Bone-targeting single-atom nanozymes for treating breast cancer bone metastasis via the synergistic effect of mild photothermal and chemodynamic therapy.

Silk fibroin/poly(L-lactic acid) Janus nanofibre membranes enhanced with Al-Ti₃C₂Tₓ MXene for dual-modal conductive and NIR-photothermal synergistic therapy of infected diabetic wounds.

Preparation of hybrid SPIONs and nanodiamonds in view of neurodegenerative diseases treatments.

Background Statins reduce cardiovascular risk but may increase new-onset type 2 diabetes mellitus (NO-T2DM). Ezetimibe, a cholesterol absorption inhibitor, is often added to statins to improve lipid control, yet its impact on NO-T2DM remains uncertain. Objective This systematic review evaluated moderate-intensity statin plus ezetimibe dual therapy versus high-intensity statin monotherapy for NO-T2DM risk. Methods Five databases were searched to identify eligible studies. Random-effects meta-analyses generated pooled relative risks (RR) quantifying the effect of ezetimibe plus moderate-intensity statins on NO-T2DM. The Attributable Risk Fraction (ARF) was quantified utilizing the pooled estimate. Results Ten observational studies and four clinical trials were included. In four cohort studies, ezetimibe plus moderate-intensity statin compared to high-intensity statin monotherapy was significantly linked to 18% reduced risk of NO-T2DM (pooled RR: 0.82; 95% CI: 0.77–0.87; I2 = 0.0%; p < 0.001). In three methodologically similar studies, compared to moderate-intensity statin monotherapy, adding ezetimibe to moderate-intensity statin dual therapy showed non-statistically (p > 0.05) significant 4% increased risk of NO-T2DM development (pooled RR: 1.04; 95% CI: 0.94–1.14, I2= 0.0%). Compared with patients receiving high-intensity statin therapy, 22% of NO-T2DM cases could potentially be averted with dual therapy (moderate-intensity statin plus ezetimibe). In four studies involving 5,072 patients on high-intensity statins who developed NO-T2DM, 1,115 patients (812–1,420) could have been prevented with ezetimibe plus moderate-intensity statin dual therapy. Conclusion Incorporating ezetimibe with moderate-intensity statins, rather than relying solely on high-intensity statins, may reduce the risk of NO-T2DM in patients with dyslipidemia and elevated cardiovascular disease risk. Prospero Registration number CRD42024518630.

Dual versus monotherapy with SGLT2 inhibitor and GLP-1 receptor agonist:PRECIDENTD pragmatic randomized trial.

This study aims to evaluate the effect of maternal antiseizure medication (ASM) exposure on fetal malformations, accounting for specific periods of medication use during pregnancy and differentiating between monotherapy and dual therapy. Using data from the Korean National Health Insurance Service between 2010 and 2020, we conducted a population-based retrospective cohort study of pregnant women with epilepsy who were administered ASMs during pregnancy and those who were not, to assess the associated risk of congenital malformations. Participants were divided into four subgroups based on ASM exposure: Subgroup 1, first trimester (T1) exposure (first 12 weeks); Subgroup 2, exposure limited to the first 140 days; Subgroup 3, exposure only after day 141; Subgroup 4, continuous exposure. Each subgroup was analyzed separately to compare the effects of monotherapy and dual therapy. The primary outcome was the relative risk (RR) of congenital malformations associated with ASM monotherapy and dual therapy. Between 2012 and 2020, 1 916 583 women gave birth. Among these, 8939 (.47%) were diagnosed with epilepsy and required continuous ASM therapy for part or all of the observation period, whereas 4968 women with epilepsy had no ASM exposure during pregnancy and served as the unexposed comparator group. Subgroup 2 showed lower adjusted RR of congenital malformations with monotherapy and dual therapy. In dual therapy, lamotrigine was linked to an increased risk of overall malformations in Subgroups 1 (adjusted RR = 1.81, 95% confidence interval [CI] = 1.22-2.70, p = .0033) and 4 (adjusted RR = 1.81, 95% CI = 1.21-2.70, p = .0039). Valproate dual therapy in Subgroup 4 showed higher risk of overall malformations (adjusted RR = 3.40, 95% CI = 1.36-8.48, p = .0086) and cardiac malformations (adjusted RR = 5.50, 95% CI = 1.29-23.51, p = .0214). Prolonged ASM exposure throughout pregnancy was associated with a significantly increased risk of malformations compared with exposure limited to T1 or to the first half of pregnancy.

This study aimed to evaluate the one-year metabolic and renal effects of combined therapy with SGLT-2 inhibitors and GLP-1 receptor (GLP-1R) agonists in patients with type 2 diabetes mellitus (T2DM), both with and without diabetic kidney disease (DKD). The primary objective was to assess changes in BMI, HbA1c, LDL-C, eGFR, and UACR in a real-world setting. A retrospective analysis was conducted on 250 patients with type 2 diabetes mellitus (T2DM) treated with SGLT-2 inhibitors and GLP-1 receptor agonists at the Diabetology Service of CTO-Alesini Hospital, Rome, between 2022 and 2025. Metabolic and renal parameters were collected at baseline and after 12 months. Patients were stratified according to the presence of diabetic kidney disease (DKD). The primary outcomes included changes in BMI, HbA1c, LDL-C, eGFR, and UACR. Secondary analyses evaluated the impact of adding an SGLT-2 inhibitor to pre-existing GLP-1 receptor agonist therapy, or vice versa. After 12 months, we observed significant reductions in BMI (p = 0.03), HbA1c (p < 0.001), LDL-C (p < 0.01), and UACR (p < 0.001). In patients with DKD (46% of the cohort), UACR improved markedly (p < 0.001), while eGFR remained stable. Significant reductions in HbA1c (p < 0.001) and LDL-C (p < 0.01) were also observed. In non-DKD patients, HbA1c and LDL-C decreased after one year, with eGFR remaining within the normal range. Importantly, among DKD patients, the addition of an SGLT-2 inhibitor to GLP-1 receptor agonist therapy resulted in significant reductions in both HbA1c (p = 0.04) and UACR (p < 0.01), whereas the addition of a GLP-1 receptor agonist primarily reduced HbA1c (p < 0.01). In non-DKD patients, both treatment sequences improved HbA1c and LDL-C. Dual therapy with SGLT-2 inhibitors and GLP-1 receptor agonists was associated with improvements in glycemic control, lipid profile, and albuminuria, particularly among patients with DKD. The sequence of drug addition appeared to influence outcomes, with the addition of SGLT-2 inhibitors providing superior renal benefits in DKD. These findings may provide support for early combined use of both agents in high-risk patients with T2DM.

Background: Blood pressure variability (BPV) is an independent predictor of cardiovascular risk, particularly in patients with hypertension and diabetes. This study aimed to evaluate BPV in hypertensive patients with comorbidities using ambulatory blood pressure monitoring (ABPM) and assess the influence of gender and antihypertensive therapy. Methods: This prospective observational study included 58 patients (aged 26–85 years) undergoing 24-hour ABPM in Mumbai, India. BPV was assessed using the standard deviation of 24-hour systolic blood pressure (SD 24-h SBP). Patients were categorized based on hypertension and diabetes status, gender, and antihypertensive therapy (monotherapy, dual, or triple therapy). Statistical comparisons were made using t-tests and chi-square tests, with significance set at p&lt;0.05. Results: Patients with diabetes exhibited significantly higher BPV than those without diabetes (p&lt;0.05). Gender differences were observed, with females showing greater BPV than males. Among hypertensive patients, those on triple therapy had higher BPV than those on dual therapy, indicating greater difficulty in achieving BP control. Despite antihypertensive and adjunct therapies, BPV remained elevated in some patients, particularly those with diabetes and those requiring multiple antihypertensive agents. Conclusions: BPV is significantly elevated in patients with diabetes and those on intensive antihypertensive regimens, highlighting the challenges in BP management. The observed gender differences suggest potential influences of hormonal and vascular factors. These findings underscore the need for personalized treatment strategies to improve BP control and reduce cardiovascular risk in high-risk populations.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual incretin therapies, including semaglutide and tirzepatide, have reshaped the management of obesity and type 2 diabetes. Their rapid uptake in Saudi Arabia has created both opportunities and challenges, notably the rise in cosmetic-driven use, socioeconomic disparities, and emerging regulatory concerns. This narrative review synthesizes clinical, mechanistic, sociocultural, and policy-related evidence on GLP-1 and dual incretin therapies in Saudi Arabia, with a particular focus on real-world use patterns, misuse, and implications for Vision 2030 health goals. Evidence was drawn from randomized clinical trials, observational studies, national reports, and Gulf-region literature published between 2016 and 2025. Key thematic areas include pharmacologic mechanisms, efficacy, safety, public behaviour, affordability, off-label misuse, and policy gaps. Tirzepatide demonstrates superior glycemic and weight-loss outcomes compared to semaglutide, largely due to its dual GLP-1/GIP activity and enhanced neurobehavioral effects on appetite regulation. Semaglutide, however, retains proven cardiovascular benefits, while similar outcomes for tirzepatide await results from the ongoing SURPASS-CVOT trial. In Saudi Arabia, off-label and cosmetic use of these agents has proliferated, fueled by social media influence, inequitable access, and unregulated parallel markets. High drug costs and limited insurance coverage continue to restrict access for clinically indicated patients. Clinical audits and qualitative studies further reveal significant misuse among non-obese individuals, contributing to medication shortages and threatening equitable distribution. While GLP-1 and dual incretin therapies hold transformative potential for metabolic health, their misuse, affordability barriers, and sociocultural pressures must be addressed. National strategies involving pricing regulation, controlled prescribing policies, public awareness campaigns, and enhanced pharmacovigilance are urgently needed to optimize clinical impact and safeguard public health.

Introduction In chronic granulomatous disease (CGD), Aspergillus is the most common cause of invasive fungal infections and accounts for a high percentage of mortality. Methods The current study included 45 patients with a genetic diagnosis of CGD recruited between 2005 and 2024 from seven public hospitals in four Mexican cities. Results We recruited 45 patients of CGD with invasive aspergillosis (IA) events. The median age between the first CGD manifestation and first aspergillosis event was 65 months. Mortality rate was 57.7% for proven aspergillosis events, 23.1% for probable events, and 19.2% for possible events (p = 0.038). Aspergillus fumigatus was the most common species. Of the 45 patients, 26 (58%) had one IA event, nine (20%) had two, five (11%) had three, and five (11%) had four IA events. The median time between the first and second events was 35 months (15–65), between the second and third events was 26 months (17.5–32.5), and between the third and fourth events was 22 months (15.5–43.5). Of the 78 IA events, 43 (55%) were treated with monotherapy, 16 (20.5%) with dual therapy, 15 (19.2%) with triple therapy, three (3.8%) with quadruple therapy, and one (1.5%) with quintuple therapy. Twenty-six (58%) of the 45 patients died, out of which 18 (69%) had IA. The median age at death was 107.5 months (44.7–196). Overall survival of the 45 patients was 80.8% at 64 months. Conclusions The high mortality rate of IA in CGD patients could be reduced by early suspicion, initiating correct antifungal treatment over a long period, and considering the performance of hematopoietic stem cell transplantation.

This study was undertaken to investigate the efficacy of antiseizure medications in reducing interictal epileptic discharges (IEDs) in patients with idiopathic generalized epilepsies (IGEs) and to explore the relationship between IED measures and clinical events. We hypothesize that valproate and ethosuximide are superior to levetiracetam, which in turn is superior to lamotrigine in reducing IED activity. We performed a retrospective analysis of 577 video-electroencephalographic studies in individuals with IGEs over a median recording duration of 5 days. Clinical variables analyzed for each study included the following: antiseizure medication regimen, seizure occurrence, mean, median, and maximum IED durations, IED rate (events per hour), and IED burden (percentage of the recording containing IEDs). All IED outcomes were measured twice: for all detected IEDs and for IEDs ≥3 s. Linear regression analysis of the monotherapy regimens found that carbamazepine was associated with greater IED rates (all: β = 20.0 events/h, p < .001; ≥3 s: β = 2.4 events/h, p < .001). Similarly, regression analysis of the dual therapy regimens revealed that valproate and lamotrigine were associated with reduced IED rates and burdens in the overall cohort (rate: β = -18.0 events/h, p = .028; burden: β = -.62%, p = .031). Additionally, participants with detected seizures exhibited higher IED durations, rates, and burdens than those without seizures, in both the overall and ≥3-s cohorts (all p < .001). These findings do not conclusively support or reject the hypothesis. Carbamazepine is associated with increased interictal event rate, whereas the valproate and lamotrigine combination is associated with reduced interictal event rate and burden. Our findings also demonstrate that increased IED outcomes are associated with seizure occurrence.

Shareable abstractTHARROS, a first-of-its-kind event-driven cardiopulmonary trial, will assess BGF benefits versus dual therapy with GFF on cardiopulmonary outcomes in a COPD population with elevated cardiovascular risk and who are not on ICS-containing maintenance therapy.https://bit.ly/4dK58Tw

ABSTRACT Background Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer globally with high mortality rates, highlighting the urgent need for novel therapeutic strategies. We investigated the efficacy of combining phosphoinositide 3-kinase gamma (PI3Kγ) inhibition with programmed death-ligand 1 (PD-L1) blockade in a poorly immunogenic HNSCC model. Materials and methods Mouse bone marrow-derived macrophages (BMDMs) were differentiated and polarized in the presence or absence of the PI3Kγ inhibitor IPI-549 or culture supernatants from MOC2 cells treated with or without IPI-549. MOC2 cells were orthotopically injected into C57BL/6 mice, and treated with anti-PD-L1, IPI-549, combined anti-PD-L1 and IPI-549 or vehicle control. Tumor burden, survival, and immunological responses were evaluated. Results and conclusion Dual inhibition of PI3Kγ (using IPI-549) and PD-L1 demonstrated nearly significant reduction in primary tumor burden and significantly increased survival compared to single or control treatments. PI3Kγ inhibition promoted macrophage differentiation toward an antitumoral M1 phenotype. In the bone marrow, dual therapy significantly increased MHC-II expression across various myeloid cell subsets and effectively normalized myelopoiesis. Notably, combination therapy increased CD8+ T-cell infiltration into tumors while decreasing T-cell exhaustion marker (LAG-3, CTLA-4, and TIM-3) and protumoral cytokine (IL-4). Combined PI3Kγ and PD-L1 inhibition offers a promising strategy for treating poorly immunogenic HNSCC by simultaneously targeting multiple immunosuppressive mechanisms. These findings provide a strong rationale for combining PI3Kγ and PD-L1 inhibitors as a therapeutic strategy for poorly immunogenic HNSCC, potentially improving clinical outcomes for patients.

BACKGROUNDHelicobacter pylori (H. pylori) infection is highly prevalent worldwide, and rising antibiotic resistance has reduced the efficacy of standard therapy, underscoring the need for simplified and better-tolerated regimens.AIMTo evaluate the efficacy, safety, and optimal dosing of vonoprazan (VPZ)-amoxicillin (AMO) dual therapy in a non-inferiority randomized trial for H. pylori eradication.METHODSIn this multi-center, randomized trial conducted at 17 hospitals in Sichuan Province, China, 1717 adults with confirmed infection were assigned (1:1:1) to 14-day regimens: (1) VPZ 20 mg BID + AMO 0.5 g QID; (2) 0.75 g QID; or (3) 1.0 g TID. The primary endpoint was the eradication rate based on intention-to-treat (ITT) and per-protocol (PP) analyses; secondary endpoints included adverse events (AEs) and treatment compliance.RESULTSEradication rates were consistently high (92.35%-97.43%). In the 0.5 g QID group, ITT and PP eradication rates were 93.3% (95%CI: 91.2-95.1) and 97.4% (95%CI: 95.7-98.5), respectively, with no significant differences among groups (P > 0.05). Compliance ranged from 98.1% to 98.3%, and AEs were infrequent (5.2%-7.5%), predominantly mild gastrointestinal symptoms, which occurred least often in the 0.5 g QID group.CONCLUSIONVPZ-AMO dual therapy achieved excellent eradication, safety, and patient compliance. All regimens were similarly effective, whereas the 0.5 g QID dosing strategy offered the most favorable balance of efficacy and tolerability, supporting its use as a first-line option in high-prevalence settings.

Background: With modern antiretroviral regimens, durable viral suppression is now achieved in most people with HIV (PWH), whose life expectancy approaches that of the general population. Consequently, recent guidelines emphasise, beyond virological and immunological control, health-related quality of life and patient-reported outcomes (PROs) as targets of HIV care, including for dual regimens. Methods: We conducted a narrative review of clinical trials and observational studies evaluating PROs in adults treated with dual antiretroviral therapies, either oral or long-acting injectable. We also examined guideline documents and implementation studies addressing the role, feasibility, and interpretation of PROs in routine HIV care. Results: Trials of dual regimens reported high treatment satisfaction, convenience, and stable or improved quality of life, with some concerns related to injection-site reactions and visit burden for long-acting formulations. Emerging real-world data broadly confirm these findings but remain heterogeneous, with variability in instruments, assessment timing, and analytic approaches, limiting comparability and clinical use. Conclusions: PROs may support shared decision-making and optimise the use of dual therapies in PWH, but their uptake in clinical practice is still limited. Standardised tools, clearer interpretative frameworks, and pragmatic implementation strategies are needed to better integrate PROs into everyday HIV care.

Abstract Purpose: The aim of this study was to evaluate the safety and feasibility of ipatasertib combined with trastuzumab and pertuzumab (HP) as maintenance therapy after first-line treatment in patients with HER2-positive metastatic breast cancer harboring PIK3CA mutations (PIK3CAmut). Experimental Design: This prospective, multicenter, single-arm, phase Ib study evaluated the safety and preliminary efficacy of ipatasertib, an AKT inhibitor, combined with HP, with or without endocrine therapy as maintainance therapy, in patients with unresectable locally advanced or metastatic PIK3CAmut, HER2-positive breast cancer following first-line induction chemotherapy and HP. Results: Seventeen patients were enrolled, with a median follow-up of 27.7 months. During the dose-selection phase, ipatasertib at 400 mg daily (21 days on and 7 days off) with standard HP was established as the recommended phase II dosage. This decision was based on the absence of dose-limiting toxicities in the first six patients treated at this dosage during the initial 28-day cycle, which constituted the primary endpoint. Grade 3 treatment-related adverse events (TRAE) occurred in seven patients (41.2%), most commonly diarrhea and nausea. Two (11.8%) reported four serious TRAE (diarrhea, vomiting, ischemic stroke, and pneumonitis, one case each) related to ipatasertib, from which they recovered. The confirmed overall response rate was 31.1% [95% confidence interval (CI), 12.1%–58.5%], clinical benefit rate 84.6% (95% CI, 53.7%–97.3%), and median progression-free survival 16.4 months (95% CI, 9.4–NR); 47.3% of patients were progression free at 18 months. Conclusions: These results support ipatasertib plus HP as a safe and promising maintenance strategy for HER2-positive breast tumors harboring PIK3CAmut.

Antiplatelet therapy in patients with chronic coronary syndrome requiring oral anticoagulation: An updated meta-analysis of randomized trials.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, progressive pulmonary hypertension characterized by chronic fibrotic thrombi. Treatment includes surgical, endovascular, and pharmaceutical options. With varied treatments, it is essential to understand how they are deployed across real-world settings. We aimed to describe clinical characteristics, treatment patterns, and quality of life across real-world settings in the USA. Data were drawn from the Adelphi Real World CTEPH Disease Specific Program™, a cross-sectional survey of US physicians and patients, conducted September 2023-May 2024. Physicians recruited by local fieldwork agents using a short screening questionnaire provided demographics, clinical characteristics, and treatment patterns for 1-6 consecutively consulting patients with right heart catheterization confirmed CTEPH. These patients self-completed a form containing the EQ-5D-5L, visual analog scale (EQ-VAS), workplace and activity impairment scale (WPAI), pulmonary arterial hypertension symptom and impact scale. Data were stratified by treatment setting (accredited or nonaccredited pulmonary hypertension center). Analyses were descriptive. In total, 98 physicians provided data on 153 patients, of whom 53 completed the patient self-complete form. Mean (standard deviation) patient age was 59.2 years, 59.5% female, and 73.2% considered operable. Of those who had undergone a surgery/procedure (n = 68), 82.1% had undergone pulmonary thromboendarterectomy (PTE), and 19.1% balloon pulmonary angioplasty (BPA). Overall, 82.4% were prescribed any pharmaceutical medication for their CTEPH; of those treated, 81.0% were prescribed anticoagulants. Monotherapy (45.7%) was the most reported regimen in nonaccredited settings; for accredited settings, this was dual therapy (45.5%). EQ-5D-5L scores were low with nearly a quarter of patients reporting problems with usual activities and mobility, and 26.4% needing to change work patterns. Though treatment patterns generally followed guidelines, BPA was potentially underutilized. Dyspnea was common, despite treatment, with patients experiencing reduced quality of life, highlighting an unmet need.

Infection is a nearly universal complication among patients with major burns, yet guidance on early empiric antibiotic therapy remains limited. Broad-spectrum antibiotics are commonly initiated in the early phase of care but carry risks of antimicrobial resistance and drug toxicities. This single-centre, retrospective study evaluated the microbiological profiles and antibiotic prescribing patterns associated with first positive cultures (FPCs) in major burn patients admitted to Canada's highest-volume adult burn centre between January 1, 2018 and May 1, 2023. A total of 114 patients with ≥20% total body surface area burns were included. Among 145 FPCs, the most commonly cultured sites were respiratory (55%) and wound (30%). The most frequently identified organisms were methicillin-sensitive Staphylococcus aureus (19%), Haemophilus influenzae (15%), Enterobacter cloacae complex (8%), Escherichia coli (7%), MRSA (7%), and Pseudomonas aeruginosa (6%). Notably, only 3% of patients who screened negative for MRSA on admission developed MRSA-positive cultures. Antibiotic therapy was initiated in 99% of patients with FPCs, most commonly with piperacillin-tazobactam (41%), vancomycin (16%), and cefazolin (14%). Dual therapy, typically piperacillin-tazobactam plus vancomycin, was used in 13% of cases. Sensitivity data demonstrated that meropenem (90%) and the combination of ciprofloxacin with cefazolin (83%) covered the highest proportion of isolates. While piperacillin-tazobactam remains effective for early empiric use, our findings indicate that targeted alternatives-such as reserving meropenem for select cases or using ciprofloxacin plus cefazolin in appropriate patients-could provide comparable coverage while adhering to antimicrobial stewardship principles. A negative MRSA screening swab on admission demonstrated a high negative predictive value (~97%), supporting the withholding of vancomycin in screen-negative patients. This study supports evidence-based antibiotic use in burn patients and underscores the need for local, data-driven stewardship.

ABSTRACT Background Chronic obstructive pulmonary disease (COPD) imposes a substantial clinical and economic burden in Colombia, particularly among older adults. Despite widespread use of dual therapy, many patients remain at high risk of exacerbations. Our objective was to evaluate the long-term cost-effectiveness of single-inhaler triple therapy (FF/UMEC/VI) versus dual therapy (FF/VI) in patients with moderate-to-severe COPD in Colombia. Research design and methods A Markov model was developed to simulate disease progression, healthcare costs, and quality-adjusted life years (QALYs) over a lifetime horizon, from the perspective of the Colombian healthcare system. Clinical inputs were based on randomized controlled trial data, and cost/resource use data were derived from national sources. Deterministic and probabilistic sensitivity analyses were performed. Results FF/UMEC/VI provided an additional 2.34 QALYs at an incremental cost of $3,013 USD versus FF/VI, resulting in an incremental cost-effectiveness ratio (ICER) of $1,287 per QALY, below the national willingness-to-pay threshold of $5,180 per QALY. Sensitivity analyses confirmed the robustness of results, with FF/UMEC/VI remaining cost-effective in >60% of simulations. Conclusions FF/UMEC/VI is a cost-effective strategy for managing moderate-to-severe COPD in Colombia, offering improved clinical outcomes at an acceptable cost and supporting its adoption in treatment guidelines and reimbursement decisions.