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Herpes zoster (HZ) is common in Finland, leading to long-term postherpetic neuralgia (PHN) especially with ageing. HZ reduces productivity, placing an economic burden on society. An integrated actuarial and macroeconomic model assessed the return on investment of recombinant zoster vaccine (RZV) in Finland for adults ≥ 50 years versus no vaccination. A validated economic model determined HZ cases and complications avoided, health gains (quality-adjusted life-years, QALYs), and healthcare cost-savings. Actuarial techniques projected population trends incorporating employment factors. Lost productivity averted through vaccination provided fiscal revenue for the government, and increased gross domestic product (GDP) for society. QALY gains were monetised using 1-3xGDP per QALY. RZV was administered for 20 years, with lifetime impact assessment. RZV vaccination of around 790,000 50year-olds was estimated to save 3,779 QALYs and €52 million (M) in healthcare costs. Averted productivity losses generated €152 M in fiscal revenue and €367 M in GDP, while vaccination costs were €236 M. From the fiscal perspective, 90% of vaccination costs were offset by fiscal and healthcare cost savings (without considering QALY gains). From the societal perspective, for every €1 invested in vaccination, €2.60-4.10 was saved (depending on QALY value). The benefit-cost ratio (BCR) remained positive across sensitivity analyses. The highest BCRs were achieved when vaccinating adults aged 50 years; or 65 years when excluding productivity benefits. RZV vaccination in working-age adults yielded economic benefits in Finland, generating €2.60-4.10 for society per €1 invested in vaccination, and with fiscal benefits offsetting 90% of vaccination costs. WHAT IS THE CONTEXT?: Shingles (herpes zoster, HZ) is a common illness in Finland, especially in older adults. It can cause long-term nerve pain (postherpetic neuralgia, PHN) and other complications. HZ also reduces work productivity, creating economic costs for individuals and society. This economic study assessed the return on investment of introducing vaccination for adults aged 50 years and older with the recombinant zoster vaccine (RZV) versus no HZ vaccination (current situation). WHAT WAS DONE?: An economic model estimated the benefits of vaccination over 20 years, considering avoided HZ and PHN cases, healthcare cost-savings, and economic gains from reduced productivity loss, such as tax revenue and increased economic output (gross domestic product, GDP). The study also calculated the return on investment by comparing vaccination costs to financial benefits. The financial value of health benefits (quality-adjusted life-years, QALYs) gained through vaccination were also considered. WHAT WAS LEARNED?: Over the analysis timeframe, around 790,000 adults aged 50 years were vaccinated, saving 3,779 QALYs and €52 million in healthcare costs. Reduced productivity loss generated €367 million in GDP gains, including €152 million in tax revenue. The benefit-cost ratio showed that every €1 spent on vaccination returned €2.60–4.10 to society. The highest returns were seen when vaccinating at age 50, or at age 65 when productivity gains were excluded. CONCLUSION: RZV vaccination in working-age adults is a positive investment for Finland, benefiting both public health and the economy.

After inadequate response to first-line biologic or targeted synthetic (b/ts) disease-modifying antirheumatic drug (DMARD) therapy in adults with rheumatoid arthritis, there are numerous alternative DMARD options, and current understanding of their comparative benefits and harms is limited. The aim of this living systematic review and network meta-analysis was to compare the benefits and harms of DMARDs after failure of biologic or targeted synthetic DMARDs in adults with rheumatoid arthritis. We searched CENTRAL, MEDLINE, Embase, and two trial registries (ClinicalTrials.gov and the WHO ICTRP) from inception until 28 November 2025, with no restrictions on language or date of publication. We included randomised controlled trials (RCTs) of adults aged 18 years or older diagnosed with rheumatoid arthritis according to 1958, 1987, or 2010 classification criteria who previously demonstrated inadequate response to a b/ts DMARD. Eligible interventions included conventional synthetic DMARDs (methotrexate, antimalarials, sulfasalazine, leflunomide, ciclosporin, and azathioprine), biologic DMARDs (adalimumab, certolizumab, etanercept, golimumab, infliximab, abatacept, rituximab, tocilizumab, sarilumab, and anakinra), and targeted synthetic DMARDs (tofacitinib, baricitinib, and upadacitinib). Our critical outcomes were American College of Rheumatology 50% (ACR50) response, withdrawals due to adverse events, radiographic progression, Disease Activity Score 28 (DAS28) remission, pain as measured by visual analogue scale, function as measured by the Health Assessment Questionnaire (HAQ), and serious adverse events. Important outcomes included ACR20, ACR70, serious infections, fatigue, and quality of life. We used Cochrane's RoB 1 tool to assess risk of bias in the included studies. We first screened the records using an approach that combined machine learning and crowdsourcing to identify probable RCTs. We then reviewed the records identified as RCTs for eligibility and simultaneously classified them to the appropriate Population, Intervention, Comparator, and Outcome (PICO) question(s). Two review authors then extracted relevant data from the included studies in duplicate and independently, with any disagreements resolved by a third review author. A Bayesian random-effects network meta-analysis was conducted using a semi-informative prior probability distribution. We assessed the certainty of evidence for each outcome using the GRADE approach. We included 19 unique studies (4779 participants) in the review, all of which were parallel-design RCTs. Eleven trials were placebo controlled; two trials had an inactive comparator arm; and six trials had an active comparator arm. The trials were performed in a well-established rheumatoid arthritis population, with the median baseline disease duration ranging from 6.4 to 14 years, median age of participants ranging from 49 to 58 years, and median baseline disease activity (DAS28) ranging from 4.87 to 6.79. ACR50 response We found moderate-/high-certainty evidence that using a tumour necrosis factor (TNF) inhibitor not previously tried, interleukin-6 (IL-6) inhibitors, abatacept, rituximab, and Janus kinase (JAK) inhibitors was more effective than placebo: TNF inhibitor not previously tried (odds ratio (OR) 6.04, 95% credible interval (CrI) 2.49 to 16.3; high-certainty evidence), sarilumab (OR 3.11, 95% CrI 1.25 to 7.76; high-certainty evidence), tocilizumab 4 mg/kg intravenous (OR 5.31, 95% CrI 2.09 to 12.09; high-certainty evidence), tocilizumab 8 mg/kg intravenous (OR 10.03, 95% CrI 3.65 to 31.27; high-certainty evidence), subcutaneous abatacept (OR 4.31, 95% CrI 0.97 to 18.28; moderate-certainty evidence), intravenous abatacept (OR 4.57, 95% CrI 2.21 to 10.18; high-certainty evidence), rituximab (OR 5.50, 95% CrI 2.31 to 13.12; high-certainty evidence), upadacitinib (OR 3.93, 95% CrI 1.53 to 10.32; high-certainty evidence), tofacitinib (OR 3.93, 95% CrI 1.53 to 10.32; high-certainty evidence), baricitinib 2 mg (OR 2.00, 95% CrI 0.77 to 5.23; moderate-certainty evidence), baricitinib 4 mg (OR 2.79, 95% CrI 1.10 to 7.22; high-certainty evidence). With an assumed risk for placebo of 78 out of 1000 patients, the expected effects for the active drugs ranged from 143 (baricitinib 2 mg) to 455 (tocilizumab 8 mg/kg). Withdrawals due to adverse events For most interventions, there were sparse data with low-certainty evidence, except for TNF inhibitor not previously tried (risk ratio (RR) 0.32, 95% CrI 0.07 to 1.1; moderate-certainty evidence), which is probably less harmful than placebo, and sarilumab (RR 1.98, 95% CrI 0.57 to 7.19; moderate-certainty evidence), which is probably more harmful than placebo. Low-certainty evidence suggests that intravenous abatacept (RR 0.92, 95% CrI 0.34 to 2.79), upadacitinib (RR 0.41, 95% CrI 0.08 to 1.83), and baricitinib 2 mg (RR 0.93, 95% CrI 0.22 to 4.01) may be less harmful than placebo. Low-certainty evidence suggests that tocilizumab 4 mg/kg (RR 1.39, 95% CrI 0.39 to 5.28), tocilizumab 8 mg/kg (RR 1.49, 95% CrI 0.51 to 4.81), subcutaneous abatacept (RR 3.11, 95% CrI 0.05 to 249.6), rituximab (RR 2.38, 95% CrI 0.44 to 23.31), tofacitinib (RR 1.37, 95% CrI 0.35 to 5.58), and baricitinib 4 mg (RR 1.43, 95% CrI 0.38 to 5.81) may be more harmful than placebo. Data were insufficient to perform a network meta-analysis for radiographic progression. For DAS28 and the HAQ, there was mostly moderate-/high-certainty evidence of a benefit, with some exceptions for comparisons with indirect evidence only that was of low or very low certainty. For the other efficacy outcomes, data were sparse with wide credible intervals, and the certainty of evidence was typically low. We found high-certainty evidence that nine therapies and moderate-certainty evidence that two therapies provide a clinically important benefit in improving disease activity compared to placebo for people with rheumatoid arthritis after failure of b/ts DMARD therapy. There was significant uncertainty surrounding treatment-related harms, with the evidence having been downgraded for serious or extremely serious imprecision. Pair-wise comparisons showed no significant differences among therapies, although the certainty of evidence was low. The lack of clarity regarding safety and comparative efficacy suggests that treatment decisions should be guided by individual patient characteristics and preferences. This work was supported by grants from the Canadian Institutes for Health Research (CIHR) [Funding Reference Numbers (FRN) 178375 and 180324] and the National Health and Medical Research Council (NHMRC) Cochrane Collaboration. This research was supported by Arthritis Society Canada (Doctoral Studentship TGP-23-0211). This study was outlined in a Cochrane protocol (CD013562; DOI 10.1002/14651858.CD013562).

Immune checkpoint blockers (ICBs) have transformed advanced non-small cell lung cancer (aNSCLC) treatment, but identifying patients who benefit from adding chemotherapy remains challenging, especially in PD-L1 &#x2265; 50%. PD-L1 is an imperfect biomarker, highlighting the need for better selection tools. Liquid biopsy (LBx) assessment was performed using hybrid capture-based next-generation sequencing of plasma cell-free DNA. LBx data, molecular profile, and clinico-pathological data were collected. The predictive and prognostic values of tumor fraction (TF) were assessed using a de-identified nationwide (US-based) NSCLC clinicogenomic database (CGDB). An independent cohort with aNSCLC from Gustave Roussy was used to validate the findings and to study the correlation of ctDNA tumor fraction and total metabolic tumor volume (tMTV) and its molecular correlates. In the CGDB Database (n=965), elevated ctDNA TF was prognostic for worse outcomes on ICBs and, when &#x2265;5%, predictive of benefit from ICB+chemotherapy (HR for real-world progression-free survival 0.58 [0.41-0.82], p=0.002). The 5% cutoff for TF was validated in an independent cohort from Gustave Roussy. In 283 patients with paired PET scans, ctDNA TF correlated with metabolic tumor volume (rho=0.46, p<0.001) and was influenced by TP53/RB1 mutations. ctDNA TF integrates disease burden and biology. Patients with high ctDNA TF derive greater benefit from chemo-immunotherapy, supporting its use as a biomarker to guide treatment intensification.

Gram-positive infections continue to pose a therapeutic challenge owing to their invasive nature (e.g., Staphylococcus aureus and Streptococcus pyogenes) and eradication difficulties (e.g., methicillin-resistant Staphylococcus aureus [MRSA] and vancomycin-resistant enterococci [VRE]). Long-acting lipoglycopeptides (laLGPs) present an effective and conveniently dosed option for the treatment of most invasive Gram-positive pathogens. Improved compliance monitoring associated with their infrequent intravenous dosing, that is not available to such degree with more frequently dosed antimicrobials outside of inpatient settings, is another benefit of laLGPs over more frequently dosed antimicrobials. In this article, we provide a narrative review, including the pharmacological characteristics of dalbavancin (DAL) and oritavancin (ORI), the only currently available laLGPs, as well as their approved and "off-label" use reported in the literature to date. We discuss their respective mechanism of action, caveats in compartments where they do not achieve sufficient concentrations (i.e., central nervous system [CNS]; potentially pneumonias with ORI), as well as their reported efficacy in individual organ systems as reported in literature. Lastly, we summarize insights about laLGP use in special populations and discuss the benefits of therapeutic drug monitoring of these agents, mainly in conditions requiring prolonged therapy (e.g., hardware-associated orthopedic infections).

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: Our objective is to evaluate the benefits and harms of vector-control strategies in preventing dengue transmission in endemic populations. This protocol describes the approach for our four interventions of interest, which we intend to publish as four separate Cochrane reviews. These will evaluate the benefits and harms of: biological vector-control strategies; chemical vector-control strategies; environmental vector-control strategies; and combined vector-control strategies.

This narrative review summarizes evidence on the topic of de-escalation of medications in patients with Type 2 Diabetes (T2D) who achieve glycemic control on combination therapy. The study reviews evidence from available clinical studies, expert opinions, and observations to assess the strategies, risks, and outcomes of de-escalating antidiabetic therapy in patients with T2D who have met their glycemic goals. It concludes that once the targets are achieved, continuing with complicated medication regimes can be even more risky without any benefit. Once glucose is controlled, the stepwise de-intensification of regimens may reduce polypharmacy and hypoglycemia. The evidence supports decreasing or discontinuing the use of insulin and sulfonylureas first because they are associated with the highest risk of hypoglycemia. Insulin remains the site of de-escalation. Sequential withdrawal is demonstrated to be safer than discontinuation of medications concurrently, with discontinuation of high-risk medications ranked first. SGLT2 inhibitors and GLP-1 receptor agonists have cardiovascular and renal protective effects, and therefore, it is important to consider their withdrawal. DPP-4 inhibitors may be among the safest agents to discontinue from a glycemic standpoint, given their glucose-dependent mechanism of action and low risk of hypoglycemia, while metformin should remain the mainstay of therapy. Medication de-escalation is more likely to be successful in patients who have been diabetic for a shorter period, have a lower baseline HbA1c, have fewer complications, and are committed to healthy lifestyle choices. Older people and patients with comorbidities need a more individualized approach and the chance to contribute to decision-making. As there are limited high-quality trials to define best practices for de-escalation, structured monitoring, and clear criteria for re-escalation are required. In addition, any benefits of de-escalation must be weighed against the risks of withdrawing agents that provide cardiovascular or renal protection. Medication de-escalation seems feasible in patients who are motivated and have good glycemic control, and this is associated with a decreased treatment burden and lower risks. Nevertheless, additional quality trials are required to inform and normalize the pathways of de-intensification.

The latest type 2 diabetes mellitus (T2DM) management guidelines from the UK National Institute for Health and Care Excellence (NICE; NG28) have raised the profile of sodium-glucose cotransporter-2 inhibitors (SGLT2is) so that they are now the preferred first-line therapy in combination with modified-release metformin (or as monotherapy where metformin is contraindicated/not tolerated) for most individuals. Previous NICE recommendations limited use to those with high cardiovascular disease (CVD) risk or existing CVD and/or kidney disease for first-line treatment or people with a need for additional glycaemic optimisation at later stages in the pathway. This change brings the guidelines in line with other national and international recommendations regarding SGLT2i use for the achievement and maintenance of glycaemic targets and lowering of progressive risk for cardiovascular, renal and metabolic (CVRM) complications. Yet, despite a plethora of evidence supporting the role that SGLT2is can play in sustaining long-term health outcomes in people with T2DM, prescribing data from real-world clinical practice show that these therapies are under-prescribed, particularly among those populations most likely to benefit from their use (including individuals with CVD or high CVRM risk). This latest narrative review from the Improving Diabetes Steering Committee examines the place of SGLT2is within the latest NG28 guidelines and likely reasons for suboptimal SGLT2i use, providing pragmatic advice on appropriate approaches to initiation and management in daily practice and setting perceived risks into context against the potential benefits. Practical tools for healthcare professionals and people with T2DM are included, and the Committee's previously published SGLT2i Prescribing Decision Tool for T2DM Management has been updated and aligned with the most recent guidelines with the aim of providing a helpful and high-quality quick reference resource.

To evaluate the efficacy and safety of flexible and navigable suction ureteral access sheath (FANS) versus conventional ureteric access sheath (C-UAS) in Retrograde Intrarenal Surgery (RIRS) for renal stone disease through meta-analysis and trial sequential analysis (TSA). The FANS technology has emerged as a potential solution, incorporating active suction mechanisms to enhance stone clearance and visualization. PubMed, EMBASE, Cochrane, and Scopus were searched from 2000 to June 2025 for randomized controlled trials (RCTs) and prospective studies comparing FANS vs. C-UAS in adult RIRS. The primary outcome was stone-free rates at various time points; secondary outcomes included complications, operative, and recovery parameters. The risk of bias was assessed, and random-effects meta-analyses with subgroup, meta-regression, TSA, and Bayesian modeling were performed. Fifteen studies comprising 11 RCTs and 4 observational studies with 3030 participants were included. Flexible and navigable suction ureteral access sheath achieved a significantly higher immediate stone-free rate (79.1% vs. 54.5%; Relative Risk (RR): 1.47, 95% CI: 1.23-1.7; P < .001). Significant heterogeneity was noted (I2 = 89.3%). The absolute risk difference was 24.6% (number needed to treat = 6). Stone-free rates favored FANS at 30 days (93.5% vs. 82.7%; RR = 1.13) and 3 months (96.2% vs. 88.4%; RR = 1.09), both statistically significant. Flexible and navigable suction ureteral access sheath reduced overall complications by 52% (9.7% vs. 20.2%). Benefits were greatest for stones >20 mm (RR = 2.14), density &#x2265;1000 HU (RR = 1.94), and non-pre-stented patients (RR = 1.37). Trial sequential analysis (3030 patients; 106.4% information size) confirmed FANS superiority. Machine learning prediction of stone-free success showed high accuracy (Area Under the ROC Curve [AUC] = 0.89). Flexible and navigable suction ureteral access sheath shows clear superiority, improving immediate stone-free rates by 47% with notable safety benefits, TSA confirms evidence sufficiency. Cite this article as: Mittal A, Subramanyam AD, Panwar VK, Malhotra K, et al. Comparison of flexible and navigable suction ureteral access sheath versus conventional ureteric access sheath in RIRS: A systematic review and meta-analysis. Urol Res Pract. 2026, 52, 0119, doi:10.5152/tud.2026.25119.

Lung cancer is typically a cancer of the elderly, with a median age at diagnosis of 71, and more than one third of the people diagnosed with lung cancer are over 75 years old. Immune checkpoint inhibitors (ICIs) have revolutionised the treatment of cancers, including lung cancer. ICIs targeting the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) axis, administered in the neoadjuvant setting, the adjuvant setting, or both, are currently the standard of care for resectable non-small-cell lung cancer (NSCLC) worldwide. These ICIs are commonly used in combination with platinum-based chemotherapy and have shown superior efficacy in patients eligible for curative surgery. The concept of immunosenescence, which refers to age-related changes in the immune system - particularly a decline in the efficiency of T-cell mediated responses - raises concerns about the benefits of ICIs in the elderly population. To assess the benefits and harms of ICI with or without chemotherapy compared to no treatment or placebo with or without chemotherapy given before surgery, after, or both in older adults diagnosed with NSCLC at the early resectable stage. We searched for all eligible randomised controlled trials (RCTs) in electronic databases (CENTRAL, MEDLINE, and Embase), trial registries (clinicaltrials.gov and the World Health Organization ICTRP), references of eligible studies, meeting abstracts of the main world conferences, and the Food and Drug Administration (FDA) and European Medicines Agency (EMA) websites. The search was up to 3 July 2025. We included parallel designed RCTs comparing ICI with or without chemotherapy versus no treatment or placebo with or without chemotherapy administered before surgery, after, or both for early-stage resectable NSCLC. We excluded studies comparing differential sequencing of ICIs or combinations of ICIs with alternate interventions (e.g. radiotherapy). Our critical outcomes were overall survival and grade &#x2265; 3 treatment-related adverse events. Our important outcomes were disease-free survival, event-free survival, pathological complete response rate, major pathological response rate, and health-related quality of life. Two review authors independently used version 2 of the Cochrane risk of bias tool for randomised trials (RoB 2) to assess bias in the included studies. We synthesised results for each outcome and pooled data where possible (using a random-effects model with DerSimonian and Laird methods for all outcomes; and the Mantel-Haenszel method for dichotomous outcomes). Where this was not possible due to the nature or the amount of data, we narratively summarised the results. Three authors independently assessed the certainty of the evidence, using the five GRADE considerations for each outcome. We included a total of 11 studies with 6788 participants, of whom 3152 were &#x2265; 65 years old (46.4% of all participants). We were also interested in those aged &#x2265; 75 years old but could not obtain the exact number of such participants in nine studies. The inclusion criteria were similar across studies: adults presenting with a resectable NSCLC (stages II to IIIB according to the eighth edition of the Tumor, Node, Metastasis (TNM) classification), with an Eastern Cooperative Oncology Group performance status score of 0 or 1. One study excluded people &#x2265; 70 years old. Six studies excluded NSCLC with known alterations in epidermal growth factor receptor and anaplastic lymphoma kinase genes. The following results relate to people &#x2265; 65 years old only. The term perioperative is used to label studies evaluating the administration of treatment before (neoadjuvant) and after (adjuvant) surgery. Overall survival at any time point (in all studies) Aggregated data from three studies (590 participants) showed that perioperative ICI probably results in little to no difference in overall survival compared to placebo or no treatment, with a hazard ratio (HR) of 0.88 (95% confidence interval (CI) 0.61 to 1.26) and moderate-certainty evidence (downgraded for risk of bias). Treatment-related adverse events &#x2265; grade 3 at any time point One study (39 participants) provided data indicating that perioperative ICI combined with neoadjuvant chemotherapy may result in little to no difference in treatment-related adverse events &#x2265; grade 3 compared to neoadjuvant chemotherapy alone, with a risk ratio (RR) of 2.75 (95% CI 0.38 to 19.83) and low-certainty evidence (downgraded for indirectness and imprecision). Disease-free survival at any time point Aggregated data from three studies (1403 participants) showed that adjuvant ICI probably slightly increases disease-free survival compared to placebo or no treatment (HR 0.85, 95% CI 0.73 to 0.99) with moderate-certainty evidence (downgraded for risk of bias). Event-free survival at any time point Aggregated data from seven studies (1531 participants) showed that neoadjuvant or perioperative ICI likely increases event-free survival compared to placebo or no treatment (HR 0.61, 95% CI 0.52 to 0.71) with moderate-certainty evidence (downgraded for risk of bias). Pathological complete response Aggregated data from six studies (1068 participants) showed that neoadjuvant or perioperative ICI may result in a large increase in pathological complete response rates compared to placebo or no treatment (RR 5.07, 95% CI 3.40 to 7.54) with low-certainty evidence (downgraded for risk of bias and imprecision). Major pathological response Aggregated data from six studies (1068 participants) showed that neoadjuvant or perioperative ICI probably results in a large increase in major pathological response rates compared to placebo or no treatment (RR 2.94, 95% CI 2.32 to 3.72) with moderate-certainty evidence (downgraded for risk of bias). In people aged &#x2265; 65 years old, the addition of ICIs probably results in little to no improvement in overall survival. Based on one study, treatment-related adverse events showed a similar profile, with low-certainty evidence. However, ICIs probably increase disease-free survival, event-free survival, and major pathological response rates by a clinically meaningful margin. ICI may also increase complete pathological response rates. No study reported health-related quality of life assessments in older adults. Data were also insufficient to evaluate outcomes precisely in participants aged 65 to 75 years, those &#x2265; 75 years, or in PD-L1 stratified subgroups. We classified 12 studies as ongoing, as no results are yet available for elderly participants. This Cochrane review had no dedicated funding. Protocol available via DOI: 10.1002/14651858.CD014907.

To evaluate the effectiveness and safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors in elderly patients with type 2 diabetes mellitus, with particular focus on renal and cardiovascular outcomes. This retrospective cohort study analyzed data from 9,915 diabetic patients aged &#x2265;65&#x2009;years who received antihyperglycemic therapy at Changhua Christian Hospital, Taiwan, between January 2021 and September 2023. Patients were categorized as SGLT2 inhibitor users (n&#x2009;=&#x2009;3,345) or non-users (n&#x2009;=&#x2009;6,570). After 1:1 propensity score matching, 1,529 patients remained in each group. Primary outcomes included renal function (measured by eGFR decline), coronary artery disease, ischemic stroke, and heart failure. Secondary outcomes included urinary tract infection, genital infection, diabetic ketoacidosis, and hypoglycemia. SGLT2 inhibitor use was associated with significant renoprotective effects, demonstrated by reduced risk of 30% eGFR decline (HR 0.69, 95% CI 0.59-0.80, p&#x2009;<&#x2009;0.001) and 50% eGFR decline (HR 0.60, 95% CI 0.45-0.80, p&#x2009;<&#x2009;0.001). Subgroup analyses revealed that renoprotective effects were more pronounced in patients with higher baseline eGFR (&#x2265;50&#x2009;mL/min/1.73 m2), suggesting greater benefit with early initiation of SGLT2 inhibitors for kidney protection. However, SGLT2 inhibitor use was associated with an increased risk of genital infections (HR 4.29, 95% CI 1.02-18.04, p&#x2009;=&#x2009;0.047) in patients without prior history of such infections. In elderly patients with type 2 diabetes, SGLT2 inhibitors demonstrate significant renal protective effects, particularly among those with preserved renal function (eGFR &#x2265;50&#x2009;mL/min/1.73 m2). These findings highlight the importance of considering patient characteristics when evaluating potential benefits of SGLT2 inhibitor therapy. The differential risk patterns suggest that clinicians should consider individual patient profiles and medical histories when prescribing these medications. The occurrence of major adverse cardiovascular events (MACE) did not exhibit a statistically significant difference between the cohort administered SGLT2 inhibitors and the cohort not receiving SGLT2 inhibitors (log-rank p-value = 0.160). Conversely, the recurrence of MACE was markedly reduced in the cohort receiving SGLT2 inhibitors (log-rank p-value < 0.001). These findings should be interpreted in the context of a single-center retrospective design and the inherent limitations of propensity-score-matched observational analyses.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the benefits and harms of methotrexate for people with osteoarthritis of the hand.

Glioblastoma remains the most aggressive primary brain malignancy, with poor survival despite maximal safe resection, radiotherapy, and temozolomide-based chemotherapy. A major obstacle to effective treatment is the spatially heterogeneous blood-brain barrier/blood-tumor barrier, which restricts drug penetration into infiltrative tumor regions and limits uniform intratumoral exposure. Albumin-based delivery is attractive in glioblastoma because it addresses several formulation-level barriers at once: poor aqueous solubility of hydrophobic payloads, short systemic exposure, and the need for a biocompatible carrier that can interact with albumin-handling pathways such as gp60/albondin, SPARC, FcRn, and caveolin-associated transport. This review examines albumin-based strategies explored for glioblastoma, with an emphasis on albumin-bound paclitaxel nanoparticles, engineered albumin nanoparticles, dual-payload systems, albumin-binding photosensitizers, macrophage-assisted delivery, and albumin-bound pathway-directed agents. Preclinical evidence suggests that these platforms can improve brain-tumor drug exposure, support rational combinations, and synergize with BBB/BTB-opening technologies. Early clinical studies combining low-intensity pulsed ultrasound with microbubbles and albumin-bound paclitaxel provide human proof of concept for regional pharmacokinetic enhancement in recurrent glioblastoma, although survival benefit remains unproven. The available evidence supports albumin-based delivery as a rational formulation strategy. Its clinical value in GBM will depend on three testable requirements: spatial pharmacokinetic confirmation, biomarker-guided patient selection, and reproducible BBB/BTB modulation.

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality worldwide and is characterized by extensive vascularization, aggressive progression, and limited therapeutic responsiveness. Angiogenesis plays a central role in HCC development by supporting tumor growth, metabolic adaptation, invasion, and metastatic dissemination. Although anti-angiogenic therapies targeting the vascular endothelial growth factor (VEGF) pathway have improved clinical management, their overall survival benefit remains modest because of compensatory signaling, adaptive resistance, and the highly complex nature of the tumor microenvironment (TME). Astrocyte elevated gene-1/metadherin (AEG-1/MTDH) has emerged as a multifunctional oncogene that functions by orchestrating interconnected angiogenic, inflammatory, metabolic, and immune-regulatory programs within the hepatic tumor microenvironment. AEG-1 regulates angiogenesis through modulation of VEGF-family signaling, NF-&#x3ba;B activation, hypoxia-responsive pathways, PI3K/AKT signaling, endothelial remodeling, and translational control of pro-angiogenic mediators. Emerging evidence further implicates AEG-1 in hypoxia adaptation, immune evasion, extracellular vesicle signaling, and metabolic reprogramming, supporting its role as a systems-level regulator of HCC angiogenesis. This review summarizes the current understanding of the molecular mechanisms through which AEG-1 regulates angiogenesis in HCC, discusses its interactions with the TME and anti-angiogenic resistance pathways, and highlights future translational opportunities for developing multi-targeted therapeutic strategies beyond conventional VEGF-centric approaches.

Tobacco smoking and non-communicable disease (NCD) comorbidities are positively associated with psoriasis severity, but their combined association with treatment response remains unclear. This study evaluated their interactive associations with PASI75 achievement. We prospectively recruited 551 psoriasis patients from Shanghai Skin Disease Hospital (2022-2024). Treatment efficacy was evaluated from baseline to Week 48. Logistic regression assessed associations of smoking and NCD comorbidities with PASI75, and additive interaction was examined using the relative excess risk due to interaction (RERI). Tobacco smoking and NCD comorbidities were present in 51.2% and 42.6% of patients, respectively. Compared with those with both risk factors, patients with neither had higher PASI75 achievement at Weeks 8, 12, 24, and 48. At Week 48, PASI75 rates were 76.9% versus 55.8%, a 21.1% absolute difference. RERI indicated synergistic associations with PASI75 achievement at Week 12 (RERI = 0.71, 95% CI 0.05-2.38) and Week 24 (RERI = 0.80, 95% CI 0.11-2.39). Smoking and NCD comorbidities were jointly associated with poorer PASI75 achievement, while their concurrent absence was associated with added therapeutic benefit. These findings support integrating smoking cessation and NCD management into routine psoriasis care. Chinese Clinical Trial Registry, ChiCTR2200066894.

The predictive value of FGFR amplifications (amp) and the role of FGFR mutations (mut) beyond known activating variants remain unclear. We aimed to establish a translational research platform to characterize FGFR alterations (alt) and explore their potential as predictive biomarkers for FGFR-targeted agents. This ambispective study included a retrospective analysis of patients with FGFR-alt tumors treated with selective FGFR inhibitors (FGFRi) and a prospective collection of longitudinal tumor samples. Patient-derived xenografts (PDX) were generated to investigate FGFRi mechanisms of action and resistance. Molecular characterization included genomic, transcriptomic, proteomic and functional analyses using the Functional Annotation for Cancer Treatment (FACT&#x2122;) assay. Among 36 retrospectively analyzed patients, clinical benefit from FGFRi was observed in cases with FGFR mRNA over-expression or FGFR2/11q co-amp, but no association was found with the amplification levels. In archival tumor samples, exploratory proteomic analysis showed FGFR1-4 protein expression in 78% of FGFR1/2-amp tumors detected by FISH. RNA sequencing identified a higher prevalence of FGFR mRNA over-expression than proteomic analysis. Among patients harboring FGFR-mut, only one bladder cancer with a FGFR3-mut S249C derived benefit. FACT&#x2122; assay supported the functional activity of selected variants, including FGFR3 T689M, and suggested potential resistance mechanisms involving PI3K/PTEN and MAPK pathway co-alterations. A prospective FGFR-alt PDX biorepository enabled exploratory biomarker analyses, supporting the hypothesis that FGFR1-4 mRNA expression may better reflect FGFR dependency than genomic alterations alone. These findings highlight the complexity of FGFR-driven oncogenesis and support integrative molecular approaches to refine patient selection for FGFR-targeted therapies.

To evaluate the safety, feasibility, and effectiveness of esomeprazole via continuous subcutaneous infusion, in palliative care patients unable to tolerate oral acid suppression therapy. A retrospective review of 92 prescriptions in 76 patients receiving 24-h esomeprazole via continuous subcutaneous infusion was undertaken. Electronic records were examined for dose, duration, infusion characteristics, site reactions, indications, and symptom outcomes. Across 637 treatment days, esomeprazole was well tolerated, only two patients developed injection site reactions (1%). Symptomatic benefit was observed in over 70% of cases for symptoms relating to dyspepsia, malignant bowel obstruction, and gastrointestinal bleeding. Esomeprazole as a continuous subcutaneous infusion appears safe, feasible, and clinically beneficial. Further prospective studies are warranted.