DBP) and mean arterial pressure (MAP), though systolic blood pressure (SBP) remained relatively stable. Our study indicates that adding empagliflozin to a drug regimen consisting of multiple OHAs can effectively control glycemia in T2DM patients with more pronounced target achievement (< 7%) and HbA1c reduction along with improvement in cardiometabolic parameters, suggesting its potential as a promising alternative for long-term glycemic management., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent: Informed consent was obtained from all individual participants included in the study., (© 2025. The Author(s).)

Background: Nocardia are widely present in nature and considered opportunistic pathogens. They can result in hematogenous spread infection through the ruptured skin or respiratory tract when the host's immune system is compromised. Currently, 119 species of Nocardia have been identified, with 54 capable of causing infections in humans. Nocardial brain abscesses are a rare intracranial lesion that accounts for only 2% of all brain abscesses, but have a mortality rate of 20-55%. This article reports a successfully cured case of mediastinal Nocardia infection with disseminated brain abscess., Case Presentation: The patient presented with intermittent chills, shivering, and fever, with the highest temperature of 39˚C, accompanied by shoulder and back pain, dizziness, and headaches. A chest-enhanced computed tomography (CT) revealed multiple enhanced nodulars in the bilateral hilum and mediastinum. A head-enhanced CT revealed scattered multiple ring-enhanced nodules in both cerebral hemispheres and the left cerebrum, accompanied by extensive surrounding edema. The mediastinal puncture tissue culture confirmed the growth of Nocardia. After twice discussions with multidisciplinary team (MDT) to rule out the possibility of mediastinal and intracranial metastatic tumors, we promptly initiated treatment with a triple-drug antibiotic regimen consisting of imipenem/cilastatin sodium, linezolid dextrose, and Trimethoprim-sulfamethoxazole (TMP-SMX). The patient ultimately achieved complete remission., Conclusions: Mediastinal nocardiosis with disseminated brain abscesses is a rare condition that can be difficult to differentiate from brain metastases caused by lung cancer. Bacterial culture results, imaging features, and MDT discussions are crucial for accurate diagnosis and treatment. A triple-drug antibiotic regimen has been found to be effective in treatment with acceptable levels of toxicity., Competing Interests: Declarations. Ethics approval and consent to participate: This is an observational description of a clinical case. The Ethics Committee of the General Hospital of Western Theatre Command has confirmed that no ethical approval is required. Consent for publication: Written informed consent was obtained from the patient for publication of this case report and any accompanying images. The patient has given written informed consent for his personal and clinical details. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Objective: To evaluate the additive effect of naldemedine tosylate (naldemedine) on opioid-induced constipation in cancer patients insufficiently responding to magnesium oxide treatment., Methods: We combined two randomized, double-blind, placebo-controlled, phase IIb and III trials of naldemedine and conducted a post hoc subgroup analysis. We evaluated the effect and safety of naldemedine in 116 patients who received naldemedine in addition to magnesium oxide (naldemedine group) and 117 patients who received placebo in addition to magnesium oxide (placebo group). Both groups included patients insufficiently responding to magnesium oxide for opioid-induced constipation. Effect was assessed using spontaneous bowel movement responder rate, complete spontaneous bowel movement responder rate, changes in spontaneous bowel movements and complete spontaneous bowel movements. Safety was also assessed., Results: During the 2-week treatment period, the responder rates for spontaneous bowel movement and complete spontaneous bowel movement were 73.3 and 43.1% in naldemedine group, respectively, which were significantly higher (P < 0.0001) than 41.9 and 14.5% in placebo group, respectively. Median time to first spontaneous bowel movement and first complete spontaneous bowel movement was significantly shorter (P < 0.0001) in the naldemedine group (4.0 and 21.3 h, respectively) than in the placebo group (27.7 and 211.7 h, respectively). The incidence of adverse events and diarrhoea was significantly higher (P < 0.05) in the naldemedine group than in the placebo group, while the incidence of serious adverse events and severe diarrhoea was not significantly different between the naldemedine and placebo groups., Conclusion: The study suggested the addition of naldemedine as an effective treatment option for opioid-induced constipation in cancer patients insufficiently responding to magnesium oxide treatment., (© The Author(s) 2024. Published by Oxford University Press.)

PROPEL (ATB200-03; NCT03729362) compared the efficacy and safety of cipaglucosidase alfa plus miglustat (cipa + mig), a two-component therapy for late-onset Pompe disease (LOPD), versus alglucosidase alfa plus placebo (alg + pbo). The primary endpoint was change in 6-min walk distance (6MWD) from baseline to week 52. During PROPEL, COVID-19 interrupted some planned study visits and assessment windows, leading to delayed visits, make-up assessments for patients who missed ≥ 3 successive infusions before planned assessments at weeks 38 and 52, and some advanced visits (end-of-study/early-termination visits). These were remapped to the respective planned visits. To evaluate if remapping may have overestimated treatment effects, we conducted post hoc analyses using a mixed-effect model for repeated measures based on actual time points of assessments. In this post hoc analysis, estimated mean treatment difference between cipa + mig and alg + pbo for change from baseline to week 52 in 6MWD was 11.7 m (95% confidence interval [CI] - 1.0 to 24.4; p = 0.072). In the original published analyses, between-group difference using last observation carried forward was 13.6 m (95% CI - 2.8 to 29.9; p = 0.071 [p value from separate non-parametric analysis of covariance]). Both statistical analysis approaches led to similar results and consistent conclusions, confirming the efficacy of cipa + mig for adults with LOPD. NCT03729362; trial start date: December 4, 2018.Trial registration number., Competing Interests: Declarations. Conflicts of interest: This study was supported by Amicus Therapeutics, Inc. Benedikt Schoser has received unrestricted research grants from Amicus Therapeutics, Inc., Astellas, Roche Diagnostics, Marigold Foundation, and AMDA Foundation and speaker’s honoraria from Amicus Therapeutics, Inc., Alexion, Kedrion, and Sanofi. He has participated as a scientific advisor for Amicus Therapeutics, Inc., Argenx, Astellas, Bayer, Maze, Pepgen, Sanofi, Spark, and Taysha. He declares no stocks or shares. Shahram Attarian has received consulting fees/honoraria from Sanofi, Amicus Therapeutics, Inc., Argenx, and Alexion and grant support from Biogen. He has received payment for speaking from Sanofi, Pfizer, LFB, Argenx, Alexion, Janssen, Alnylam, Novartis, Biogen, and Roche. Ryan Graham and Fred Holdbrook are employees of, and hold stock in, Amicus Therapeutics, Inc. Mitchell Goldman is a former employee of Amicus Therapeutics, Inc. Jordi Díaz-Manera has received consulting fees/honoraria from Amicus, Astellas, Sarepta, Sanofi, Argenx, and Lupin and grant support from Sanofi, Spark, Sarepta, and Boehringer Ingelheim. He has received payment for speaking from Sanofi, Sarepta, and Lupin. Ethics approval: This study was conducted in accordance with ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments, and in compliance with the United States Food and Drug Administration regulations in 21 Code of Federal Regulations 56, European Union Clinical Trials Regulation 536/2014, and the International Council for Harmonisation Good Clinical Practice guidelines. For each study site, the clinical study protocol (and any amendments) and informed consent form were reviewed and approved by the appropriate independent ethics committee/institutional review board. Consent: All patients provided signed informed consent before any study-related procedures were performed. In Japan, the patient’s parental guardian (or legal representative) also had to sign the informed consent form for patients under 20 years of age., (© 2024. The Author(s).)

Although polymyxins are a suboptimal option for difficult-to-treat resistant infections, they are still preferred as the first-line treatment, especially in low- and middle-income countries. This study assesses the efficacy of ceftazidime-avibactam (CAZ-AVI) following polymyxin B failure in patients with carbapenem-resistant Klebsiella pneumoniae (CRKP) infections. We retrospectively reviewed cases of infections caused by CRKP in adults who received CAZ-AVI as salvage therapy. Clinical features and outcomes were described, and a logistic regression model was used to assess the risk factors associated with in-hospital crude mortality. One hundred and six patients were included in this study. The median age was 56 years. The most common infectious sites were lung. The patients received CAZ-AVI as salvage therapy for a median duration of 9 days following initial treatment with polymyxin B (median, 12.5 days). Also, 91 (85.8%) patients received CAZ-AVI combination therapy, and 34 (32.1%) patients received CAZ-AVI in combination with polymyxin B. The rate of in-hospital crude mortality was 25.5% (27/106), with the highest rate observed in patients treated with regimens containing polymyxin B (41.2%; 14/34). Therapeutic response was observed in 81 (76.4%) patients, with microbiological eradication achieved in 77.1% (74/96) of cases. Multivariable analysis identified that the length of intensive care unit stays, the sequential organ failure assessment (SOFA) score at CAZ-AVI withdrawal, and regimens containing polymyxin B were independently associated with in-hospital mortality, whereas the duration of CAZ-AVI treatment was independently associated with survival. CAZ-AVI salvage therapy demonstrated improved survival outcomes in patients who experienced failure with polymyxin B therapy.IMPORTANCEFor patients with carbapenem-resistant Klebsiella pneumoniae (CRKP) infections, published experience with salvage therapy is limited after the failure of polymyxin-based initial therapy. Here, we found that ceftazidime-avibactam salvage therapy for patients with CRKP infections offers benefit in mortality., Competing Interests: The authors declare no conflict of interest.

Background: The ionic mechanism underlying Brugada syndrome (BrS) arises from an imbalance in transient outward current flow between the epicardium and endocardium. Previous studies report that artemisinin, originally derived from a Chinese herb for antimalarial use, inhibits the Ito current in canines. In a prior study, we showed the antiarrhythmic effects of artemisinin in BrS wedge preparation models. However, quinidine remains a well-established antiarrhythmic agent for treating BrS. Therefore, this study aims to investigate the efficacy of combining artemisinin with low-dose quinidine in suppressing ventricular tachyarrhythmia (VTA) in experimental canine BrS models., Methods: Transmural pseudo-electrocardiogram and epicardial/endocardial action potential (AP) were recorded from coronary-perfused canine right ventricular wedge preparation. To mimic the BrS model, acetylcholine (3 μM), calcium channel blocker verapamil (1 μM), and Ito agonist NS5806 (6-10 μM) were administered until VTA was induced. Subsequently, low-dose quinidine (1-2 μM) combined with artemisinin (100 μM) was perfused to mitigate VTA. Key parameters, including AP duration, J wave area, notch index, and T wave dispersion, were measured., Results: After administering the provocation agents, all sample models exhibited prominent J waves and VTA. Artemisinin alone (100-150 μM) suppressed VTA and restored the AP dome in all three preparations. Its infusion resulted in reductions in the J wave area and epicardial notch index. Consequently, low-dose quinidine (1-2 μM) did not fully restore the AP dome in all six sample models. However, when combined with additional artemisinin (100 μM), low-dose quinidine effectively suppressed VTA in all six models and restored the AP dome while also decreasing the J wave area and epicardial notch index., Conclusion: Low-dose quinidine alone fails to fully alleviate VTA in the BrS wedge model. However, its combination with artemisinin effectively suppresses VTA. Artemisinin may reduce the therapeutic dose of quinidine, potentially minimizing its associated adverse effects., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2025 The Korean Academy of Medical Sciences.)

Background: Mucormycosis is an opportunistic fungal infection which is associated with poor prognosis. Only a few antifungals are available in the arsenal against mucormycosis. The global guidelines for diagnosing and managing mucormycosis recommend high doses of liposomal amphotericin B (LAmB) as the first-line treatment. Isavuconazole is another potential treatment option for mucormycosis., Main Body: This systematic review aims to consolidate and analyse existing evidence concerning the efficacy and safety of isavuconazole in treating mucormycosis alone or in combination with LAmB. For data aggregation, comprehensive searches were conducted across various electronic databases, such as PubMed, Science Direct, Trip, Google Scholar, the Cochrane Library, and Open-Gray. Furthermore, we explored the gray literature, employing tailored keywords. The reference lists of the selected articles were scrutinized to identify additional pertinent publications. Articles reporting any studies, case series, or case reports on any form of mucormycosis exclusively involving human subjects published in English were included. There were no time restrictions involved. We extracted crucial data, such as publication year, country, disease form, isavuconazole dosage, frequency, duration, overall outcomes, and reported adverse effects. A total of 31 articles, which included four case series, 24 case reports, one open-label trial, one randomized controlled trial, and one non-interventional registry study, were included in the final analysis. 135 adult patients and 14 children were treated with isavuconazole as primary monotherapy, primary combination therapy, nonprimary monotherapy, or nonprimary combination therapy. The mortality rate following LAmB monotherapy, amphotericin B plus azole, amphotericin B followed with azole, posaconazole only and isavuconazole only was 32%, 6.6%, 13.7%, 17.2% and 24.6%, respectively. The heterogeneity of the studies did not allow for a comparison of the different treatment strategies (primary mono- vs. primary combination, etc.)., Short Conclusion: The use of isavuconazole in combination therapies during the acute phase via intravenous administration alongside LAmB or other triazoles, followed by long-term monotherapy via the oral route, has yielded promising recovery rates. Adverse events associated with the use of isavuconazole are infrequently reported., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Chronic anal fissures (CAFs) are the second most common anorectal disease. Non-surgical treatment includes several options with controversial efficacy. The aim of this study was to evaluate the efficacy and safety of a new ointment based on methylene blue in addition to glyceryl trinitrate., Methods: A phase II randomized single-centre triple-blinded study was carried out in a tertiary proctology unit on patients with CAF. The enrollment started after local ethics committee approval (study n. 6461, protocol approval n. 0045085). Eligible consecutive patients were randomized to one of three different groups, each receiving a different ointment. The efficacy of the treatment was evaluated with the REALISE score., Results: Nine patients were treated with cream A (median age 47 years, IQR 40-56, 22% female), nine with cream B (median age 52 years, IQR 49-57, 33% female), and nine with cream C (median age 58 years, IQR 46-62, 55% female). In group A, REALISE scores decreased significantly from a median of 22 (IQR 12-25) to 6 (IQR 4-8) (p < 0.05) after 40 days. In group B, REALISE scores improved significantly from a median of 20 (IQR 17-22) to 5 (IQR 4-9) (p < 0.05). In group C, REALISE scores decreased significantly from a median of 19 (IQR 19-20) to 4 (4-5) (p < 0.05). No statistically differences were recorded. The healing rate was 77% with creams A and C, while it was 44% with cream B., Conclusion: Methylene blue-based ointments could be a new and innovative treatment for the non-operative management and healing of CAFs., Competing Interests: Declarations. Conflict of interest: The authors have no conflicts of interest to declare. All co-authors have seen and agree with the contents of the manuscript and there is no financial interest to report. We certify that the submission is original work and is not under review at any other publication. Ethics approval and consent to participate: The local ethics committee of Hospital University of Bari approved this study (n. 6461) and protocol (approval n. 0045085/17.05.2022). The methods were carried out in accordance with the relevant guidelines and regulations. Informed consent was obtained from all participants and/or their legal guardian(s). Consent for publication: Written informed consent was obtained from all participants., (© 2025. Springer Nature Switzerland AG.)

Background: Pneumocystis jirovecii pneumonia (PcP) is an opportunistic infection for which the standard of care is co-trimoxazole. However, safety concerns and intolerance may compromise its utility., Objectives: To evaluate the safety and efficacy of the combination of echinocandins and clindamycin to treat PcP., Patients and Methods: We investigated 14 patients treated with a co-trimoxazole-free combined regimen that included echinocandins and clindamycin., Results: Clinical cure was achieved in 8 out of 14 patients, while 5 had a fatal outcome due to their primary disease; however, only one patient died due to PcP., Conclusions: Echinocandin and clindamycin may be a safe and effective alternative treatment for patients who cannot be given co-trimoxazole for PcP., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Mycoplasma genitalium, which causes sexually transmitted diseases, is increasingly resistant to key antibiotics such as macrolides and quinolones, posing a challenge for treatment., Objectives: To assess the effectiveness of prolonged sitafloxacin and doxycycline combination therapy as a new alternative treatment strategy for highly drug-resistant M. genitalium strains., Methods: A prospective cohort study was conducted at the National Center for Global Health and Medicine, Tokyo, Japan, from 1 January 2020 to 31 October 2022. Patients with M. genitalium urogenital or rectal infections and those who did not receive the initial sitafloxacin monotherapy were included. Patients were administered sitafloxacin and doxycycline for 21 days as salvage therapy. M. genitalium isolates were tested for parC, gyrA and 23S rRNA resistance-associated mutations., Results: Twenty-seven patients received the combination therapy. All M. genitalium strains available for resistance analysis had parC (24/24) and macrolide resistance-associated (25/25) mutations, and 68% (17/25) had gyrA mutations. The overall cure rate was 77.8%. For strains with concurrent parC and gyrA mutations, the cure rate was 68.8% (P = 0.053) compared with that for monotherapy (37.5%)., Conclusions: Prolonged combination therapy is highly effective against M. genitalium strains with concurrent parC and gyrA mutations. Future research should focus on establishing the optimal treatment duration and monitoring the risk of resistance., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Second-generation integrase strand transfer inhibitors (InSTIs) have a high barrier to resistance and potent antiretroviral activity. They are recommended as first- or second-line (FL and SL) options in two- and three-drug regimens (2DR and 3DR) in international treatment guidelines. However, there are limited real-world data on emerging resistance at the time of virological failure (VF) with these regimens., Objectives: The Virostar-1 study objective is to analyse the emergence of resistance-associated mutations (RAMs) over 3 years with DTG-based 2DRs and DTG- or bictegravir (BIC)-based 3DRs in people living with HIV (PLWH) experiencing a VF (FL or SL)., Methods: Retrospective analysis of genotypic resistance detected at the time of a FL or SL VF with BIC/FTC/TAF, DTG/ABC/3TC, DTG/3TC and DTG/RPV between 2019 and 2022 was conducted from a French multicentre database. VF was defined as two consecutive HIV-1 plasma viral loads > 50 c/mL. Sanger assays were performed at VF within standard clinical care. Resistance mutations were reported using the ANRS algorithm. Selection biases prevent group comparisons., Results: During the period, N = 5986 PLWH were followed either in FL or SL. The VF rate was overall low: BIC/FTC/TAF, 6.8%; DTG/ABC/3TC, 7.5%; DTG/3TC, 5.1%; and DTG/RPV, 2.1%. Some emergent InSTI or NRTI RAMs were detected with BIC/FTC/TAF 4%, DTG/ABC/3TC 8.5%, DTG/3TC 18% and 39% emergent NNRTI RAMs with DTG/RPV. However, a complete absence of dual resistance against NRTIs and InSTIs was observed., Conclusions: We detected rare emergent InSTI RAMs and few emergent NRTI RAMs in PLWH failing DTG- or BIC-based regimens in FL or SL. The observed rates of emergent RAMs at VF were 4% with BIC/FTC/TAF, 8.5% with DTG/ABC/3TC, 18% with DTG/3TC and 39% with DTG/RPV., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: Nonalcoholic fatty liver disease (NAFLD) is the extremely usual reason of chronic liver disease, extending from simple hepatic steatosis (HS), nonalcoholic steatohepatitis (NASH) to advanced hepatic fibrosis and cirrhosis. Though orlistat is a Food and Drug Administration (FDA) approved drug for long-duration management of obesity, few cases of severe hepatic insult were declared. Melatonin is an efficient antioxidant; it also regulates metabolic processes that lead to fat accumulation and obesity., Aim of the Work: The current research aimed to compare the impact of orlistat, melatonin, and their combination on the structural changes of the hepatic tissue of adult male albino rats supplied with high fat diet (HFD)., Material and Methods: Thirty adult male albino rats divided into five groups. Liver specimens were divided into two parts. One-half was processed to obtain paraffin blocks, and the other half was processed to obtain semithin sections. Morphometric study and statistical analysis were done., Results: Hepatic tissue from the HFD group showed steatosis, ballooning, and inflammation and all these parameters were moderately improved - except for inflammation which worsened with therapy. Combined orlistat and melatonin-treated groups showed marked improvement of all parameters as well as marked improvement in the hepatic fibrosis.Orlistat/Melatonin combination therapy is both safe and effective in comparison to orlistat and melatonin monotherapy.

Therapeutic nucleic acids (TNAs) are a new class of drugs that exhibit different properties and mechanisms of action from those of small molecules or biological drugs. Over twenty oligonucleotide drugs and several COVID-19 vaccines have received regulatory approval for clinical use. A characteristic feature of these TNAs is that they are directed against one specific biological target and one specific RNA or DNA sequence. Consequently, TNAs currently used are administered as monotherapy. Due to the known advantages of multidrug therapy with low molecular weight drugs, it may be time to intensify work on such a treatment protocol, also in the case of TNAs., (© 2024 Wiley-VCH GmbH.)

Several trials have evaluated diuretic-based strategies to improve symptoms and outcomes in patients with acute heart failure (AHF). The authors sought to summarize the effect of different combination strategies on symptoms, physical signs, physiological variables, and outcomes in patients with AHF. Twelve trials were identified that assessed the addition of thiazide diuretics, sodium-glucose cotransporter 2 inhibitors, mineralocorticoid receptor antagonists, vasopressin receptor antagonists, carbonic anhydrase inhibitors, or loop diuretic intensification to conventional therapy for AHF. The trials evaluated short-term markers of congestion and symptoms, and none were powered for clinical outcomes. Short-term responses (such as relief from dyspnea, physical signs of congestion, and weight change) varied greatly across studies; all diuretic strategies were accompanied by short-term increases in serum creatinine and did not demonstrate benefits on mortality or recurrent heart failure events. The available evidence suggests that intensification of loop diuretic agents produces relief of physical signs of decongestion, but the importance of different strategies for short-term decongestion strategy for health status and long-term outcomes has not been established., Competing Interests: Funding Support and Author Disclosures Dr Packer has received consulting fees from 89bio, Abbvie, Altimmune, Amgen, Ardelyx, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Lilly, Moderna, Novartis, Reata, Regeneron, Relypsa, and Salamandra, and is a Trial Executive Committee member of the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance. Dr Ezekowitz has received research grants from American Regent, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb/Pfizer, eko.ai, US2.ai, Merck, Novartis, Otsuka, Sanofi, and Servier, and consulting fees from American Regent, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb/Pfizer, Merck, Novartis, Otsuka, Sanofi, and Servier. Dr Fonarow has served as a consultant for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Eli Lilly, Johnson and Johnson, Medtronic, Merck, Novartis, and Pfizer. Dr Greene has received research support from the Duke University Department of Medicine Chair’s Research Award, American Heart Association, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, Otsuka, Pfizer, and Sanofi; has served on advisory boards or as a consultant for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Corteria Pharmaceuticals, CSL Vifor, Cytokinetics, Eli Lilly, Lexicon, Merck, Novo Nordisk, Otsuka, Roche Diagnostics, Sanofi, scPharmaceuticals, Tricog Health, and Urovant Pharmaceuticals; and has received speaker fees from Bayer, Boehringer Ingelheim, Cytokinetics, Lexicon, and Roche Diagnostics. Dr Mentz has received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Eli Lilly, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Medtronic, Merck, Novartis, Relypsa, Respicardia, Roche, Sanofi, Vifor, Windtree Therapeutics, and Zoll. Dr Testani has received fees from 3ive labs, Bayer, Bristol-Myers Squibb, AstraZeneca, Novartis, Cardionomic, MagentaMed, Reprieve, Fire1, W.L. Gore and Associates, Sanofi, Sequana Medical, Otsuka, Abbott, Merck, Windtree Therapeutics, Lexicon Pharmaceuticals, Precardia, Relypsa, Regeneron, Becton Dickinson, Edwards Lifesciences, and Lilly, and holds a patent for treatment of diuretic resistance issued to Yale and Corvidia Therapeutics, a patent for methods for measuring renalase issued to Yale, and a patent for treatment of diuretic resistance pending with Reprieve. Dr Voors has received research support and/or has been a consultant for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, Myokardia, Novo Nordisk, Novartis, and Roche Diagnostics. Dr Butler has received payment or honoraria for lectures, presentations, Speakers Bureau, manuscript writing, or educational events from Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca, Bayer, BerlinCures, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, Sequana Medical, Occlutech, and Vifor, and is a Trial Executive Committee member of Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance. All other authors have no relationships relevant to the contents of this paper to disclose., (Copyright © 2025 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Catechol-O-methyl transferase (COMT) inhibitors are routinely used to manage motor fluctuations in Parkinson's disease (PD). We assessed the effect of opicapone on motor symptom severity in levodopa-treated patients without motor complications., Methods: This was a randomized, double-blind, 24-week, placebo-controlled study of opicapone 50 mg as adjunct to levodopa (NCT04978597). Levodopa-treated patients without motor complications were randomized to 24 weeks of double-blind treatment with adjunct opicapone 50 mg or matching placebo. The primary efficacy endpoint was the mean change from baseline to week 24 in Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) total score., Results: A total of 355 patients were randomized (opicapone 50 mg n = 177, placebo n = 178) and 322 (91%) completed the double-blind period. The adjusted mean [95% CI] change from baseline to week 24 in MDS-UPDRS-III subscore was -6.5 [-7.9, -5.2] in the opicapone group versus -4.3 [-5.7, 3.0] in the placebo group resulting in a significant difference of -2.2 [-3.9, -0.5] favoring opicapone (p = 0.010). There was no difference in the incidence of patients who developed motor complications (5.5% with opicapone vs. 9.8% with placebo) and the incidence of adverse events considered related to study medication was similar between groups (opicapone 10.2% vs. placebo 13.5%)., Conclusions: Treatment with once-daily adjunct opicapone was well tolerated, improved motor severity, and did not induce the development of motor complications. These results support the clinical usefulness of opicapone in the management of PD patients without motor complications., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

The first combination inhaled corticosteroid and short-acting beta₂ agonist (ICS-SABA) was approved by the Food and Drug Administration (FDA) in 2023 for as-needed treatment or prevention of bronchoconstriction and to reduce the risk of asthma exacerbations in patients 18 years of age and older. The recently approved product contains an ICS-albuterol combination. The 2024 Global Initiative for Asthma (GINA) guidelines recommend as-needed ICS-formoterol as the preferred asthma reliever therapy; however, a GINA alternative recommendation is the use of ICS whenever an as-needed (SABA) is used. There is no difference in as-needed asthma treatment recommended by the GINA guidelines in older adults, and there has been minimal study in older adults. Because of limited guidance on the use of the ICS-SABA reliever inhaler in older adults, the purpose of this review is to evaluate the DENALI and MANDALA studies and the potential role of ICS-SABA in older adults. The mean ages in both studies were 50 years. The MANDALA primary outcome result was a statistically significant lower risk of severe exacerbations in the ICS-SABA reliever group compared with the as-needed albuterol (ALB) group at 24 weeks. In the MANDALA older adults subgroup analysis, there was not a statistically significant difference in the ICS-SABA reliever group compared with the as-needed ALB-alone group but the results favored ICS-SABA. The DENALI primary outcome results were a greater change from baseline in forced expiratory volume in the first second (FEV1) area under the curve averaged over 12 weeks with albuterol/budesonide (ALB-BUD) 180/160 ug compared with budesonide alone and placebo and a greater change from baseline in trough FEV1 with ALB-BUD 180/160 ug and 180/80 ug than ALB-alone and placebo. Because of minimal adverse effects in both trials and the benefits in preventing asthma exacerbations reported in the MANDALA trial, it is important to assess and recommend that older adults with asthma receive inhaled corticosteroid with their reliever asthma inhaler.

The APLAR has published a set of recommendations on the management of systemic lupus erythematosus (SLE) in 2021. The current consensus paper supplements and updates specifically the treatment of lupus nephritis (LN) according to two rounds of Delphi exercise from members of the APLAR SLE special interest group, invited nephrologists, histopathologists, and lupus nephritis patients. For initial treatment of LN, we recommend a combination of glucocorticoids (GCs) with cyclophosphamide (CYC), mycophenolate mofetil (MMF), or the calcineurin inhibitors (CNIs) as first-line options. An upfront combination of immunosuppressive drugs and the biological agents may be considered in patients at significant risk of disease progression and renal function deterioration. Switching or "add-on" among different immunosuppressive agents, including biological agents, may be considered for refractory disease. Subsequent/maintenance therapy of LN should continue for at least 3 years to reduce the risk of renal flares. Lower dose MMF and azathioprine are options, but MMF maintenance should follow induction by the same drug. Prednisolone or equivalent should be maintained at a dose of 5 mg/day or less. The APLAR consensus for the management of LN includes recommendations for adjunctive therapies, monitoring and treatment of LN-related co-morbidities, and renal replacement therapies. It is hoped that this consensus paper can provide an evidence-based and pragmatic approach to the management of LN, taking into account the evidence level of therapies in Asian patients, cost-effectiveness, and differences in health care resources and reimbursement policies in the Asia-Pacific region., (© 2025 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Introduction: Novel approaches to improve long-term outcomes in kidney transplant recipients are required. Here, we present the 5-year data from a multicenter, prospective, Phase 3b trial evaluating treatment outcomes with standard (STD) or low (LOW) dose prolonged-release tacrolimus (TAC) combined with ACEi/ARB or other antihypertensive therapy (OAHT) in Canadian kidney transplant recipients., Methods: Adult de novo kidney transplant recipients were randomized 2 × 2 to STD or LOW dose TAC and ACEi/ARB or OAHT. Patients had received a first or second transplant from a living or deceased donor and had ≥ 1 human leukocyte antigen mismatch with their donor., Results: There were 281 patients from 13 sites across Canada. Overall patient survival was 95.7% and was comparable between groups. Graft survival at study end was 89.7% in the LOW+OAHT group and 94.4%-97.1% in the other groups and BPAR, and Class II de novo donor-specific antibodies (dnDSA) were higher in the LOW+OAHT group than in the other groups. However, these differences were not statistically significant. Graft function, blood pressure (BP), and proteinuria were similar between the groups; however, between 2 and 5 years there was a 2-fold or greater increase in the use of ACEi/ARB in patients randomized initially to OAHT, mostly because of hypertension and proteinuria. There were no unexpected safety findings., Conclusion: Patients randomized to LOW TAC with renin-angiotensin system (RAS) blockade had similar outcomes at 5 years as patients treated with STD TAC with or without RAS blockade, whereas those randomized to LOW TAC without RAS blockade showed a non-significant trend towards more rejections and dnDSA TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00933231., (© 2024 The Author(s). Clinical Transplantation published by Wiley Periodicals LLC.)

Sesamol (SES) and linalool (LIN) are aromatic compounds that have neuroprotective effects. The main purpose of this study is to evaluate the anxiolytic activity of LIN and SES co-treatment on Swiss albino mice and analyze its possible mechanism through in silico study. In this sense, the mice were given the gamma-aminobutyric acid type A receptors (GABA A ) agonist diazepam (DZP; 3 mg/kg, p.o.) as a positive control. A vehicle (10 mL/kg) was served as control. The tested chemicals, single-dose LIN (50 mg/kg) and SES (50 mg/kg), as well as a combination (LIN + SES) and (DZP + LIN + SES), were administered orally in order to conduct several behavioral tests, including open-field, swings box, hole-crossing, and dark-resident time tests. Further, molecular docking studies of LIN, SES, and DZP were carried out through different software. The results showed that LIN and SES individually have significant anxiolytic-like activity in mice. Further, when LIN was combined with SES and with (SES + DZP), it exhibited a relatively lower locomotor activity in mice compared to individual treatment groups, indicating a synergistic action. In addition, the molecular docking analysis revealed that LIN and SES have a moderate binding affinity (-5.0 and -5.1 kcal/mol) toward the GABA A receptor α3 subunit. In conclusion, our findings suggest that LIN and SES exerted synergistic anxiolytic activity on Swiss albino mice, possibly through the GABAergic interaction pathways., (© 2024 Wiley Periodicals LLC.)

The efficacy of opioids in the treatment of chronic pain is limited; however, the adverse effects they produce are considerable. N-palmitoylethanolamide (PEA), a bioactive lipid mediator with structural similarities to endocannabinoids, has exhibited notable anti-inflammatory and analgesic effects in preclinical models. The objective of this study was to investigate the antinociceptive properties, motor coordination (MC), and constipation effects of tramadol and PEA in combination within a neuropathic pain model. The antinociceptive effects of tramadol (TRA) and PEA in various combination ratios were assessed using a CCI model of neuropathic pain in 126 male Wistar rats, divided into 21 groups: vehicles, GBP (1.0-177.78 mg/kg), TRA (1.0-31.62 mg/kg), PEA (0.0316-10 mg/kg), or TRA (1.0-10 mg/kg) with PEA (0.0316-1.0 mg/kg), all compounds were administered orally. The results of the dose-response analyses indicated that PEA was approximately five and eightfold more potent than tramadol in producing anti-hyperalgesic and anti-allodynic effects, respectively. The results of the surface of synergistic interaction (SSI) analysis indicated that the combination of TRA 10 mg/kg + PEA 0.0316 mg/kg exhibited the most pronounced anti-hyperalgesic effects and the most favorable anti-allodynic outcomes among the various combinations. No significant differences in MC or constipation were observed between the vehicle and optimal combination group. The results of this study demonstrate that sub-antinociceptive doses of tramadol, when combined with PEA, significantly enhance the antinociceptive efficacy of tramadol without the induction of typical opioid-associated side effects. These findings propose a novel approach to the treatment of pain., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Mild cognitive impairment is increasingly recognized as a complication of type 2 diabetes (T2D). Although currently no disease-modifying treatments for cognitive disorders exist, interest surged in potential neuroprotective effects of newer anti-diabetic drugs. This study investigates the impact of newer anti-diabetic drug classes, dipeptidyl peptidase-4 (DPP-4i) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) - on cognitive decline in T2D patients on metformin therapy. A prospective observational cohort study was conducted, with a follow-up duration of 6 months. The study compared the cognitive performance of T2D patients on metformin monotherapy to those on a combination of metformin with DPP-4i or SGLT2i, using the Montreal Cognitive Assessment Battery. A group of healthy volunteers served as a reference. At baseline, patients receiving combination therapy had a cognitive performance comparable to that of healthy volunteers, while those on metformin monotherapy scored lower. These differences persisted for patients who completed the follow-up, though there was no change within group. Baseline differences were independent of glycemic control, blood lipids, renal function, and serum inflammatory markers. Comprehensive metabolomics and lipidomics revealed that T2D patients on metformin monotherapy exhibited enriched purine, glutathione and sphingolipid metabolism, with alterations in xanthine, L-pyroglutamic acid, and several sphingomyelins. These changes suggest increased oxidative stress in T2D, mitigated in the combination therapy group, as evidenced by total serum antioxidant capacity. As such, we conclude that the combination of DPP-4i or SGLT2i with metformin positively impacts cognitive function in T2D patients by modulating metabolic pathways rather than improving glycemic control, peripheral diabetic complications, or systemic inflammation., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Albendazole/ivermectin combination therapy is a promising alternative to benzimidazole monotherapy alone for Trichuris trichiura control. We used fecal DNA metabarcoding to genetically characterize Trichuris spp. populations in patient samples from Côte d'Ivoire showing lower (egg reduction rate <70%) albendazole/ivermectin sensitivity than those from Laos and Tanzania (egg reduction rates >98%). Internal transcribed spacer (ITS) 1 and ITS2 metabarcoding revealed the entire detected Côte d'Ivoire Trichuris population was phylogenetically distinct from T. trichiura found in Laos and Tanzania and was more closely related to T. suis. Mitochondrial genome sequencing of 8 adult Trichuris worms from Côte d'Ivoire confirmed their species-level differentiation. Sequences from human patients in Cameroon and Uganda and 3 captive nonhuman primates suggest this novel species, T. incognita, is distributed beyond Côte d'Ivoire and has zoonotic potential. Continued surveillance by using fecal DNA metabarcoding will be needed to determine Trichuris spp. geographic distribution and control strategies.

Aluminum chloride (AlCl 3 ), a known neurotoxic and Alzheimerogenic metal disrupts redox homeostasis which plays a pivotal role in pathophysiology of neurodegenerative disorders, particularly cognitive decline. The current study was designed to unveil the long-term neuroprotective outcomes and efficacy of CoQ10 and curcumin low dose (100 mg/kg each) combination in 18-months old geriatric male Balb/c mice subjected to AlCl 3 -prompted memory derangements (200 mg/kg in water bottles) for 28 days. The neuroprotective properties driven by antioxidant mechanisms were assessed via observing cellular pathology in key-memory related brain regions including the cornuammonis (CA3 and DG) and cortex 2/3 layer. Our outcomes revealed that AlCl 3 exposure significantly reduced spatial learning and memory. In contrast, CoQ10 and curcumin combinatorial regime markedly mitigated cognitive deficits Vs. individual high-dose in AlCl 3 -treated animals as demonstrated by their improved performance in neurobehavioral tests such as the Y-maze, novel object recognition, passive avoidance and Morris-water maze test. Additionally, CoQ10 and curcumin co-administration restored redox balance by significantly reducing the levels of oxidative stressor (MDA) and increasing the anti-oxidant capacity (SOD,GPx). AchE is an enzyme involved in acetylcholine breakdown which negatively impacts acetylcholine levels and memory function. AlCl 3 exposure elevated AchE levels in mice brains vs. treatment. This neurochemical alteration was notably reversed in the dual-treatment group. Furthermore, CoQ10 and curcumin ameliorated AlCl 3 -induced neurotoxicity by preserving neuronal cytoarchitecture in both cortical and hippocampal regions. In conclusion, CoQ10 and curcumin combination might attenuate memory loss induced by AlCl 3 -intoxication via restoring aberrant AchE activity, enhanced anti-oxidant defenses and salvaging the deleterious neuronal damage., Competing Interests: Declaration of competing interest The authors indicated no potential conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: DONATE (NCT03156985) is a large-scale real-world study investigating the safety of dapagliflozin in Chinese type 2 diabetes mellitus (T2DM) patients. This post-hoc analysis aims to further evaluate the real-world safety of dapagliflozin plus metformin., Methods: Safety outcomes were assessed in patients receiving concomitant dapagliflozin and metformin, with or without other antidiabetics. The safety of dapagliflozin-based dual-therapies and dapagliflozin and metformin-based triple-therapies were also analysed., Results: Among the 2,990 patients in DONATE, 2,165 (72.4%) received concomitant metformin. Among these 2,165 patients, 780 (36.0%) experienced ≥1 adverse event (AE), 129 (6.0%) experienced serious AE (SAE), and 96 (4.4%) experienced AE leading to dapagliflozin discontinuation. The most common AEs were upper respiratory tract infection (4.0%), urinary tract infection (UTI, 2.1%) and constipation (1.5%). The most common AEs of special interest of dapagliflozin were UTI (2.3%), genital tract infection (1.5%) and hypoglycaemia (1.1%). In the dapagliflozin and metformin dual-therapy subgroup, the incidences of AE, SAE and AE leading to dapagliflozin discontinuation were 26.7%, 2.5%, and 1.9%, respectively, numerically lower than that of the total population and most other dual-therapy subgroups. These patients also had numerically improved metabolic outcomes than baseline., Conclusion: Dapagliflozin and metformin combination therapy is well-tolerated in real-world Chinese T2DM patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Objective: Cenobamate is a novel anti-seizure medication (ASM) with unusually high responder rates even in patients with refractory epilepsy. Due to its enzyme-inducing properties, cenobamate could negatively affect bone metabolism, similar to other ASMs; however, effects of long-term cenobamate treatment on bone health have not yet been investigated. The aim of this longitudinal observational study was to assess the effects of 1 year of continuous, adjunctive cenobamate treatment on bone health in patients with drug-resistant, focal epilepsy., Methods: Adult patients from a tertiary epilepsy centre received cenobamate add-on to their concomitant anti-seizure medication. Bone mineral density at femoral neck and lumbar spine, as well as bone formation biomarkers, electrolytes and liver enzymes in serum were assessed at baseline and after 12 months of continuous cenobamate therapy., Results: Forty-seven patients (29 male, median age 40 years) were included in the study. Median daily dose of cenobamate at 12 months was 250 mg. Moderate, yet statistically significant reduction of the T-score at femoral neck but not lumbar spine was found after 1 year of cenobamate treatment, also in a subgroup of patients (n = 37) without enzyme inducers in the comedication. Additionally, we observed statistically significant changes in bone formation biomarkers: decreased serum level of osteocalcin and increased bone-specific alkaline phosphatase. Bone minerals (calcium and phosphorus) as well as vitamin D3 remained unchanged. Parathormone was statistically significantly reduced. There was a highly statistically significant increase in serum gamma-glutamyl transferase (GGT) levels after 12 months of treatment, reflecting an underlying hepatic enzyme induction by cenobamate., Conclusion: A statistically significant decrease of the T-score at femoral neck, as well as prominent alterations in the bone formation biomarkers, suggest an increase in bone turnover after 1 year of cenobamate treatment. The underlying mechanism is most likely attributed to the hepatic enzyme activation, indicated by a prominent elevation of serum GGT. The results alert for bone density control in susceptible patient groups., Trial Registration Number: DRKS00027568, March 2, 2022 retrospectively registered., Competing Interests: Declarations. Funding: Open Access funding enabled and organized by Projekt DEAL. Conflict of interest: Yulia Novitskaya received lecture fees from Eisai. Andreas Schulze-Bonhage received honoraria for lectures or consulting fees from Angelini Pharma, Bial, Desitin, Eisai, GW Pharmaceuticals, JAZZ Pharma, and UCB Pharma outside the submitted work. Elisa Schütz received honoraria for lectures and support for attending one congress from Angelini Pharma, outside of the present work. Martin Hirsch received lecture fees and consulting fees from UCB, Liva Nova, Precisis AG, Bial, Eisai and Angelini Pharma outside of the present work. Ethics Approval: Approval was obtained from the ethics committee of University of Freiburg, Germany (reference number 21-1505). The procedures used in this study adhere to the tenets of the Declaration of Helsinki. Consent to Participate: Written informed consent was obtained from participants or their legal guardian to participate in the study. Consent for Publication: Not applicable. Data Availability: The dataset generated and analyzed during the current study is not publicly available due to restrictions in sharing patients’ data according to the European Data Protection Regulation. Code Availability: Not applicable. Author Contributions: Yulia Novitskaya: data collection, analysis and interpretation of results, visualization, writing—original draft. Andreas Schulze-Bonhage: conceptualization, writing—review & editing. Elisa Schütz: data collection, writing—review & editing. Martin Hirsch: conceptualization, methodology, data collection, writing – review & editing, supervision. All authors have read and approved the final submitted manuscript, and agree to be accountable for the work., (© 2024. The Author(s).)

Introduction: Drug-resistant epilepsy usually requires the use of polytherapy with antiseizure medications (ASMs) for management, which could involve side and adverse effects that may impact quality of life (QOL). This systematic review summarizes the evidence about the relationship between ASM polytherapy and QOL in epilepsy patients, considering clinical, sociodemographic, and psychological variables., Method: This review followed the PRISMA guidelines and was registered in PROSPERO. The studies examined were collected from PubMed/MEDLINE, Scopus, Web of Science, and Embase. The data extracted were categorized into three categories: therelationship between the number of ASMs and QOL, differences in QOL between patients taking polytherapy and patients taking monotherapy, and therole of other variables on QOL., Results: The review included 34 studies. Thirty examined the relationship between the number of ASMs and QOL, 93.3% of them identifying a significant association between a higher number of ASMs and poorer QOL. Fifteen studies analyzed differences in QOL between patients receiving polytherapy and those on monotherapy, all of them showing poorer QOL in those on polytherapy. Thirty-two studies considered other factors beyond polytherapy as determinants of QOL, including clinical, sociodemographic, and psychological variables, and higher seizure frequency and mood comorbidities (depression and anxiety) emerged as the strongest predictors of poor QOL., Conclusions: Polytherapy, despite being necessary for managing drug-resistant epilepsy, significantly contributes to impairing QOL. Effective seizure control remains critical, but a multifactorial approach addressing mental health and social determinants is essential for improving QOL in epilepsy patients. Future research should focus on optimizing treatment strategies that balance seizure control by minimizing the negative impact of polytherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Exacerbations of asthma and chronic obstructive pulmonary disease (COPD) are important events and are associated with critical illness. Eosinophilic inflammation is a treatable trait commonly found during acute exacerbations of asthma and COPD. We hypothesised that for patients with eosinophilic exacerbations, a single injection of benralizumab, a humanised monoclonal antibody against interleukin-5 receptor-α, alone or in combination with prednisolone, will improve clinical outcomes compared with prednisolone, the standard of care., Methods: The Acute exacerbations treated with BenRAlizumab trial (ABRA) was a multicentre, phase 2, double-blind, double-dummy, active placebo-controlled randomised trial completed in the UK at Oxford University Hospitals NHS Foundation Trust and Guy's and St Thomas' NHS Foundation Trust. Patients were recruited from urgent care clinics and emergency departments of these two hospitals. At the time of an acute exacerbation of asthma or COPD, adults with blood eosinophil counts of equal to or more than 300 cells per μL were randomly assigned in a 1:1:1 ratio to receive acute treatment with: prednisolone 30 mg once daily for 5 days and 100 mg benralizumab subcutaneous injection once (BENRA plus PRED group); placebo tablets once daily for 5 days and 100 mg benralizumab subcutaneous injection once (BENRA group); or prednisolone 30 mg once daily for 5 days and placebo subcutaneous injection once (PRED group). Randomisation was performed with a centralised interactive computer randomisation service. All patients and study research staff involved in data collection were masked to study blood results and treatment allocation. The co-primary outcomes were proportion of treatment failures over 90 days and total visual analogue scale (VAS) symptoms at day 28 in the pooled benralizumab groups compared with the prednisolone alone group and analysed in the intention-to-treat population. The trial was registered on Clinicaltrials.govNCT04098718., Findings: Between May 13, 2021, and Feb 5, 2024, 287 patients were screened for study inclusion. 129 were excluded due to not having an exacerbation captured or not meeting the eosinophil exclusion criteria. 158 patients were randomly assigned at acute eosinophilic exacerbation of asthma or COPD where 86 (54%) patients were female and 72 (46%) were male with a mean age of 57 years (range, 18-84). 53 patients were randomly assigned to the PRED group, 53 were randomly assigned to the BENRA group, and 52 were assigned to the BENRA plus PRED treatment group. At 90 days, treatment failures occurred in 39 (74%) of 53 in the PRED group, and 47 (45%) of 105 in the pooled-BENRA group (OR 0·26 [95% CI 0·13-0·56]; p=0·0005). The 28-day total VAS mean difference was 49 mm (95% CI 14-84; p=0·0065), favouring the pooled-BENRA group. There were no fatal adverse events and benralizumab was well tolerated. Notably, hyperglycaemia and sinusitis or sinus infection adverse events were related to the prednisolone study drug only., Interpretation: Benralizumab can be used as a treatment of acute eosinophilic exacerbations and achieves better outcomes than the current standard of care with prednisolone alone. These results offer a new way of treating eosinophilic endotypes of asthma and COPD exacerbations., Funding: AstraZeneca., Competing Interests: Declaration of interests SR declares salary support from the Charlies Foundation for Research and the National Institute for Health and Care Research Clinical Research Network during the study period. Unrelated to the study, SR declares speaker honoraria from AstraZeneca and GlaxoSmithKline and declares conference travel support from AstraZeneca. Unrelated to the study, IDP has received grant funding to his institution from Chiesi and also received consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Regeneron, Sanofi, Teva, Circassia, Dey Pharma, Genentech, Knopp Biosciences, Merck, MSD, Napp Pharmaceuticals, RespiVert, and Schering-Plough. IDP has also received speaker fees from Aerocrine, Almirall, AstraZeneca, Boehringer, Chiesi, GSK, Novartis, Regeneron, Sanofi, Teva. IDP has also received support to attend conference meetings from AstraZeneca, Boehringer, Cheisi, GSK, Novartis, Regeneron, Sanofi, Teva, and Napp Pharmaceuticals. Unrelated to the study, REKR has received speakers honorarium to his institution from AstraZeneca, GSK, and Chiesi. REKR has also received conference travel support from Chiesi. IH declares conference travel support from GSK unrelated to this study. TB and SP have received funding from the University of Oxford for the statistical analysis of the study data. Unrelated to the study, TB and SP declare funding from AstraZeneca for statistical tasks. MB has received grant funding from AstraZeneca to her institution, related to this study. MB has also received grant funding from Asthma+Lung UK, Roche, the NIHR, and Horizon Europe to her institution, unrelated to this study. MB has received consulting fees to her institution from AstraZeneca, Sanofi, GSK, and Areteia, and honoraria from AstraZeneca and GSK paid to her institution. MB has been supported to attend conference meetings from Chiesi. MB is a scientific advisor to AlbusHealth and Proaxsis and is a member of the British Thoracic Society research and scientific committee. All other authors declare no competing interests., (Copyright © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background and Purpose: Patients with stroke due to large artery atherosclerosis are at risk of early progression and recurrence. The efficacy and safety of argatroban in stroke patients who did not receive reperfusion therapy, and which patients may benefit from it, are uncertain., Methods: We conducted a cohort study to assess whether argatroban given within 72 hours of symptom onset, combined with antiplatelet therapy, improved neurological outcomes of patients with acute mild to moderate ischemic stroke in China. Patients were divided into the combined treatment group and the control group. Inverse probability of treatment weighting was used to balance baseline covariates. The primary efficacy outcome is the proportion of mRS score 0-2 at 90 days. The secondary efficacy outcomes included END proportion, change in NIHSS score from the baseline to day 7, recurrent cardiovascular events, and cardiovascular death. The safety outcomes were hemorrhagic transformation (HT) of infarction and organ hemorrhage at 7 days., Results: Compared with the control group, a higher proportion of mRS (0-2) at 90 days was found in patients in the combined treatment group (85.3% vs 74.5%, p=0.042). There was no significant difference in the safety outcomes between the two groups. Exploratory subgroup analysis showed positive associations with argatroban combined therapy and good prognosis in NIHSS score ≥5 and age ≥70 subgroups., Conclusions: Our study suggested that argatroban can improve neurological outcomes for mild to moderate LAA patients but not increase the risk of bleeding., Competing Interests: Declaration of competing interest All the authors declare that they have no competing financial interests in this study., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Autism spectrum disorder (ASD) is characterized by deficits in communication, social interaction, and repetitive and stereotyped behaviors, with no specific drug therapy available. Studies have found that cannabidiol (CBD) can improve hyperactive and cognitive symptoms in children with ASD. However, little is known about the effect of CBD in combination with other medications, such as risperidone (RISP). This study aimed to evaluate the behavioral and biochemical effects of CBD in animals using a valproic acid (VPA)-induced ASD animal model. VPA was administered in pregnant Wistar rats on Day 12.5 of gestation to induce the ASD model. From the 10th to the 16th postnatal day (PND), the neurodevelopment of the animals was assessed through eye-opening, olfactory discrimination, and negative geotaxis behavioral tests. From PNDs 9 to 54, the animals were weighed. They were treated for 21 days with CBD alone (100 mg/kg, by gavage, twice a day) or in combination with RISP (0.1 mg/kg, by gavage, once a day). At PND 55, the animals were evaluated in social interaction and locomotor activity experiments. Finally, after behavioral assessment, the animals were euthanized, the brain was isolated, and oxidative stress parameters were evaluated in the hippocampus and cortex posterior. Animals exposed to VPA showed neurodevelopmental delays in opening their eyes, difficulties in turning around their axis, and took longer time to find the original nest when compared to control animals. They also exhibited impaired sociability and reduced exploratory activity, which indicates model impairments. Interestingly, animals exposed to VPA treated with CBD + RISP significantly improved sociability parameters, whereas isolated CBD did not affect this parameter. In the biochemical analysis, a significant decrease in the hippocampal sulfhydryl content was noted in the CT + CBD group and an increase in the VPA + CBD group. In conclusion, these results suggest that CBD, in combination with RISP, may be an interesting pharmacological approach to reducing ASD-related symptoms. Summary: Besides the increased prevalence of ASD cases in recent years, there are no medications to improve the central symptoms of autism. Numerous studies discuss CBD as an important medication for improving ASD symptoms; however, it is not known how CBD interacts with commonly used drugs in ASD individuals, such as RISP. This study demonstrated that CBD therapy, only when combined with RISP, improved sociability in a VPA-induced ASD animal model., (© 2024 Wiley Periodicals LLC.)

Corneal endothelial cells (CECs) dysfunction frequently results in a hazy, edematous cornea due to corneal endothelial decompensation and is a major cause of corneal blindness. Drug interventions provide a less invasive alternative to corneal transplantation surgery. However, endothelial-to-mesenchymal transition (EndMT) limits CECs function. Rho-kinase (ROCK) inhibitors, shown in numerous studies to be an adjunctive therapy for CECs dysfunction, cannot completely reverse pathological EndMT caused by inflammatory environmental damage. Verteporfin (VP) is an inhibitor of Yes-associated protein (YAP) and has significant inhibitory effects on cell fibrosis and mesenchymal transition. Here, we explored VP's utility in mitigating EndMT during ROCK inhibitors treatment of corneal endothelial dysfunction. We surgically constructed a rat model of CECs injury and studied VP and ROCK inhibitors' effects on EndMT, cell proliferation, and corneal edema using RNA-Seq sequencing, immunofluorescence, optical coherence tomography, and qPCR. The results indicated that YAP expression in human fetal CECs was higher than in adults and decreased with age in rats. Moreover, YAP expression in human CECs was negatively correlated with functional genes, such as AQP1 and ATP1A1. VP effectively reversed EndMT and accelerated corneal hydration regression. However, it inhibited CECs proliferation. We also confirmed that the optimal ratio of VP combined with Y-27632 (ROCK inhibitor) was 1:1, promoting CECs proliferation and reversing EndMT by down-regulating transcription factors downstream of TGF-β signaling, thereby increasing CECs functional and intercellular adhesion proteins. These combined effects promote corneal endothelial damage repair, providing a new treatment strategy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: We evaluate whether the combination of sodium-glucose cotransporter-2 inhibitor(SGLT2i) and glucagon-like peptide-1 receptor agonist(GLP1RA) disproportionally increases the reporting of adverse events compared with SGLT2i or GLP1RA monotherapy in the FDA adverse event reporting system (FAERS)., Methods and Results: Adverse events related to SGLT2i and GLP1RA were screened and selected, then data from the FAERS was underwent thorough disproportionality analysis. The proportional reporting ratio(PRR) of SGLT2i-related adverse events were compared between patients using SGLT2i alone and those using both SGLT2i and GLP1RA. Similarly, the PRR of GLP1RA-related adverse events were compared between patients using GLP1RA alone and those using both SGLT2i and GLP1RA. The results showed that the PRR of SGLT2i-related adverse events including diabetic ketoacidosis(DKA), ketosis, reproductive tract adverse events, urinary tract infection, and other adverse events, decreased in individuals using both SGLT2i and GLP1RA compared with those using SGLT2i alone, and the signal of fracture was not detected. Likewise, the PRR of GLP1RA-related adverse events including gastrointestinal adverse events, gallbladder and biliary tract disease, pancreatitis, and other adverse events, decreased in individuals using both SGLT2i and GLP1RA compared with those using GLP1RA alone, the PRR of hyperlipasaemia and hyperamylasaemia increased in the combination therapy and no signal of depression, suicidal and self-injurious behaviour was detected., Conclusion: Adverse events reporting are not disproportionally higher among those using both SGLT-2i and GLP1RA compared with SGLT2i or GLP1RA monotherapy., Competing Interests: Declaration of competing interest No potential conflicts of interest relevant to this article were reported., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Aims: HeartMate 3 (HM3), a fully magnetically levitated ventricular assist device (LVAD), has been associated with reduced thromboembolic events compared to HeartMate II. However, bleeding events remained significant. Among patients undergoing HM3 implantation, the standard antithrombotic regimen comprises both warfarin and aspirin (ASA), but there is a lack of evidence on the optimum antithrombotic therapy. We performed a systematic review and meta-analysis assessing the impact of combined ASA and warfarin therapy compared to warfarin alone on the incidence of non-surgical bleeding events in patients with HM3 LVAD., Methods: MEDLINE, Embase, and Cochrane databases were searched for randomized controlled trials (RCTs) and observational studies comparing warfarin alone with warfarin combined with ASA in patients with HM3 LVAD. Binary endpoints were analyzed using computed risk ratios (RRs) with 95% confidence intervals (CIs). A random-effect model was applied for all endpoints., Results: Five studies (one RCT and four observational) encompassing 869 patients were included, with 424 (48.8%) prescribed warfarin alone, and 662 (76.2%) being male. Compared with the combined anticoagulation regimen, warfarin alone significantly reduced non-surgical bleeding (RR 0.30; 95% CI 0.09-0.95; p = 0.04) and gastrointestinal bleeding (RR 0.26; 95% CI 0.12-0.58; p < 0.001). There was no statistically significant difference between the groups for all-cause mortality (RR 1.02; 95% CI 0.45-2.32; p = 0.963)., Conclusions: Our findings indicate that the use of warfarin alone for anticoagulation in HM3 patients is associated with a reduced risk of bleeding events when compared to the combined therapy with ASA., (© 2024 Wiley Periodicals LLC.)

Although diloxanide is a drug of choice for treating asymptomatic amoebiasis, its mechanism of action (MOA) remains unclear. This review aims to shed light on the current understanding of the effectiveness and MOA of diloxanide in treating amoebiasis . It involves analysis of articles, retrieved from PubMed, Google Scholar and EBSCOhost, on diloxanide and the treatment of Entamoeba histolytica infection. Diloxanide is used in an ester form, which allows its high luminal concentration and greater efficacy than metronidazole in the management of asymptomatic amoebiasis. The current understanding of the action of diloxanide is based on its structural similarity to chloramphenicol at dichloroacetamide group. It acts against protein synthesis in E. histolytica trophozoites, blocking their conversion to more virulent and invasive cyst forms. Furthermore, it has a parasite clearance rate of 81-96% and treats amoebic abscesses when combined with metronidazole and chloroquine. Nevertheless, it is associated with adverse events such as flatulence, anorexia, headache and urticaria. Diloxanide is efficacious against amoebiasis but there is a need to explore its structure-activity relationship.The study suggests future directions, including novel drug formulations, diagnostic improvements, and combination regimens to enhance treatment outcomes and mitigate relapse associated with the use of diloxanide., (© 2024 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

Purpose: This study aims to evaluate whether adding macrolides (MAC) to beta-lactam (BL) monotherapy in the treatment of community-acquired pneumonia (CAP) offers clinical benefits that justify the potential disadvantages or side effects., Methods: We systematically searched PubMed, Embase, and Cochrane for randomized controlled trials (RCTs) comparing BL monotherapy to combination therapy with BL and MAC for the in-hospital treatment of CAP. We pooled mean differences (MD) for continuous outcomes and risk ratio (RR) for binary outcomes, with 95% confidence intervals (CI)., Results: Six RCTs with 2661 participants (52% receiving combination therapy), revealed no significant difference in in-hospital mortality (RR 0.99; 95% CI 0.78 to 1.25; p = 0.94; I2 = 0%), 90-day mortality (RR 1.03; 95% CI 0.82 to 1.29; p = 0.83; I2 = 13%), or 30-day mortality (RR 0.90; 75% CI 0.63 to 1.29; p = 0.58; I2 = 54%). Additionally, no significant differences were observed in the length of hospital stay (MD 0.51; 95% CI - 0.50 to 1.51; p = 0.33; I2 = 63%) or respiratory insufficiency (RR 0.63; 95% CI 0.29 to 1.35; p = 0.24; I2 = 74%). However, combination therapy significantly improved the treatment success rate (RR 1.17; 95% CI 1.04 to 1.32; p = 0.009; I2 = 0%)., Conclusion: Our findings suggest that BL + MAC therapy should not be used in all cases of hospitalized patients with CAP., Prospero Id: CRD42024516383 - Data of registration: 03/03/2024., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Renal fibrosis is closely related to the prognosis of chronic kidney disease (CKD). The increase in cGMP reduces renal fibrosis. Soluble guanylate cyclase (sGC) and phosphodiesterase (PDE) are key enzymes that maintain cGMP levels. BAY 41-8543 (1 mg/kg/day) and/or BAY 73-6691 (1 mg/kg/day) were used to treat 5/6 nephrectomized rats for 13 weeks. 5/6 Nephrectomy caused an increase in cystatin C, proteinuria and glomerulosclerosis and renal interstitial fibrosis. Neither sGC stimulation nor PDE9 inhibition alone improved kidney function and morphology, whereas BAY 41-8543 in combination with BAY 73-6691 attenuated renal interstitial fibrosis. This beneficial effect could not be explained by alterations in blood pressure and the renal immune system. BAY 41-8543 in combination with BAY 73-6691 had no effect on renal macrophage, CD4 + T-cell and CD8 + T-cell in the late-stage of 5/6 nephrectomy. RNA sequencing revealed BAY 41-8543 in combination with BAY 73-6691 down-regulated the expression of fibrosis-related genes such as Collagen Type I Alpha 1, Collagen Type III Alpha 1 Chain and Collagen Type XIV Alpha 1 Chain. sGC stimulator combined with PDE9 inhibitor attenuated renal fibrosis in 5/6 nephrectomized rats by down-regulating fibrosis-related gene expression. This novel approach of using low-dose combination therapies to minimize side effects while maintaining therapeutic efficacy offers a promising strategy for the treatment of CKD., (© 2024 The Author(s). Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Objectives: The World Health Organization recommends three drug anti-malarial combinations: cloroquine+primaquine, artesiminin+primaquine, and cloroquine+tafenoquine. These combinations aim to eradicate Plasmodium by disrupting its life cycle within the human body. We evaluated the effect of these medications on the vectorial competence of two main vectors in the New World., Methods: We recruited patients diagnosed with malaria vivax from a primary care in Manaus, Amazonas. To determine how different treatments affected vectors, we collected blood samples prior to treatment at the hospital and at six intervals over the next 68 hours at the patient's homes. These samples were used to infect Anopheles darlingi and Anopheles aquasalis. To assess the potential for Plasmodium transmission by bite to a new human host, we analyzed the infection intensity, infection rate, and presence of parasites in the salivary gland of the mosquitoes., Results: The results show the infection of the mosquitoes fed with the patient's blood during the first days of treatment with all three drug combinations. However, the cloroquine+tafenoquine combination was the least effective while artesiminin+primaquine was the most effective., Conclusions: In the first few days of treatment, two main vectors continue to spread malaria vivax from patients, potentially contributing to the ongoing transmission in malaria-endemic regions., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Randomized trials of bivalirudin in patients with ST elevation myocardial infarction (STEMI) have yielded heterogeneous results., Aims: Our aim was to evaluate the efficacy and safety of four antithrombin regimens-unfractionated heparin (UFH), bivalirudin (stopped soon after percutaneous coronary intervention [PCI]), extended bivalirudin (continued for a few hours after PCI), and combined UFH and a Gp2b3a inhibitors (GPI) in patients who present with STEMI., Methods: A PubMed, EMBASE, and clinicaltrials.gov databases were searched for randomized clinical trials (RCTs) of the above antithrombin in patients with STEMI. The primary outcome was net adverse cardiovascular events (NACE). The primary ischemic endpoint was major adverse cardiovascular events (MACE), and the primary safety endpoint was major bleeding, and other endpoints included all-cause mortality and stent thrombosis. The primary analysis compared the effect of these antithrombin regimens in reference to UFH using a mixed treatment comparison meta-analysis., Results: In the 14 RCTs evaluating 25,415 patients with STEMI, when compared to UFH monotherapy, extended bivalirudin lowered NACE (OR = 0.71 with 95% CI: 0.53-0.96; moderate level of confidence) driven by a significant decrease in major bleeding (OR = 0.42 with 95% CI: 0.26-0.68; high level of confidence) without any significant difference in MACE or all-cause mortality. When compared with UFH monotherapy, UFH+GPI reduced risk of MACE (OR = 0.76 with 95% CI: 0.60-0.97; high level of confidence) but at the expense of an increase in major bleeding (OR = 1.48 with 95% CI: 1.11-1.98; high level of confidence) with no difference in NACE or all-cause mortality. For major bleeding, extended bivalirudin infusion ranked #1, bivalirudin ranked #2, UFH monotherapy ranked #3, and combined UFH and GPI ranked #4. For NACE, extended bivalirudin infusion ranked #1, bivalirudin ranked #2, combined UFH and GPI ranked #3, and UFH monotherapy ranked #4. Cluster plots for MACE and major bleeding demonstrated that extended bivalirudin had the best balance for efficacy and safety., Conclusions: In patients undergoing PCI for STEMI, extended bivalirudin offers the best balance for primary ischemic (MACE) and safety (major bleeding) outcomes., (© 2024 Wiley Periodicals LLC.)

Objective: Tirofiban plus recombinant tissue plasminogen activator (rtPA) shows good efficacy and safety in treating acute ischemic stroke (AIS) patients, but there is a lack of comprehensive assessment. This meta-analysis aimed to compare the efficacy and safety of rtPA plus tirofiban with rtPA alone in AIS patients., Methods: This meta-analysis retrieved studies comparing rtPA intravenous thrombolysis followed by tirofiban (rtPA+T group) versus rtPA intravenous thrombolysis alone (rtPA group) for AIS patients in Excerpt Medica Database, Web of Science, Cochrane, PubMed, China National Knowledge Infrastructure, Wanfang, and SinoMed until March 2024., Results: Twenty studies with 2048 AIS patients were enrolled in this meta-analysis. National Institute of Health stroke scale (NIHSS) score after treatment was lower in the rtPA+T group than the rtPA group [standardized mean differences (SMD)=-1.41; 95 % confidence interval (CI)=-1.83, -0.98; P<0.001]. The proportion of AIS patients achieving a favorable functional outcome (modified Rankin Scale score ≤2) was increased in the rtPA+T group versus the rtPA group [relative risk (RR)=1.13; 95 % CI=1.05, 1.21; P=0.001]. The incidence of re-occlusion was lower in the rtPA+T group than in the rtPA group (RR=0.24; 95 % CI=0.10, 0.59; P=0.002), but the incidence of intracranial hemorrhage (ICH) (RR=0.85; 95 % CI=0.51, 1.43), symptomatic ICH (RR=1.10; 95 % CI=0.43, 2.84), and mortality (RR=1.39; 95 % CI=0.53, 3.65) was not different between the two groups (all P>0.05). The stability assessed by sensitivity analysis was good, and no publication bias was found., Conclusion: rtPA plus tirofiban achieves superior efficacy with comparable safety profiles compared to rtPA alone in AIS patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Diabetes is a major risk factor for all types of dementia. The underlying reasons are not fully understood, and preventive therapeutic strategies are lacking. Previously we have shown that diabetic but not control rats developed a progressive cognitive decline in a microemboli (ME) model of vascular contributions to cognitive impairment & dementia (VCID). Given the cerebrovascular dysfunction is a mutual pathological change between diabetes and VCID, we hypothesized that the cognitive impairment in this ME model can be prevented by improving the endothelial function in diabetes. Our treatment paradigm was based on the LACI-2 Trial which assessed the efficacy of isosorbide mononitrate (ISMN) and cilostazol (Cil) treatments in small vessel disease progression. Control and diabetic rats were treated with ISMN/Cil or vehicle for 4 weeks, then injected with cholesterol crystal ME and the behavioral outcomes were monitored. Brain microstructure integrity was assessed by diffusion MRI. Plasma biomarkers were assessed using angiogenesis, neurology and amyloid β 42/40 panels recommended by the MarkVCID consortium. Behavioral deficits and the loss of tissue integrity previously observed in untreated diabetic rats were not noted in the treated animals in this study. Treatment improved tissue perfusion but there were no differences in plasma biomarkers. These results suggest that restoration of endothelial function with ISMN/Cil before ME injection prevented the possible deleterious effects of ME in diabetic rats by improving the endothelial integrity and it is a practical preventive and therapeutic strategy for VCID., Competing Interests: Declaration of competing interest Weiguo Li reports financial support was provided by Diabetic Complications Research Consortium. Adviye Ergul reports financial support was provided by US Department of Veterans Affairs. Adviye Ergul reports financial support was provided by National Institutes of Health. Maria Fatima Falangola reports financial support was provided by National Institutes of Health. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: This study sought to assess the cardiorespiratory safety of parenteral olanzapine and benzodiazepine combination treatment compared to parenteral droperidol or haloperidol and benzodiazepine combination treatment., Materials and Methods: This was a retrospective chart review conducted in adult emergency department patients who received intramuscular (IM) or intravenous (IV) droperidol, haloperidol, or olanzapine within one hour of IM or IV benzodiazepine. Patients were stratified into groups based on whether they received either olanzapine in combination with a benzodiazepine (n = 48) or droperidol or haloperidol in combination with a benzodiazepine (n = 48)., Results: Patients in each group had a decrease in their systolic blood pressure (SBP) after IM/IV olanzapine and IM/IV droperidol or haloperidol when used in combination with an IM/IV benzodiazepine ((Olanzapine + benzodiazepine (mmHg), median (IQR): Pre-SBP: 132 (117-151) vs. Post-SBP: 117 (99-131), p < 0.01) (Droperidol or haloperidol + benzodiazepine (mmHg), median (IQR): Pre-SBP: 138 (122-149) vs. Post-SBP: 106 (98-127), p < 0.01)). Both groups had similar percent SBP decreases post-combination treatment (Olanzapine + benzodiazepine (15.6 %) vs. Droperidol or haloperidol + benzodiazepine (15.2 %); p = 0.55). We did not observe any statistically significant between group differences for hypotension (Olanzapine + benzodiazepine: 1/48, 2.1 % vs. Droperidol or haloperidol + benzodiazepine: 3/48, 6.3 %; p = 0.62)), escalation in oxygen requirements (Olanzapine + benzodiazepine: 7/48, 14.6 %) vs. Droperidol or haloperidol + benzodiazepine: 5/48, 10.4 %; p = 0.76)), or intubation due to cardiorespiratory depression (Olanzapine + benzodiazepine: 0/0, 0 % vs. Droperidol or haloperidol + benzodiazepine: 0/0, 0 %; p = 1.00))., Conclusion: This study found decreases in SBP after administering parenteral olanzapine and parenteral droperidol or haloperidol in combination with a parenteral benzodiazepine. The percent change in SBP and the frequency of hypotensive episodes post-combination treatment were not different between groups. There were also no differences between groups in need of increased oxygen requirements post-combination treatment or need for intubation due to cardiorespiratory depression. This study suggests parenteral olanzapine in combination with a parenteral benzodiazepine may have comparable cardiorespiratory safety versus parenteral droperidol or haloperidol in combination with a parenteral benzodiazepine when treating agitation in the adult ED., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: The use of cost-effectiveness methods to support policy decisions has become well established, but difficulties can arise when evaluating a new treatment that is indicated to be used in combination with an established backbone treatment. If the latter has been priced close to the decision maker's willingness-to-pay threshold, this may mean that there is no headroom for the new treatment to demonstrate value, at any price, even if the combination is clinically effective. Without a mechanism for attributing value to component treatments within a combination therapy, the health system risks generating negative funding decisions for combinations of proven clinical benefit to patients. The aim of this work was to define a value attribution methodology, which could be used to allocate value between the components of any combination treatment., Methods: The framework is grounded in the standard decision rules of cost-effectiveness analysis and provides solutions according to key features of the problem: perfect/imperfect information about component treatment monotherapy effects and balanced/unbalanced market power between their manufacturers., Results: The share of incremental value varies depending on whether there is perfect/imperfect information and balance/imbalance of market power, with some scenarios requiring the manufacturers to negotiate a share of the incremental value within a range defined by the framework., Conclusions: It is possible to define a framework that is independent of price and focuses on benefits expressed as quality-adjusted life-year gains (and/or quality-adjusted life-year equivalents for cost savings), a standard metric used by many health technology assessment agencies to evaluate novel treatments., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2025. Published by Elsevier Inc.)

Aims: To evaluate the efficacy and safety of add-on dapagliflozin in patients with type 2 diabetes mellitus (T2D) who had inadequate glycaemic control with metformin and linagliptin., Materials and Methods: A total of 235 patients with inadequate response to metformin (≥1000 mg/day) plus linagliptin (5 mg/day) were randomized to receive either dapagliflozin/linagliptin fixed-dose combination (FDC [AJU-A51]) 10/5 mg/day (n = 117) or linagliptin 5 mg plus placebo (n = 118) for 24 weeks. After the main treatment period, patients who received linagliptin plus placebo were treated with AJU-A51 for an additional 28 weeks. Change in glycated haemoglobin (HbA1c) from baseline to Week 24 was the primary endpoint., Results: AJU-A51 significantly reduced HbA1c levels (from 7.93% ± 0.82% to 7.11% ± 0.61%) compared with linagliptin plus placebo (from 7.80% ± 0.71% to 7.87% ± 0.94%), with a least squares mean difference of -0.88% (95% confidence interval -1.07 to -0.68; p < 0.0001) at 24 weeks. The AJU-A51 group had a significantly higher proportion of patients who achieved HbA1c <7.0% at Week 24 than the control group (44.8% vs. 18.6%; p < 0.001). The AJU-A51 group maintained glycaemic efficacy up to 52 weeks, whereas the control group showed a substantial reduction in HbA1c after switching to AJU-A51 in the extension study period. Both groups had similar incidence of treatment-emergent and serious adverse events, and no cases of symptomatic hypoglycaemia were reported., Conclusions: Dapagliflozin and linagliptin FDC (AJU-A51) showed potent glucose-lowering effects, with good tolerability, in patients with T2D who had poor glycaemic control on metformin and linagliptin (ClinicalTrials.gov [NCT06329674])., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: Pharmacotherapeutic options for obesity treatment include glucagon-like peptide-1 receptor (GLP-1R) agonists, for example, liraglutide. However, an unmet need remains, particularly in patients with a high body mass index (BMI), as GLP-1R agonists are associated with gastrointestinal adverse events (AEs) and some patients do not respond to treatment. Neuropeptide Y (NPY) and peptide YY bind G-protein-coupled Y receptors and represent attractive targets for modulating bodyweight., Materials and Methods: This first-in-human, three-part, partially blinded phase I study (NCT04903509) investigated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of the peptidic NPY2R agonist BI 1820237, with/without low-dose liraglutide: part 1 (participants randomized to receive BI 1820237: 0.075-2.4 mg or placebo), part 2 (BI 1820237: 1.2 mg or placebo) and part 3 (BI 1820237: 0.025-1.2 mg + liraglutide 0.6 mg or placebo + liraglutide 0.6 mg). Primary endpoint is the proportion of participants with drug-related AEs. Secondary endpoints are tolerability, PK and PD., Results: In total, 95 otherwise healthy men with increased BMI (25.0-34.9 kg/m 2 ) were randomized. Drug-related AEs, mainly gastrointestinal events, were reported by 39.0% of participants (n = 23) in parts 1 + 2 and 30.6% of participants (n = 11) in part 3; one drug-related AE (11.1%, part 3) was reported in a participant receiving placebo with liraglutide. Post-dose paracetamol PK suggested that BI 1820237 and low-dose liraglutide exhibited additive effects on gastric emptying., Conclusions: BI 1820237 treatment was associated with transient nausea and vomiting at higher doses. No differences in tolerability were observed when combined with liraglutide; effects on gastric emptying appeared additive., (© 2024 John Wiley & Sons Ltd.)

Objectives: According to most guidelines, dietary interventions are essential in the management of diabetes. Fasting has emerged as potential therapeutic regimes for diabetes. The proof-of-concept study and the fasting in diabetes treatment trial are the first to explore the clinical impact of the Fasting Mimicking Diet (FMD) in patients with type 2 diabetes mellitus. Their results showed that FMD cycles improve glycemic management and can be integrated into usual care complementary to current guidelines. This economic evaluation aims to assess the 10-year quality-of-life effects, cost implications, and cost-effectiveness of adding a 3-year FMD program to diabetes standard care in diabetic population on dual or triple medications at baseline from the perspective of the US payer., Methods: We constructed a microsimulation model in TreeAge using a published US-specific diabetes model. The model was populated using FMD effectiveness outcomes and publicly available clinical and economic data associated with diabetes complications, use of diabetes medications, hypoglycemia incidence, direct medical costs in 2021 USD, quality of life, and mortality. All benefits were discounted by 3%., Results: This cost-utility analysis showed that the FMD program was associated with 11.4% less diabetes complications, 67.2% less overall diabetes medication use, and 45.0% less hypoglycemia events over the 10-year simulation period. The program generated an additional effectiveness benefit of 0.211 quality-adjusted life year and net monetary benefit of 41 613 USD per simulated patient. Thus, the FMD program is cost saving., Conclusions: These results indicate that the FMD program is a beneficial first-line strategy in T2DM management., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2025. Published by Elsevier Inc.)

Tuberculosis is the most common opportunistic infection in individuals with HIV, and rifampicin is crucial in the treatment of tuberculosis. Drug-drug interactions complicate the use of DTG in HIV/TB co-infection, which makes drug administration more difficult. This study aimed to develop the population pharmacokinetic model of DTG when co-administered with rifampicin. The developed model was further used to investigate different dosing regimens. Forty HIV/TB-co-infected participants receiving DTG 50 mg once daily (OD) with food or DTG 50 mg twice daily (b.i.d.) without food were included in the analysis. Intensive pharmacokinetic samples were collected. The data were analyzed using a nonlinear mixed-effects modeling approach. A total of 332 DTG concentrations from 40 PLWH were analyzed. The pharmacokinetics of DTG co-administered with rifampicin can be best described by a one-compartment model with first-order absorption (incorporating lag time) and elimination. Total bilirubin was the only covariate that significantly affected CL/F. DTG 50 mg b.i.d. results in the highest proportion of individuals achieving in vitro IC 90 of 0.064 mg/L and in vivo EC 90 of 0.3 mg/L, while more than 90% of individuals receiving DTG 100 mg OD would achieve the in vitro IC 90 target. Therefore, DTG 100 mg OD could serve as an alternative regimen by minimizing the difficulty of drug administration. However, its clinical efficacy requires additional evaluation., (© 2024 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: A significant proportion of inflammatory bowel disease (IBD) patients fail to respond to advanced therapies. Combining advanced therapies may improve treatment outcome. This study aimed to assess the effectiveness, adverse events, and costs associated with combining advanced therapies in IBD patients., Methods: Combination advanced therapy was defined as the concurrent use of two biological agents or one biological agent with a small molecule therapy. Clinical data, including disease characteristics, treatment regimens, and adverse events, were collected from electronic patient records. Clinical response rates, biochemical markers, and treatment costs were evaluated., Results: The study included 109 IBD patients receiving combination advanced therapies from 9 academic centers in Ireland. Corticosteroid-free clinical response rates at 12 weeks and 52 weeks were 39 % and 38 %, respectively. Adverse events occurred in 26 % of therapeutic trials, with disease-related events being the most common. Notably, there were 3 cases of non-melanomatous skin cancer and 10 infectious complications. The annual cost of maintenance therapy for combination advanced therapies ranged from €17,560 to €30,724 per patient., Conclusion: Combination advanced therapies demonstrated effectiveness and acceptable safety profiles in a cohort of treatment-refractory IBD patients. Further large, prospective trials are required to definitively evaluate the role of combination advanced therapies in IBD., Competing Interests: Conflicts of interest There are no conflicts of interest pertaining to this paper., (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Patients with type 2 DM (T2DM) and established cardiovascular disease (CVD) are at high risk of recurrent CV events. We analysed the use of the CNIC-polypill (acetylsalicylic acid, ramipril, and atorvastatin) compared with other therapeutic strategies in patients with T2DM and CVD from the retrospective NEPTUNO study., Methods: Patients were stratified into four therapeutic approaches: CNIC-polypill, its monocomponents as loose medications, equipotent medications, and other therapies. Outcomes included the 2-year cumulative incidence and risk of recurrent major adverse CV events (MACE) and CV death, risk factors control, medication persistence, and utilisation of healthcare resources and costs., Results: After two years, T2DM patients treated with Monocomponents, Equipotent drugs, or Other therapies had increased recurrent MACE risk compared to CNIC-polypill (11 %, 23 %, and 44 %, respectively; P < 0.05) and shorter median time to CV events (305-377 vs. 396 days; P < 0.05). The CNIC-polypill group achieved a significant 11.2 % increase in patients reaching LDL-c targets <70 mg/dL, outperforming other strategies. It also exhibited superior triglyceride control and a higher proportion achieving the <130/80 mmHg blood pressure goal. The CNIC-polypill cohort displayed significantly higher 24-month persistence (71.5 % vs. 54.7 %-58.3 %, p < 0.05) and lower mean adjusted costs per patient (€5083 vs. €6000-€6523; p < 0.05). In a comparative analysis, T2DM patients had lower baseline LDL-c and total cholesterol levels than non-T2DM counterparts yet experienced a higher incidence of recurrent MACE over two years., Conclusion: The CNIC-polypill (ASA, atorvastatin and ramipril) emerged as a promising treatment for patients with CVD, particularly those with T2DM, offering improved clinical outcomes and economic efficiency., (Copyright © 2024. Published by Elsevier B.V.)

Background: Susac syndrome is a rare disease affecting mainly young women and is characterised by an occlusive microvessel disease limited to the brain, retina, and inner ear. No randomised controlled trial has been published or declared as ongoing to investigate treatments for Susac syndrome. We aimed to compare the effect of glucocorticoids given alone or in combination with immunosuppressive agents or intravenous immunoglobulin for the prevention of relapse in patients with Susac syndrome., Methods: The Phenotypic and Etiological Characterization of Susac Syndrome-National Clinical Research Hospital Program study is a prospective national cohort study that started enrolling on Nov 29, 2011, and included all consecutive patients aged 18 years or older with Susac syndrome who were referred to the French reference centre (Department of Internal Medicine, Bichat-Claude Bernard Hospital, Paris). Susac syndrome was defined by either the triad of encephalopathy with typical brain MRI abnormalities, cochleo-vestibular damage, and multiple occlusions of retinal central artery branches, or at least two of the three criteria without any alternative diagnosis. Collected data included fundoscopy, retinal angiography, audiometry, cerebrospinal fluid, brain MRI, and treatment received at diagnosis; months 1, 3, 6, and 12 after diagnosis; and then annually for 5 years or in the case of a relapse. The primary outcome was defined as the first relapse occurring within a 36-month follow-up period from the first day of treatment, characterised by new clinical symptoms or signs, and new abnormalities observed on retinal angiography, audiometry, or brain MRI, necessitating treatment intensification. There was no involvement of people with lived experience at any stage. The study is registered at ClinicalTrials.gov, NCT01481662., Findings: Between Nov 29, 2011, and Dec 2, 2022, 64 patients were included in the study, with a mean age at diagnosis of 35 years (SD 11); 41 (64%) were women and 23 (36%) were men. At diagnosis, 60 patients received glucocorticoids; 40 (63%) of 64 patients received glucocorticoids alone as a first-line therapy while 20 (31%) received glucocorticoids in combination with immunosuppressive agents or intravenous immunoglobulin. Overall, 46 (72%) of 64 patients had a first relapse with a median relapse-free survival time of 3·96 months (95% CI 2·24-16·07). Comparison of relapse-free survival showed no significant difference between the two treatment strategies (hazard ratio [HR] 1·11 [95% CI 0·56-2·17], p=0·76), compared with glucocorticoids alone as the reference group. In patients who first relapsed while treated with glucocorticoids alone, there was no significant difference in second relapse-free survival between those who did or did not receive immunosuppressive agents or intravenous immunoglobulin as a second-line therapy (HR 2·66 [95% CI 0·63-11·18], p=0·18)., Interpretation: The combination of glucocorticoids with immunosuppressive agents or intravenous immunoglobulin did not appear to reduce the risk of Susac syndrome relapse compared with glucocorticoids alone. Our findings did not support the systematic use of immunosuppressive agents in Susac syndrome., Funding: French Ministry of Health., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Co-administration of mirogabalin besylate and nonsteroidal anti-inflammatory drugs is effective for neuropathic pain; however, mechanism of its action remains unknown. We aimed to evaluate the mechanism of this synergistic effect of the concomitant administration for neuropathic pain using chronic constriction injury model rats. Fifty male Wister rats of 7-week-old were used. Right sciatic nerve ligation was performed in 40 rats and they were sub-divided into four groups: vehicle, mirogabalin, diclofenac sodium and co-administration of them. Ten rats underwent sham surgery. Fluorogold was attached to sciatic nerve during surgery. Von Frey filament and weight bearing tests were performed on postoperative Day 6 as behavioral assessments and drug was administrated intraperitoneally. Half rats in each group underwent behavioral assessment and perfusion fixation using 4% paraformaldehyde on postoperative Day 7 and remaining on postoperative Day 14. Subsequently, dorsal root ganglion at L4 to L6 was collected and examined immunohistochemistry for calcitonin gene-related peptide, and their immunoreactivity in fluorogold-labeled neurons was measured. Spinal cord at lumbar swelling was resected, immunostained for ionized-calcium-binding adapter molecule-1 and glial fibrillary acidic protein, and immunoreactive neurons in dorsal horn of spinal cords were calculated as the occupancy of them. Mirogabalin suppresses the neuropeptide-release from presynaptic afferent neuron directly and it resulted in suppressing glia cells activation. Diclofenac sodium inhibits cyclooxygenase-2 and prostaglandin production, related to allodynia. These effects of mirogabalin and diclofenac sodium, respectively, inhibited glia cells strongly, which is presumed to be one of the mechanisms for the effectiveness of their co-administration for neuropathic pain., (© 2024 Orthopaedic Research Society.)

Background: Recent guidelines on acute coronary syndromes (ACS) recommend initiating lipid-lowering therapy (LLT) as early as possible to obtain >50% low-density-lipoprotein cholesterol (LDL-c) reduction and an LDL-c < 1.4 mmol/l., Methods: A multinational European survey study of ACS patients between 2021-2022 and acquired data on LLT and lipid levels on admission and during 1-year posthospitalization. We compared plasma lipid changes and adherence to post-ACS lipid targets across two in-hospital LLT groups: high-intensity statin (HIS) monotherapy (mono-HIS) and a combination of HIS and ezetimibe (combo-HIS)., Results: Of 286 patients, 268 (94%) received in-hospital HIS and were included in the final analysis. Patients (median age: 61.1 years) had a median baseline LDL-c of 3.3 mmol/l. Mono-HIS was the predominant in-hospital LLT (72.4%). In-hospital combo-HIS was administered in 27.6% of the cases. Patients from high-income countries ( n  = 141) were more likely to receive in-hospital combo-HIS than patients from middle-income countries [ n  = 127; 38.3% vs. 15.7% patients, P  < 0.001). One-year post-ACS, 50 (26.5%) patients from the mono-HIS group received ezetimibe. The target of LDL-c ≤ 55 mg/dl was reached in 85 patients (31.7%), without significant difference between study groups [mono-HIS: 56 (28.9%) and combo-HIS: 29 (39.2%) patients, P  = 0.10]. The target of >50% reduction was achieved more frequently among the combo-HIS group than in the mono-HIS group (50.0% vs. 29.9%, respectively, P  = 0.002)., Conclusion: LDL-c targets were achieved in less than half of the patients post-ACS, regardless of the LLT regimen. Combo-HIS was initiated in-hospital post-ACS in only 28% and was associated with greater LDL-c reduction compared to a staged approach of mono-HIS with up-titration at follow-up., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)