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ABSTRACT BACKGROUND: Nowdays, more relevant applications of perinatal derivatives, such as amniotic membrane (AM), are emerging in our environment as a source of biomaterials for use in different healing processes. The study of anastomosis healing associated with antimetabolic drugs such as 5-fluorouracil (5-FU) is a potential target of AM. AIMS: To evaluate the healing effects of AM in rats treated with 5-FU at a dose of 20 mg/kg on the seventh day of postoperative evolution, regarding the parameters percentage of type I collagen (mature), cell viability, microvascular density and formation of granulation tissue. METHODS: Thirty-two Wistar rats were used, submitted to colotomy and colorraphy, separated into four groups of eight, which received different treatments daily, intraperitoneally, until the day of sacrifice: saline solution (C), 20 mg/kg 5-FU, 20 mg/kg 5-FU and AM. RESULTS: Treatment with 20 mg/kg of 5-FU, on the seventh postoperative day, induced adverse effects on the anastomotic healing process, evidenced by a decrease in the percentage of type I (mature) collagen, cell viability, microvascular density, fibrin-leukocyte scab formation and angiofibroblast proliferation; the use of AM under these conditions induced an improvement in the percentage of type I (mature) collagen. CONCLUSIONS: Treatment with 20 mg/kg of 5-FU on the seventh postoperative day induced adverse effects on the anastomotic healing process, and the use of AM under these conditions induced an improvement in the percentage of type I (mature) collagen.

Introduction: Tramadol/paracetamol combination is one of the most prescribed pain medications in Portugal. At the Regional Health Administration of Lisbon and Tagus Valley, 1 119 229 packages of tramadol/paracetamol were prescribed for 12 months, corresponding to the second most prescribed analgesic. We ask whether this drug is prescribed for acute and irruptive pain or if it is prescribed as a long-term treatment for chronic pain. Methods: This cross-sectional study describes the prescription of tramadol/paracetamol in a Portuguese primary care unit. The population studied corresponds to the 344 patients who received a tramadol/paracetamol prescription between July 2020 and June 2021. Results: In this period, a total of 687 prescriptions were made, corresponding to 2500 packages of tramadol/paracetamol, of which 1874 were bought. There was no statistically significant difference between the number of packages bought over the 4 trimesters (p = 0.275) and 35.3% of the patients bought this medication in more than one trimester. We found that 16.5% bought tramadol/paracetamol in an amount that allows a use of more than 90 days. Conclusion: This demonstrates that the tramadol/paracetamol combination plays a central role in the treatment of pain and that a significant percentage of patients use this medication chronically, questioning the adequacy of this therapy in these patients. However, larger studies that assess pain control are needed to support the results presented in this work.

Background There is still a lack of research on which diabetic drugs are more effective in preventing stroke. Our network metaanalysis aimed to compare cerebrovascular benefits among glucose-lowering treatments. Methods We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the ClinicalTrials.gov registry for clinical trials from inception through May 25, 2021. We included both prespecified cerebrovascular outcomes and cerebrovascular events reported as severe adverse events. Subgroup analyses were conducted by stroke subtype, publication type, age of patients, baseline glycosylated hemoglobin (HbA1c), duration of type 2 diabetes mellitus, and cardiovascular risks. Results Of 2,861 reports and 1,779 trials screened, 79 randomized controlled trials comprising 206,387 patients fulfilled the inclusion criteria. In the pairwise meta-analysis, the use of glucagon-like peptide-1 (GLP-1) agonist was associated with a lower risk of total stroke compared with placebo (relative risk [RR], –0.17; 95% confidence interval [CI], –0.27 to –0.07). In the network meta-analysis, only the use of sodium-glucose cotransporter-2 (SGLT-2) inhibitor was associated with a reduction of total stroke, compared with placebo (RR, 0.81; 95% CI, 0.67 to 0.98). In the subgroup analyses, the use of SGLT-2 inhibitor and GLP-1 agonist was associated with a lower risk of stroke in those with high HbA1c (≥8.0) and low-risk of cardiovascular disease, respectively. Conclusion SGLT-2 inhibitors and GLP-1 agonists were shown to be beneficial for stroke prevention in patients with type 2 diabetes mellitus.

Type 2 diabetes (T2D) is a progressive disease in which it is challenging to achieve long-term durable glycemic control. However, intensive glycemic control is crucial for preventing diabetes-related complications. Previous studies showed that monotherapy with a stepwise add-on approach was seldom effective for long-term durable glycemic control. Combination therapy, which refers to the use of two or more drugs to control hyperglycemia, has multiple benefits, including the ability to target a variety of pathophysiological processes underlying hyperglycemia. In clinical trials, initial combination therapy showed better glycemic control than monotherapy or a stepwise approach. Emerging evidence indicates that initial combination therapy is associated with preserved β-cell function and fewer complications in T2D. However, cost-effectiveness and adverse events with combination therapy are issues that should be considered. Therefore, initial combination therapy is an important option for patients with T2D that clinicians should consider with a view toward balancing benefits and potential harms. In this review, we summarize the literature addressing initial combination therapy in T2D, and we suggest optimal strategies based on clinical situations and patient characteristics.

Background To investigate the efficacy and safety of moderate-intensity rosuvastatin/ezetimibe combination compared to highintensity rosuvastatin in high atherosclerotic cardiovascular disease (ASCVD) risk patients with type 2 diabetes mellitus (T2DM). Methods This study was a randomized, multicenter, open, parallel phase 4 study, and enrolled T2DM subjects with an estimated 10-year ASCVD risk ≥7.5%. The primary endpoint was the low-density lipoprotein cholesterol (LDL-C) change rate after 24-week rosuvastatin 10 mg/ezetimibe 10 mg treatment was non-inferior to that of rosuvastatin 20 mg. The achievement proportion of 10-year ASCVD risk

Background This study investigates the long-term efficacy and safety of evogliptin add-on therapy in patients with inadequately controlled type 2 diabetes mellitus (T2DM) previously received dapagliflozin and metformin (DAPA/MET) combination. Methods In this multicenter randomized placebo-controlled phase 3 trial, patients with glycosylated hemoglobin (HbA1c) levels 7.0% to 10.5% (n=283) previously used DAPA 10 mg plus MET (≥1,000 mg) were randomly assigned to the evogliptin 5 mg once daily or placebo group (1:1). The primary endpoint was the difference in the HbA1c level from baseline at week 24, and exploratory endpoints included the efficacy and safety of evogliptin over 52 weeks (trial registration: ClinicalTrials.gov NCT04170998). Results Evogliptin add-on to DAPA/MET therapy was superior in HbA1c reduction compared to placebo at weeks 24 and 52 (least square [LS] mean difference, –0.65% and –0.55%; 95% confidence interval [CI], –0.79 to –0.51 and –0.71 to –0.39; P

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Byline: Vishal. Tandon, Sheikh. Ismail, Amarjeet. Singh We hereby describe a rare case of levosulpiride-induced atypical parkinsonism presenting with sluggish movements, atypical kinetic tremors (tremors with voluntary movement), periorbital tremors, [...]

Objective To analyse sales of fixed-dose combination and single antibiotics In India In relation to World Health Organization (WHO) recommendations and national regulatory efforts to control antibiotic sales. Methods We extracted data on sales volumes of systemic antibiotics in India from a market research company sales database. We compared the market share of antibiotic sales in 2020 by WHO AWaRe (Access, Watch and Reserve) category and for those under additional national regulatory controls. We also analysed sales of fixed-dose combinations that were: formally approved for marketing or had a no-objection certificate; on the national essential medicines list; and on the WHO list of not-recommended antibiotics. Findings There were 78 single and 112 fixed-dose combination antibiotics marketed in India, accounting for 7.6 and 4.5 billion standard units of total sales, respectively. Access, Watch and Reserve antibiotics comprised 5.8, 5.6 and 0.1 billion standard units of total market sales, respectively. All additionally controlled antibiotics were Watch and Reserve antibiotics (23.6%; 2.9 billion standard units of total sales). Fixed-dose combinations on the WHO not-recommended list were marketed in 229 formulations, with 114 formulations (49.8%) having no record of formal approval or no-objection certificate. While there were no not-recommended fixed-dose combinations on the national list of essential medicines, 13 of the top-20 selling antibiotic fixed-dose combinations were WHO not-recommended. Conclusion The sale of Watch group drugs, and antibiotics banned or not approved, needs active investigation and enforcement in India. The evidence base underpinning formal approvals and no-objection certificates for not-recommended fixed-dose combinations should be audited. Objectif Analyser les ventes d'antibiotiques en association fixe et a dose unique en Inde, a la lumiere des recommandations de l'Organisation mondiale de la Sante (OMS) et des efforts de reglementation a l'echelle nationale visant a controler la vente d'antibiotiques. Methodes Nous avons preleve des donnees relatives aux volumes de vente d'antibiotiques systemiques en Inde dans la base de donnees commerciales d'une societe d'etudes de marche. Nous avons ensuite compare la part de marche qu'occupe, en 2020, la vente d'antibiotiques appartenant a chaque categorie AWaRe (Access, Watch and Reserve) etablie par l'OMS, mais aussi de ceux cibles par des mesures nationales de controle supplementaires. Enfin, nous avons examine les ventes d'associations fixes: dont la commercialisation a ete officiellement approuvee ou qui ont fait l'objet d'un certificat de non-objection; figurant sur la liste nationale de medicaments essentiels; et reprises dans la liste des antibiotiques non recommandes par l'OMS. Resultats Nous avons comptabilise 78 antibiotiques a dose unique et 112 antibiotiques en association fixe sur le marche indien, representant respectivement 7,6 et 4,5 milliards d'unites standard sur l'ensemble des ventes. Les antibiotiques des categories Access (dont l'accessibilite est essentielle), Watch (a utiliser selectivement) et Reserve (de reserve, non recommandes) equivalaient a 5,8 milliards, 5,6 milliards et 0,1 milliard d'unites standard sur le total des transactions. Tous les antibiotiques soumis a des controles supplementaires faisaient partie des categories Watch et Reserve (23,6%; 2,9 milliards d'unites standard sur l'ensemble des ventes). Des associations fixes deconseillees par l'OMS etaient commercialisees dans 229 formulations, dont 114 (49,8%) ne possedaient ni attestation d'approbation officielle, ni certificat de non-objection. Bien qu'aucune association fixe deconseillee ne soit mentionnee sur la liste nationale de medicaments essentiels, 13 des 20 antibiotiques en association fixe les plus vendus n'etaient pas recommandes par l'OMS. Conclusion Il est necessaire de mener une enquete approfondie en Inde sur la vente de medicaments appartenant a la categorie Watch et d'antibiotiques interdits ou non approuves, et de prendre des mesures concretes. Les preuves sur lesquelles reposent les autorisations officielles et les certificats de non-objection pour les associations fixes non recommandees doivent etre verifiees. Objetivo Analizar las ventas de los antibioticos combinados en dosis fijas y en dosis unicas en la India en relacion con las recomendaciones de la Organizacion Mundial de la Salud (OMS) y los esfuerzos nacionales de regulacion para controlar las ventas de los antibioticos. Metodos Se extrajeron datos sobre los volumenes de ventas de antibioticos sistemicos en la India de una base de datos de ventas de empresas de investigacion de mercado. Se comparo la cuota de mercado de las ventas de antibioticos en 2020 por categoria AWaRe (Access, Watch and Reserve) de la OMS y para los que estaban sometidos a controles regulatorios nacionales adicionales. Tambien se analizaron las ventas de combinaciones en dosis fijas que estaban: formalmente aprobadas para su comercializacion o tenian un certificado de no objecion; en la lista nacional de medicamentos esenciales; y en la lista de antibioticos no recomendados de la OMS. Resultados En la India se comercializaron 78 antibioticos en dosis unica y 112 antibioticos combinados en dosis fijas, que representaron 7,6 y 4,5 mil millones de unidades estandar de ventas totales, respectivamente. Los antibioticos de acceso, vigilancia y reserva supusieron 5,8, 5,6 y 0,1 mil millones de unidades estandar de las ventas totales del mercado, respectivamente. Todos los antibioticos controlados adicionalmente fueron antibioticos de vigilancia y reserva (23,6 %; 2,9 mil millones de unidades estandar de las ventas totales). Las combinaciones en dosis fijas incluidas en la lista no recomendada de la OMS se comercializaron en 229 formulaciones, de las que 114 (49,8 %) no tenian registro de aprobacion formal ni certificado de no objecion. Mientras que no habia combinaciones en dosis fijas no recomendadas en la lista nacional de medicamentos esenciales, 13 de las 20 combinaciones en dosis fijas de antibioticos mas vendidas no estaban recomendadas por la OMS. Conclusion Se debe investigar y controlar activamente la venta de medicamentos del grupo Watch y de antibioticos prohibidos o no aprobados en la India. Asimismo, se debe auditar la base de pruebas que sustenta las aprobaciones formales y los certificados de no objecion para las combinaciones en dosis fijas no recomendadas., Introduction The overuse and misuse of antibiotics contribute to the development of antimicrobial resistance, eroding the drugs' effectiveness. (1) Consequently, efforts continue to be made to improve antibiotic stewardship internationally [...]

Transcatheter arterial chemoembolization (TACE) is recommended by domestic and international guidelines for the treatment of patients with unresectable hepatocellular carcinoma (uHCC), and it is one of the most common treatment methods for patients with uHCC. The chemotherapy drugs commonly used in TACE for HCC include epirubicin, cisplatin, and fluorouracil, while it is still unclear which chemotherapy drug has a better clinical effect. This article summarizes the studies of different TACE regimens using different chemotherapy drugs in the treatment of patients with uHCC in the recent five years. TACE combined with sorafenib can significantly improve the survival of patients with advanced HCC and has been recommended for the treatment of such patients by Chinese Society of Clinical Oncology guidelines, and the efficacy of TACE combined with other tyrosine kinase inhibitors (TKI) has become a research hotspot. Studies have shown that compared with TACE combined with sorafenib in the treatment of patients with advanced HCC, TACE combined with lenvatinib can achieve a significantly longer progression-free survival time and a tendency of increase in median overall survival time. However, due to the variation of target receptors or downstream signals, resistance to molecular-targeted agents is still a challenging problem. TKI combined with immune checkpoint inhibitors may be a promising strategy for the treatment of patients with uHCC. Some studies suggest that triple therapy using TACE combined with TKIs and anti-PD-1/PD-L1 monoclonal antibody has better efficacy in improving the survival of patients with uHCC. This article reviews the studies of the efficacy and safety of TACE combined with targeted agents and TACE combined with anti-PD-1/PD-L1 monoclonal antibody in the treatment of patients with uHCC in the recent five years. [ABSTRACT FROM AUTHOR]

Objective To observe the efficacy and prognosis of edaravone dexborneol combined with intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) in the treatment of ultra-early acute cerebral infarction (ACI). Methods A total of 163 patients with ultra-early ACI were randomly divided into the combination group (treated with edaravone dexborneol combined with intravenous thrombolysis with rt-PA, n=78) and the control group (treated with intravenous thrombolysis with rt-PA, n=85). Therapeutic effects and changes of superoxide dismutase (SOD), reactive oxygen species (ROS), malondialdehyde (MDA), neuron-specific enolase (NSE), matrix metalloproteinase-9 (MMP-9), matrix metalloproteinase-12 (MMP-12), central nervous system-specific protein β (S100β), low density lipoprotein cholesterol (LDL-C), total cholesterol (TC), creatine kinase (CK), creatine kinase isoenzyme (CK-MB), D-dimer (D-D), C-reactive protein (CRP), the National Institutes of Health Stroke Scale (NIHSS) scores, Modified Rankin Scale (mRS) scores and activity of daily living (ADL) scores were observed before and after treatment in the 2 groups. The fatality rate and the incidence of adverse reactions were compared between the two groups. Results After treatment, the total effective rate, SOD level and ADL score were higher in the combination group than those in the control group. Levels of ROS, MDA, NSE, MMP-9 and S100β, NIHSS score and mRS score were lower in the combination group than those in the control group (P＜ 0.05). There were no significant differences in fatality rate and incidence of adverse reactions between the two groups (P＞ 0.05). Conclusion Edaravone dexborneol combined with intravenous thrombolysis with rt-PA can improve the clinical effect in the treatment of patients with ultra-early ACI, and improve the prognosis. [ABSTRACT FROM AUTHOR]

Copyright of Innere Medizin (2731-7080) is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract A phase II study (PRIMMO) of patients with pretreated persistent/recurrent/metastatic cervical or endometrial cancer is presented. Patients received an immunomodulatory five-drug cocktail (IDC) consisting of low-dose cyclophosphamide, aspirin, lansoprazole, vitamin D, and curcumin starting 2 weeks before radioimmunotherapy. Pembrolizumab was administered three-weekly from day 15 onwards; one of the tumor lesions was irradiated (8Gyx3) on days 15, 17, and 19. The primary endpoint was the objective response rate per immune-related response criteria (irORR) at week 26 (a lower bound of the 90% confidence interval [CI] of > 10% was considered efficacious). The prespecified 43 patients (cervical, n = 18; endometrial, n = 25) were enrolled. The irORR was 11.1% (90% CI 2.0–31.0) in cervical cancer and 12.0% (90% CI 3.4–28.2) in endometrial cancer. Median duration of response was not reached in both cohorts. Median interval-censored progression-free survival was 4.1 weeks (95% CI 4.1–25.7) in cervical cancer and 3.6 weeks (95% CI 3.6–15.4) in endometrial cancer; median overall survival was 39.6 weeks (95% CI 15.0–67.0) and 37.4 weeks (95% CI 19.0–50.3), respectively. Grade ≥ 3 treatment-related adverse events were reported in 10 (55.6%) cervical cancer patients and 9 (36.0%) endometrial cancer patients. Health-related quality of life was generally stable over time. Responders had a significantly higher proportion of peripheral T cells when compared to nonresponders (p = 0.013). In conclusion, PRIMMO did not meet its primary objective in both cohorts; pembrolizumab, radiotherapy, and an IDC had modest but durable antitumor activity with acceptable but not negligible toxicity. Trial registration ClinicalTrials.gov (identifier NCT03192059) and EudraCT Registry (number 2016-001569-97).

ABSTRACT BACKGROUND: Surgical resection remains the main curative therapeutic modality for advanced gastric cancer. Recently, the association of preoperative chemotherapy has allowed the improvement of results without increasing surgical complications. AIMS: To evaluate the surgical and oncological outcomes of preoperative chemotherapy in a real-world setting. METHODS: A retrospective review of gastric cancer patients who underwent gastrectomy was performed. Patients were divided into two groups for analysis: upfront surgery and preoperative chemotherapy. The propensity score matching analysis, including 9 variables, was applied to adjust for potential confounding factors. RESULTS: Of the 536 patients included, 112 (20.9%) were referred for preoperative chemotherapy. Before the propensity score matching analysis, the groups were different in terms of age, hemoglobin level, node metastasis at clinical stage- status, and extent of gastrectomy. After the analysis, 112 patients were stratified for each group. Both were similar for all variables assigned in the score. Patients in the preoperative chemotherapy group had less advanced postoperative p staging (p=0.010), postoperative n staging (p

ABSTRACT BACKGROUND: Peritoneal carcinomatosis in gastric cancer is considered a fatal disease, without expectation of definitive cure. As systemic chemotherapy is not sufficient to contain the disease, a multimodal approach associating intraperitoneal chemotherapy with surgery may represent an alternative for these cases. AIMS: The aim of this study was to investigate the role of intraperitoneal chemotherapy in stage IV gastric cancer patients with peritoneal metastasis. METHODS: This study is a single institutional single-arm prospective clinical trial phase II (NCT05541146). Patients with the following inclusion criteria undergo implantation of a peritoneal catheter for intraperitoneal chemotherapy: Stage IV gastric adenocarcinoma; age 18–75 years; Peritoneal carcinomatosis with peritoneal cancer index

ABSTRACT Objective To compare viral suppression in treatment-naïve adults starting antiretroviral therapy with dolutegravir (50mg)- and efavirenz (600mg)-based regimens. Methods We analyzed secondary data from Brazilian health information systems of people living with human immunodeficiency virus who started antiretroviral therapy between 2015 and 2017 in Minas Gerais, Brazil. The outcome was viral suppression, defined as the achievement of the first viral load

A phase II study (PRIMMO) of patients with pretreated persistent/recurrent/metastatic cervical or endometrial cancer is presented. Patients received an immunomodulatory five-drug cocktail (IDC) consisting of low-dose cyclophosphamide, aspirin, lansoprazole, vitamin D, and curcumin starting 2 weeks before radioimmunotherapy. Pembrolizumab was administered three-weekly from day 15 onwards; one of the tumor lesions was irradiated (8Gyx3) on days 15, 17, and 19. The primary endpoint was the objective response rate per immune-related response criteria (irORR) at week 26 (a lower bound of the 90% confidence interval [CI] of > 10% was considered efficacious). The prespecified 43 patients (cervical, n = 18; endometrial, n = 25) were enrolled. The irORR was 11.1% (90% CI 2.0–31.0) in cervical cancer and 12.0% (90% CI 3.4–28.2) in endometrial cancer. Median duration of response was not reached in both cohorts. Median interval-censored progression-free survival was 4.1 weeks (95% CI 4.1–25.7) in cervical cancer and 3.6 weeks (95% CI 3.6–15.4) in endometrial cancer; median overall survival was 39.6 weeks (95% CI 15.0–67.0) and 37.4 weeks (95% CI 19.0–50.3), respectively. Grade ≥ 3 treatment-related adverse events were reported in 10 (55.6%) cervical cancer patients and 9 (36.0%) endometrial cancer patients. Health-related quality of life was generally stable over time. Responders had a significantly higher proportion of peripheral T cells when compared to nonresponders (p = 0.013). In conclusion, PRIMMO did not meet its primary objective in both cohorts; pembrolizumab, radiotherapy, and an IDC had modest but durable antitumor activity with acceptable but not negligible toxicity. Trial registration ClinicalTrials.gov (identifier NCT03192059) and EudraCT Registry (number 2016-001569-97). [ABSTRACT FROM AUTHOR]

BackgroundAdults with relapsed/refractory acute myeloid leukemia (AML) have poor prognosis, very low long-term survival rate and cure rate, and limited chemotherapy regimens.ObjectiveTo investigate the safety and efficacy of venetoclax (VEN) with HAAG 〔homoharringtonine (HHT) , Cytarabine (Ara-C) , aclacinomycin (Acla) , granulocyte stimulating factor (G-CSF) 〕 in relapsed/refractory AML.MethodsThe clinical data of 10 adult patients with relapsed/refractory AML treated in the First Affiliated Hospital of Bengbu Medical College were analyzed retrospectively, including: clinical characteristics (sex, age, diagnosis, chromosome, gene mutation, prognosis) , peripheral blood and bone marrow cytology, and the effect of Ven+Aza+HAAG regimen.ResultsAmong the 10 patients, there were 7 men and 3 women, with an average age of (47.9±11.3) years; 4 cases of M2 and 6 cases of M5 by FAB classification; 3 cases of good prognosis, 2 cases of fair and 5 cases of poor. The median levels of WBC count, hemoglobin content, and platelet count, as well as median percentage of bone marrow blast cells before chemotherapy of the patients were 4.10×109/L, 87.5 g/L, 66.00×109/L, and 63.5%, respectively, and after chemotherapy, the values of these four indicators were 3.28×109/L, 107.0 g/L, 78.00×109/L and 5.5%, respectively. Before VEN+Aza+HAAG regimen combined chemotherapy, the median number of chemotherapy used by the patients was 5. And after the combined therapy, there were 1 case of complete remission (CR) and 4 cases of CR with incomplete count recovery (CRi) , 3 cases of partial remission (PR) , and 2 cases of non-remission (NR) . The objective response rate of 10 patients was 80%, and median survival time was 〔6.5 (3.0, 8.5) 〕months. The toxic and side effects were mainly bone marrow suppression and infection. No patients died of treatment-related complications and other toxic and side effects.ConclusionCompared with traditional chemotherapy regimen, the use of Ven + Aza + HAAG with chemotherapy could significantly improve the objective response rate and remission degree, and prolong the survival in patients with relapsed/refractory AML, which is worthy of further study and has a prospect of clinical application.

Objective: To compare viral suppression in treatment-naïve adults starting antiretroviral therapy with dolutegravir (50mg)- and efavirenz (600mg)-based regimens. Methods: We analyzed secondary data from Brazilian health information systems of people living with human immunodeficiency virus who started antiretroviral therapy between 2015 and 2017 in Minas Gerais, Brazil. The outcome was viral suppression, defined as the achievement of the first viral load <50 copies/mL within 12 months after initiating antiretroviral therapy. This outcome was also compared with viral load <1,000 copies/mL and analyzed in two scenarios: intention-to-treat versus per-protocol. Time to viral suppression and adjusted odds ratio accompanied by 95% confidence intervals were estimated. Results: Of the 2,599 participants enrolled, 77.5% were men, and the median age was 34 years. In the intention-to-treat analysis, viral suppression was 58.1% for efavirenz and 76.7% for dolutegravir. People living with HIV on dolutegravir-based regimen were more likely to achieve viral suppression (aOR: 2.44; 95%CI: 2.01-2.95) and had a shorter median time to viral suppression (p<0.0001). Antiretroviral therapy initiation within <120 days, baseline CD4=T-cells =200 cells/mm3, and viral load <100,000 copies/mL had higher odds of viral suppression. According to the per-protocol analysis, viral suppression =90% was observed by considering viral load <1,000 copies/mL. Conclusion: Our study demonstrated that viral suppression improved after introducing dolutegravir, although the proportion of patients with viral load <50 copies/mL was lower than expected. Improved access to routine viral load examinations and continuous surveillance of the effectiveness of antiretroviral therapy should be considered. [ABSTRACT FROM AUTHOR]

Extraskeletal Ewing sarcoma in pregnancy is very rare in clinic, with a high rate of recurrence and metastasis, and there is no unified and effective treatment plan at present. This paper reports a case of pregnancy complicated with extraperitoneal Ewing sarcoma. Due to lumbosacral pain, a healthy full-term live female infant was successfully cesarean section in the First Hospital of Lanzhou University, who had previously received retroperitoneal tumor resection combined with left nephrectomy, supplemented with postoperative chemotherapy, combined with relevant medical history and examination to consider the recurrence and metastasis of extraperitoneal Ewing sarcoma. Because extraosseous Ewing sarcoma in pregnancy is very rare, the treatment is more difficult and the prognosis is poor. It is suggested that the suspected pregnant women should be followed up on the basis of regular prenatal examination in clinical work to find the focus in time. Once diagnosed, treatment strategies should be developed under the multi-disciplinary joint management mode to help patients overcome the challenges posed by pregnancy associated cancer and minimize adverse outcomes. [ABSTRACT FROM AUTHOR]

Ethnopharmacological Relevance: The dried succulent stems of Cistanche tubulosa (Schenk) Wight are utilized in traditional medicine for tonifying kidney yang, which have shown to be effective in alleviating depression-like behaviors or male sexual dysfunction, respectively. However, the pharmacological effects and mechanisms of C. tubulosa and its combinations in the treatment of depression in comorbid with sexual dysfunction remain unclear., Aim of the Study: This study aims to elucidate the pharmacological effects and mechanisms of C. tubulosa aqueous extract (CTE) and its combination with fluoxetine (FLX) on depression in comorbid with sexual dysfunction., Materials and Methods: A mouse model of depression in comorbid with sexual dysfunction was created using the chronic unpredictable mild stress (CUMS) procedure. The therapeutic effects of CTE and its combination with FLX were assessed using depressive-like and mating behavior experiments, histopathological analysis, and hypothalamic-pituitary-gonadal (HPG) axis function evaluation. The mechanisms were explored by integrated serum and testicular metabolomics combined with network correlation analysis., Results: CTE was confirmed to significantly improve depressive-like behaviors, reduce mating abilities, testicular histopathological damage, and HPG axis hormone secretion disorders in CUMS mice. Subsequently, mechanism exploration findings indicated that CTE might exert its effect by regulating potential efficacy-related biomarkers (isobutyrylglycine, citric acid, D-galactose) to improve certain metabolic pathways centered around steroid hormone biosynthesis and tricarboxylic acid (TCA) cycle. Furthermore, the combination of CTE and FLX exhibited stronger antidepressant effects than FLX alone, and ameliorated the exacerbated sexual dysfunction induced by FLX. These effects were achieved through the regulation of potential efficacy-related biomarkers (17α-hydroxypregnenolone, tetrahydrodeoxy-corticosterone, sphingosine, cortol, thymine, and L-histidine), thereby improving disorders in glycerophospholipid and histidine metabolism., Conclusion: In conclusion, the amelioration effects of CTE and its combination with FLX on depression in comorbid with sexual dysfunction were confirmed for the first time. This key mechanism may be achieved by modulating the levels of potential efficacy-related biomarkers, and then emphatically intervene in steroid hormone biosynthesis, TCA cycle, glycerophospholipid and histidine metabolism. The study offers a new perspective for the development and utilization of C. tubulosa., 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 B.V. All rights reserved.)

Ethnopharmacological Relevance: The decline in cross-protection provided by the smallpox vaccine increases the risk of infection from other poxviruses. While drug combinations are a promising management, they remain underdeveloped for poxviruses. Prior to the development of the smallpox vaccine, China had long relied on herbal medicine to combat pox and accumulated a wealth of knowledge regarding different herb combinations and symptoms related to pox. The information was documented in the form of prescriptions., Aim of the Study: The extensive data of prescriptions offer the potential for uncovering commonalities underlying these prescriptions, thereby providing valuable insights into the development of drug combinations against pox., Materials and Methods: The 2344 prescriptions were collected from the LTM-TCM database and 12 traditional Chinese medicine books. Firstly, the relative frequency of citation was utilized to identify the most used herbs among these prescriptions. TCMSP and LTM-TCM databases were employed to gather information about active compounds and their targets. GeneCards and DisGeNET databases were utilized to determine the associated targets for smallpox, cowpox, chickenpox, and mpox. Subsequently, network pharmacology analysis was conducted to investigate potential pathway information related to the most used herbs. A comparison of active compounds from these herbs resulted in the identification of 29 high-frequency compounds. The functions of these compounds were elucidated through gene overlap analysis, docking, and literature review. Finally, we summarized pox-related symptoms and used fidelity levels to distinguish specific herbs for corresponding symptoms., Results: Based on 2344 traditional pox-related prescriptions, we identified 19 most used herbs and 64 associated bio-functional modules for poxvirus treatment, with the most significant one being immunoregulation primarily involving CD4 + regulation. We also identified 29 leads that possess anti-inflammatory, antimicrobial, and antiviral properties. These herbs and leads hold the potential for pox treatment. Additionally, docking analysis suggested that these leads could inhibit poxvirus DNA synthesis, RNA capping machinery processes, and mature poxvirus particle formation, as well as immunosuppressors. The clinical features of mpox in 2022 were found to align well with our description of symptoms related to the pox., Conclusion: Through the analysis of 2344 prescriptions for pox treatment, we obtained a comprehensive library of the most used herbs and high-frequency compounds, along with their potential functional spectrum. These libraries served as raw resources for drug combination development, while the identified symptom patterns and specific herbs greatly enhanced our insight into diverse treatments for pox 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 B.V.)

Yinchenhao decoction (YCHD) is widely used in the treatment of damp-heat syndrome of chronic hepatitis B (CHB), but it remains unclear about the active compounds in YCHD and its potential mechanism for treating CHB. The purpose of this work is to evaluate the clinical efficacy of YCHD combined with nucleoside analogues (NAs) for the treatment of CHB. Besides, based on the exact clinical efficacy, we combined serum metabolomics and network pharmacology to screen differential metabolites and related pathways regulated by YCHD to investigate the possible mechanism for treating CHB. It revealed that NAs plus YCHD could significantly improve alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, increase HBV-DNA negative rate (P<0.05), reduce the levels of inflammatory factors and LSM (both P<0.05), regulate lipids (P<0.05), and improve the symptoms of traditional Chinese medicine (TCM) (P<0.05) in CHB patients. YCHD was relatively safe. It showed 30 active compounds including chlorogenic acid, geniposide, emodin, quercetin, kaempferol, β-sitosterol and aloe emodin, and 115 key targets which were related to the regulation of lipids and reduction of oxidative stress related to the effect of YCHD in CHB in the network pharmacology analysis. We found 9 core targets and 4 key metabolites according to metabolomics, which were partly consistent with the network pharmacology findings. It proved that network pharmacology combined with metabolomics can well explain the "multi-component-multi-target" mechanism of complex TCM., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The number needed to treat (NNT) for efficacy and number needed to harm (NNH) for tolerability/safety were evaluated for adjunctive cariprazine in major depressive disorder (MDD)., Methods: Data were extracted from five randomized, double-blind, placebo-controlled trials of adjunctive cariprazine in MDD. NNTs (response, remission, severity shift) and NNHs (discontinuations due to adverse events [AEs], AEs, laboratory shifts) were determined in dose groupings; likelihood to be helped/harmed (LHH) was calculated., Results: NNTs (95 % CI) for adjunctive cariprazine versus placebo were statistically significant at week 6/early termination for response on the Montgomery-Åsberg Depression Rating Scale (MADRS), as defined by a decrease in total score ≥ 50 % (doses ≥ 1 mg/d = 12 [9-21]; 1-2 mg/d = 12 [8-25]; 2-4.5 mg/d = 14 [9-43]) and other response/remission outcomes. NNHs for cariprazine versus placebo were generally ≥ 10 for AEs that were statistically significant; an apparent dose-response was seen for akathisia (lower dose = 24 [17-43]; higher dose = 9 [7-11]). LHHs were ≥ 1 (acceptable benefit/harm ratio) for MADRS total score response versus most important cariprazine AEs in most dose groupings. For response versus discontinuation because of an AE, adjunctive cariprazine 1-2 mg/d had a more favorable response/tolerability profile in indirect comparison with other approved atypical antipsychotics., Limitations: Post hoc analysis; indirect comparisons., Conclusions: Patients receiving adjunctive cariprazine encountered benefits more often than harms; NNT values at week 6/early termination were statistically significant versus placebo on response/remission outcomes across dose groupings from the five pooled studies. Adjunctive cariprazine was well tolerated; NNH values versus placebo were generally > 10, with better akathisia tolerability in the lower-dose range., Competing Interests: Declaration of competing interest Leslie Citrome is a clinical professor in the Department of Psychiatry and Behavioral Sciences at New York Medical College in Valhalla, New York. He has served as consultant to AbbVie/Allergan, Acadia, Adamas, Alkermes, Angelini, Astellas, Avanir, Axsome, Biogen, BioXcel, Boehringer Ingelheim, Cadent Therapeutics, Cerevel, Clinilabs, COMPASS, Delpor, Eisai, Enteris BioPharma, HLS Therapeutics, Idorsia, INmune Bio, Impel, Intra-Cellular Therapies, Janssen, Karuna, Lundbeck, Luye, Lyndra, MapLight, Marvin, Medavante-ProPhase, Merck, Mitsubishi-Tanabe Pharma, Neumora, Neurocrine, Neurelis, Noema, Novartis, Noven, Otsuka, Ovid, Praxis, Recordati, Relmada, Reviva, Sage, Sumitomo/Sunovion, Supernus, Teva, University of Arizona, Vanda, Wells Fargo, and one-off ad hoc consulting for individuals/entities conducting marketing, commercial, or scientific scoping research; speaker for AbbVie/Allergan, Acadia, Alkermes, Angelini, Axsome, BioXcel, Eisai, Idorsia, Intra-Cellular Therapies, Janssen, Lundbeck, Neurocrine, Noven, Otsuka, Recordati, Sage, Sunovion, Takeda, Teva, and CME activities organized by medical education companies such as Medscape, NACCME, NEI, Vindico, and Universities and Professional Organizations/Societies; owns stocks (small number of shares of common stock): Bristol-Myers Squibb, Eli Lilly, J & J, Merck, Pfizer purchased >10 years ago, stock options: Reviva; and receives royalties/publishing Income from Taylor & Francis (Editor-in-Chief, Current Medical Research and Opinion, 2022-date), Wiley (Editor-in-Chief, International Journal of Clinical Practice, through end 2019), UpToDate (reviewer), Springer Healthcare (book), Elsevier (Topic Editor, Psychiatry, Clinical Therapeutics)., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: Guidelines recommend initiation of dual combination antihypertensive therapy, preferably single-pill combination (SPC), in most patients with hypertension. Evidence on narrowing gaps in clinical practice relative to guidelines is limited., Methods and Results: Monte Carlo simulation was applied to 1.1 million patients qualifying for dual combination therapy from a previously conducted retrospective analysis of clinical practice, hospital statistics, and national statistics in the UK. We provide 10-year Kaplan-Meier event rates for the primary endpoint representing a composite of non-fatal myocardial infarction, non-fatal stroke (ischaemic or haemorrhagic), non-fatal heart failure hospitalization, or cardiovascular death. Cox model results from a previously conducted study were utilized to estimate baseline risk, together with evidence on risk reduction from the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC) meta-analysis and published evidence on blood pressure-lowering efficacy of antihypertensive therapies. In the overall population, estimated 10-year event rates for the primary endpoint in patients with 100% persistence in monotherapy were 17.0% for irbesartan and 17.6% for ramipril. These rates were only modestly better than those observed in clinical practice (17.8%). In patients with 100% persistence in dual therapy, estimated event rates were 13.6% for combinations of irbesartan + amlodipine [absolute risk reduction (ARR) = 8.7% compared with untreated] and 14.3% for ramipril + amlodipine (ARR = 8.0% compared with untreated). The absolute risk of the primary endpoint was reduced by 15.9% in patients with atherosclerotic cardiovascular disease (ASCVD) and 6.6% in those without ASCVD. Similarly, the absolute risk was reduced by 11.7% in patients with diabetes and 7.8% in those without diabetes., Conclusions: This study represents the first to investigate guidelines-based treatment in hypertensive patients and demonstrates the opportunity for considerable risk reduction by ensuring recommended dual therapy in clinical practice, particularly in the form of SPC with high persistence, relative to no treatment or monotherapy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Using rosuvastatin, the RACING (randomized comparison of efficacy and safety of lipid-lowering with statin monotherapy versus statin/ezetimibe combination for high-risk cardiovascular diseases) trial showed the beneficial effects of combining moderate-intensity statin with ezetimibe compared with high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease. This study investigated whether the beneficial effects of combination lipid-lowering therapy extend to patients treated with atorvastatin, not rosuvastatin, in daily clinical practice., Methods and Results: Using stabilized inverse probability of treatment weighting, a total of 31 993 patients who were prescribed atorvastatin after drug-eluting stent (DES) implantation were identified from a nationwide cohort database: 6215 patients with atorvastatin 20 mg plus ezetimibe 10 mg (combination lipid-lowering therapy) and 25 778 patients with atorvastatin 40-80 mg monotherapy. The primary endpoint was the 3-year composite of cardiovascular death, myocardial infarction, coronary artery revascularization, hospitalization for heart failure treatment, or non-fatal stroke in accordance with the RACING trial design. Combination lipid-lowering therapy was associated with a lower incidence of the primary endpoint (12.9% vs. 15.1% in high-intensity atorvastatin monotherapy; hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.74-0.88, P < 0.001). Compared with high-intensity atorvastatin monotherapy, combination lipid-lowering therapy was also significantly associated with lower rates of statin discontinuation (10.0% vs. 8.4%, HR 0.81, 95% CI 0.73-0.90, P < 0.001) and new-onset diabetes requiring medication (8.8% vs. 7.0%, HR 0.80, 95% CI 0.70-0.92, P = 0.002)., Conclusion: In clinical practice, a combined lipid-lowering approach utilizing ezetimibe and moderate-intensity atorvastatin was correlated with favourable clinical outcomes, drug compliance, and a reduced incidence of new-onset diabetes requiring medications in patients treated with DES implantation. Trial registration:  ClinicalTrial.gov (NCT04715594)., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Rationale: Current research on antiviral treatment in children is relatively limited, especially in children under 1 year old., Patient Concerns: Liu XX, an 8-month-old infant (case number: 3001120473), presented to the hospital in August 2016 with a chief complaint of being "hepatitis B surface antigen positive for 8 months and experiencing abnormal liver function for 5 months.", Diagnoses: The patient was diagnosed as chronic hepatitis B cirrhosis (G3S3-4) with active compensatory phase., Interventions: The treatment regimen commenced with lamivudine (LAM) for the initial 8 weeks, followed by the addition of interferon α (IFNα) after 1 year of age. At 2 years old, LAM was substituted with entecavir, and at 3 years old, IFNα was replaced with pegylated interferon α (PEG IFNα)., Outcomes: After 8 weeks of LAM monotherapy, Liu XX experienced hepatitis B e antigen loss. Subsequently, after 36 weeks of IFNα add-on therapy, hepatitis B virus DNA became undetectable, and after 48 weeks of switching to PEG IFNα treatment, hepatitis B surface antigen loss was observed. Remarkably, following 50 weeks of drug discontinuation, the child remained functionally cured., Lessons: Chronic hepatitis B virus-infected infants and young children can achieve durable functional cure with PEG IFNα-based individualized therapy. This case provides a valuable reference for the diagnosis and treatment of such patients., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2025 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: This study evaluates the efficacy and safety of sitagliptin versus gliclazide, combined with metformin, in treatment-naive patients with type 2 diabetes mellitus (T2DM) and glucotoxicity., Methods: In this single-center, randomized, controlled noninferiority trial, 129 treatment-naive patients with T2DM with glucotoxicity (fasting plasma glucose [FPG] ≥ 200 mg/dL and glycated hemoglobin ≥ 9.0%) were randomized to receive sitagliptin plus metformin (n = 66) or gliclazide plus metformin (n = 63) for 12 weeks. Sitagliptin and gliclazide were given for the first 4 weeks, followed by metformin monotherapy for 8 weeks. Efficacy end points included changes in glycemic control, body weight, and β-cell function at baseline, 4 weeks, and 12 weeks., Results: After 12 weeks, mean glycated hemoglobin reductions were 4.03% in the sitagliptin group and 4.13% in the gliclazide group, with a mean difference of -0.097 (95% confidence interval, -0.648 to 0.453), confirming noninferiority. Both groups showed significant FPG reductions at 4 weeks (P < .05). The sitagliptin group achieved faster glycemic targets, greater FPG and body weight reductions, and higher rates of FPG < 6.1 mmol/L (26.2% vs 5.7%; P = .012). No significant differences were observed in β-cell function or hypoglycemia incidence (P > .05). Genetic analysis showed specific single-nucleotide polymorphisms affected drug efficacy: dipeptidyl peptidase-4 rs2909451 TT and rs4664443 GG genotypes showed lower efficacy with sitagliptin, while GLP1R rs3765467 AG and KCNJ11 rs2285676 CC genotypes responded better to sitagliptin., Conclusion: Sitagliptin combined with metformin is noninferior to gliclazide combined with metformin in treatment-naive patients with T2DM with glucotoxicity. Genetic polymorphisms significantly affect drug efficacy, highlighting the importance of personalized medicine. The sitagliptin group achieved glycemic targets more quickly and had greater weight reductions without increased adverse effects., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2025 the Author(s). Published by Wolters Kluwer Health, Inc.)

Rationale: We report the efficacy of combination prednisolone and intravenous (IV) rituximab as an immunosuppressive regimen for a young male presenting with extensive venous thromboembolism including a submassive pulmonary embolism secondary to life-threatening nephrotic syndrome from very high risk anti-phospholipase-A2 receptor (PLA2R) positive membranous nephropathy. Initial treatment was with mechanical thrombectomy and anticoagulation. Thereafter, oral prednisolone was initiated to induce remission, during a period of uninterrupted anticoagulation. He subsequently underwent a kidney biopsy for histological confirmation and IV rituximab was administered as definitive treatment., Patient Concerns: A 33-year-old Chinese male with no chronic conditions presented with shortness of breath and left-sided pleuritic chest pain., Diagnoses: He was diagnosed with a submassive pulmonary embolism which was confirmed on computer tomography imaging with additional extensive clot burden in the inferior vena cava and renal veins. Further workup revealed nephrotic syndrome, with proteinuria of 6.5g/day, and serum Albumin 26 g/L, associated with anti-PLA2R of 223 RU/ml. His presenting serum creatinine was 108 µmol/L (CKD-EPI eGFR 77ml/min/1.73m2). Additional workup for malignancy and infections were negative., Interventions: As part of acute management, immediate anticoagulation was initiated. The patient then underwent endovascular thrombectomy and inferior vena cava filter placement. Given the emergent indication for and need for 4 weeks of uninterrupted anticoagulation, his kidney biopsy had to be delayed. The patient was then preemptively treated with IV Methylprednisolone 500mg for 3 days followed by 0.5mg/kg of oral prednisolone after taking into consideration the specificity of PLA2R positivity for membranous nephrology., Outcomes: After 4 weeks of treatment, serum albumin improved to 32 g/L and anti-PLA2R levels improved significantly to 27 RU/ml. His subsequent kidney biopsy confirmed membranous nephropathy and 2 doses of IV rituximab 1g were administered 14 days apart. Six months after initial presentation, the patient is in partial remission. Albumin has improved to 41 g/L, Anti PLA2R < 2 RU/ml, and proteinuria is 1.18g/day., Lessons: This case demonstrates that preemptive treatment in patients with anti-PLA2R positive membranous nephropathy can initiated without a histological diagnosis when there are strong contraindications against a kidney biopsy. Treatment with a combination of steroids and IV rituximab could be a viable treatment option for patients with very high-risk membranous nephropathy over conventional therapy with cyclophosphamide., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2025 the Author(s). Published by Wolters Kluwer Health, Inc.)

New antimalarial combination therapies with novel modes of action are required to counter the emergence and spread of Plasmodium drug resistance against existing therapeutics. Here, we present a study to evaluate the preventive activity of a combination of clinical antimalarial drug candidates, cabamiquine and ganaplacide, that have multistage activity against the liver and blood stages of Plasmodium infection. Cabamiquine (DDD107498, M5717) inhibits parasite protein synthesis, and ganaplacide (KAF156) inhibits protein trafficking, blocks the establishment of new permeation pathways, and causes endoplasmic reticulum expansion. The pharmacodynamic parameters of a combination of the two compounds were assessed employing a pharmacometrics approach in conjunction with in vitro-in silico checkerboard analysis. The in vitro study was performed on a previously established 3D infection platform based on human hepatic cell lines that sustain infection by rodent P. berghei parasites. The in vivo efficacy of this drug combination was assessed against the liver stage of the P. berghei . Our results show that the combination of both drugs at the tested concentrations does not interfere with the drugs respective mode of action or affect hepatocyte cell viability. The drug combination was fully effective in preventing the appearance of blood stage parasites when a systemic plasma C av0-24 /EC 50 ratio >2 for ganaplacide and >5 for cabamiquine was achieved. These findings demonstrate that chemoprevention using a combination of cabamiquine and ganaplacide has the potential to target the asymptomatic liver stage of Plasmodium infection and prevent the development of parasitemia.

Diabetes mellitus, a globally prevalent condition, often complicates wound healing, leading to chronic, non-healing wounds. This study explores a novel combination therapy using Dapagliflozin and Cycas media extract for treating experimentally induced diabetic wounds in rats. By targeting the Notch signaling pathway, a critical pathway in wound healing, this research investigates the efficacy of this combination therapy in accelerating wound repair. Forty-two male Wistar albino rats were divided into control and treatment groups, receiving various Dapagliflozin and Cycas media gel combinations. The study evaluated wound healing, biochemical markers, gene expression, and histopathological changes. The findings suggest that the combination therapy significantly enhances wound healing, modulates oxidative stress, alters inflammatory responses, and influences key genes in the Notch pathway. This research provides a new perspective on diabetic wound management and underlines the potential of combining Dapagliflozin and Cycas media as a therapeutic approach., 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 B.V. All rights reserved.)

Patients with diabetes have a high risk of failure of H. pylori eradication therapy. The present study aims to evaluate the efficacy and safety of vonoprazan-amoxicillin (VA) dual therapy for the treatment of H. pylori infection in patients with type-2 diabetes mellitus (T2DM), and determine the influence of H. pylori eradication on the glycated hemoglobin A1C (A1C) level. The present prospective, single-center, single-arm, clinical trial enrolled 75 T2DM patients diagnosed with H. pylori infection. The patients were treated with the VA dual therapy regimen, which comprised of vonoprazan (20 mg, twice daily) and amoxicillin (750 mg, thrice daily), for 14 days (14-day VA dual therapy). The eradication rate in the intention-to-treat analysis and per-protocol analysis was 84.00% (63/75) and 87.14% (61/70), respectively. The multivariate analysis revealed that the independent risk factors for H. pylori eradication failure were smoking (OR: 4.59, 95% CI: 1.20-17.58, p = 0.026) and elevated A1C level (OR: 1.65, 95% CI: 1.01-2.68, p = 0.044). Patients in the successful eradication group presented with a significant decrease in the A1C level at 3 months, post-treatment, when compared to the pre-eradication level (7.70 ± 1.05% vs. 7.23 ± 1.00%, p = 0.006). VA dual therapy is a safe and effective regimen for patients with T2DM., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Introduction: Several cardiovascular outcome trials have been conducted to assess the cardiovascular safety and efficacy of glucagon-like peptide-1 receptor agonists (GLP1-RAs) on cardiorenal outcomes in patients with type-2 diabetes (T2D). However, the strict requirements of randomised controlled trials to avoid most confounding factors are at the expense of external validity. Using national real-world data, we aimed to evaluate the effectiveness of GLP-1RAs in association with metformin especially on cardiovascular events, hospitalisation for heart failure and all-cause death in comparison with other diabetes treatment schemes using dipeptidyl peptidase IV inhibitors, sulfonylureas/glinides or insulin also associated with metformin. Sodium-glucose transport protein 2 inhibitors (SGLT-2i) will be excluded as comparators, as this class of oral hypoglycaemic agents just started in 2020 to be marketed in France., Methods and Analysis: The Système National des Données de Santé is a comprehensive nationwide administrative healthcare database in France that covers approximately 67 million people.Several cohorts of adult patients with T2D initiating any GLP1-RA in dual or triple therapies, as recommended by the French Health authorities, will be identified in this database over the period 2016-2021. These cohorts will be defined by the combination of glucose-lowering drugs prescribed simultaneously with GLP1-RA and diabetes treatment received over a 6-month period before GLP1-RA initiation. They will be first matched with T2D controls (1:3 ratio) based on the year of drug initiation and treatment regimens before and simultaneously with GLP1-RA in the different selected cohorts. Comparative analyses will be conducted versus these control groups, adjusting for cardiovascular event history and a propensity score considering age, sex, area of residence, deprivation index, comorbidities, duration of diabetes, use of lipid-lowering drugs, anticoagulants, antiplatelet therapies and blood pressure-lowering therapies. Comparative analyses will be conducted versus these control groups, using a high-dimensional propensity scores method and fixed baseline characteristics. Treatment effects on the different outcomes measured will be estimated for each GLP1-RA group, through HR and their corresponding CIs (95% CI) using Cox regressions and/or competitive risk regressions when necessary., Ethics and Dissemination: The study has been approved by an independent ethics committee (Comité éthique et scientifique pour les recherches, les études et les évaluations dans le domaine de la santé, Paris, France; reference: 8699786, dated 2 June 2022) and has been registered with the French National Data Protection Commission (Commission Nationale de l'Informatique et des Libertés, Paris, France; reference: 922161, dated 26 June 2022). The findings of this study will be published in peer-reviewed scientific journals and presented at international conferences., Trial Registration Number: F20220803152803., Competing Interests: Competing interests: ND has received fees for giving talks or participating to advisory boards, or support for attending meetings from: Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Bouchara-Recordati, IBSA, Maincare, MSD, NovoNordisk, Pfizer, Servier, UCB and Vifor. GL has received fees and honoraria from Alnylam, Amarin, Amgen, Astra Zeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Boston Scientific, MSD, Novartis, Novo Nordisk, Organon, Pfizer, Recordati and Sanofi Aventis. MM has received fees and honoraria from Acticor Biotech, Astra Zeneca, Boehringer Ingelheim, Novartis, Novo Nordisk. KM has received consulting fees from Novo Nordisk; honoraria for lectures, presentations, or speaker bureaus from Novo Nordisk, Astra Zeneca, Boehringer-Ingelheim, Eli Lilly, Sanofi, Lifescan, Abbott, and Bayer; and participation to Advisory Board from Novo Nordisk, Sanofi and Amarin. FS has received research grants from and/or was speaker (with or without lecture fees) on a.o. (CME accredited) meetings sponsored by Amgen, Bayer, Novartis, Novo Nordisk, Sanofi Aventis, Recordati, Servier, Mylan and AstraZeneca. IS has received fees and honoraria from Novonordisk, Sanofi Synthé-Labo, Servier, Boheringer Ingelheim, Astra-Zeneca and Medtronic. AC, CE and CN are employees of CEMKA, a French heath care Clinical Research Organization. LV and CM are employees of NovoNordisk. BD has received fees from Astra-Zeneca, CEMKA, Novo-Nordisk, Abbott, Sanofi Winthrop Industry, Lumanity, Continuum+ and CERBA. LF has received consulting fees from AstraZeneca, Bayer, BMS/Pfizer, Boehringer Ingelheim, Novo and XO, and speaker activities for AstraZeneca, Bayer, BMS/Pfizer, Boehringer Ingelheim, Boston Scientific, Medtronic and Zoll., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

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.)