Consistent Benefit Research Articles

Pooled Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone in Patients With Advanced Melanoma.

Nivolumab (NIVO) + ipilimumab (IPI) combination and NIVO monotherapy have demonstrated durable clinical benefit in patients with unresectable/metastatic melanoma. This analysis describes long-term overall survival (OS) with the combination or monotherapy pooled across all major company-sponsored trials, as well as clinical factors associated with survival, in patients with immune checkpoint inhibitor (ICI) treatment-naïve unresectable/metastatic melanoma. Data were pooled from six CheckMate studies in ICI treatment-naïve patients receiving NIVO + IPI (NIVO 1 mg/kg + IPI 3 mg/kg or NIVO 3 mg/kg + IPI 1 mg/kg) or NIVO monotherapy (3 mg/kg). OS was assessed for each treatment, as well as in select subgroups. Cox proportional multivariate analysis (MVA) and classification and regression tree (CART) analyses were performed within treatment arms. Median follow-up for OS was 45.0 months for patients treated with NIVO + IPI (n = 839) and 35.8 months for patients treated with NIVO (n = 536). OS was longer with NIVO + IPI versus NIVO monotherapy (hazard ratio, 0.78 [95% CI, 0.67 to 0.91]), with 6-year OS rates of 52% versus 41%, respectively. Consistent benefit was observed in BRAF-mutant and BRAF-wild-type patients and those with normal and elevated lactate dehydrogenase (LDH). Numerical difference in OS was also observed across PD-L1 expression levels, although more pronounced with no/low PD-L1 expression. Clinical factors associated with decreased survival in both the MVA and CART analyses were LDH > upper limit of normal with either treatment, age ≥65 years with NIVO + IPI, and the presence of liver metastases with NIVO monotherapy. In this large, pooled nonrandomized retrospective analysis, we observed that NIVO + IPI provides longer OS than NIVO in patients with ICI treatment-naïve advanced melanoma and identifies clinical factors that appear to be associated with survival for each treatment, which may assist with treatment decision making.

Association of moderate-to-vigorous physical activity with reduction of acute exacerbation in COPD patients using a dual ultra-long-acting bronchodilators

Inhaler therapy and physical activity (PA) are important methods of chronic obstructive pulmonary disease (COPD) management. This study aimed to investigate the additional benefit of moderate-to-vigorous PA (MVPA) in patients with COPD using a long-acting beta-agonists (LABA)/long-acting muscarinic antagonist (LAMA) combination. We emulated a target trial to estimate the benefit of MVPA in patients with COPD using a dual ultra-long-acting bronchodilators. We enrolled patients aged ≥ 40 who were diagnosed with COPD between 2014 and 2018, initiated a LABA/LAMA combination, and had not undergone regular MVPA. The main exposure was the initiation of MVPA, defined as vigorous aerobic exercise > 20 min per day on ≥ 3 days/week or moderate aerobic exercise > 30 min per day on ≥ 5 days/week. The main outcomes were the future usage of inhaled corticosteroids (ICS) and severe exacerbation. We identified 1,526 patients who initiated MVPA and 4,516 who did not. The median follow-up period was 3.0 years. The hazard ratio (HR) for future ICS usage in the MVPA initiation group was 0.83 (95% confidence intervals (CI): 0.72, 0.97) compared to the control group. The HR for severe exacerbation in the MVPA initiation group was 0.81 (95% CI: 0.68, 0.96) compared to the control group. Subgroup analyses by age, sex, body mass index, residence area, smoking and drinking status showed consistent benefits in these outcomes. Initiation of MVPA may offer an additional benefit for even COPD patients who use a dual ultra-long-acting bronchodilators.

Seasonal Characteristics of Particulate Matter by Pollution Source Type and Urban Forest Type

To provide consistent air purification benefits from urban forests, it is crucial to identify common characteristics that allow for similar experimental setups. This study aimed to analyze PM10 concentrations in urban forests near pollution sources and understand their mitigation effects. Data from the Asian Initiative for Clean Air Networks, Korea, were used, focusing on three urban forests adjacent to road and industrial pollution sources in Korea, with PM10 concentrations collected during 2021. Considering high PM10 concentrations during winter and spring, these seasons were divided into two sub-periods, resulting in six seasonal periods for analysis. To address the right-skewed PM10 distribution and reduce outlier influence, the Kruskal–Wallis test was used. The results showed that “good” PM10 levels were lowest in early spring, increasing to a peak in summer before declining. High PM10 events were concentrated in spring, early spring, and early winter. The Kruskal–Wallis test indicated lower median PM10 concentrations in urban forests compared to pollution sources in the latter half of the year, while no significant median differences were found in the first half. Distribution visualizations further confirmed that even during high PM10 periods, all urban forests showed lower PM10 values compared to pollution sources. In conclusion, PM10 concentrations in urban forests were consistently lower than in pollution sources across all seasons, demonstrating their effectiveness in air purification at both road and industrial pollution sources. Future research should consider additional variables, such as PM2.5, to further explore differences between pollution sources.

Win Ratio Analyses Using a Modified Hierarchical Composite Outcome: Insights from PARAGLIDE-HF

The win ratio (WR) is an emerging alternative for reporting composite outcomes, prioritizing clinically significant events such as mortality while incorporating surrogate measures. However, its benefits should be weighed against limitations, particularly the influence of lower hierarchical outcomes. This secondary analysis of the PARAGLIDE-HF trial performed a WR sensitivity analysis using a modified hierarchical composite outcome to assess the utility of WR sensitivity analysis and the efficacy of sacubitril/valsartan versus valsartan. PARAGLIDE-HF compared sacubitril/valsartan with valsartan in heart failure (HF) patients with ejection fraction >40% (N=466). A hierarchical outcome in the primary analysis included cardiovascular death, HF hospitalizations, urgent HF visits, and change in N-terminal pro-B-type natriuretic peptide (NT-proBNP), with a 25% decrease considered a win. In the pre-specified subgroup with ejection fraction ≤60% (N=357), sacubitril/valsartan showed a treatment effect on the hierarchical outcome (WR, 1.46; 95% CI, 1.08-1.97). Sensitivity analyses for this subgroup included: 1) excluding NT-proBNP change, 2) substituting the 25% proportion change of NT-proBNP with 10% or 50%, and 3) including renal outcomes within the hierarchical outcome. In addition to the WR, the win odds (WO), in which 50% of the ties are allocated to both the numerator and denominator of the WR-a potentially more suitable modification of the WR that accounts for the presence of ties-were presented. Excluding NT-proBNP (WR, 1.49; 95% CI, 1.00-2.22; WO, 1.12; 95% CI, 1.00-1.26), adjusting the NT-proBNP threshold from 25% to 10% or 50% (WR, 1.41; 95% CI, 1.06-1.89; WO, 1.27; 95% CI, 1.04-1.56 for 10%; and WR, 1.54; 95% CI, 1.11-2.12; WO, 1.25; 95% CI, 1.06-1.48 for 50%), and incorporating renal outcomes (WR, 1.44; 95% CI, 1.07-1.94; WO, 1.28; 95% CI, 1.05-1.56) consistently favored sacubitril/valsartan. Multiple WR sensitivity analyses support a consistent treatment benefit of sacubitril/valsartan versus valsartan in patients with ejection fraction >40% to 60%. Future studies could consider prespecifying WR sensitivity analysis for comprehensive assessment of treatment effects. PARAGLIDE-HF; ClinicalTrials.gov ID, NCT03988634 (https://clinicaltrials.gov/study/NCT03988634).

Race in heart failure: a pooled participant-level analysis of the global PARADIGM-HF and PARAGON-HF trials

Abstract Background Mechanisms of disease pathobiology, prognosis, and potentially treatment responses might vary by race in patients with heart failure (HF). Early experiences with neprilysin inhibition suggested possible increased risks of angioedema, especially among Black individuals. We aimed to examine the safety and efficacy profile of sacubitril/valsartan in a pooled participant-level dataset of 2 large cohorts of patients with HF by self-reported race. Methods PARADIGM-HF and PARAGON-HF were multicenter, randomized clinical trials testing sacubitril/valsartan against a renin-angiotensin system inhibitor (RASi, enalapril or valsartan, respectively) in patients with HF and LVEF ≤40% (PARADIGM-HF) or LVEF ≥45% (PARAGON-HF). We included all patients with available data on self-reported race and categorized patients as White, Asian, or Black. We assessed adjudicated outcomes including the composite of first HF hospitalization (HFH) or cardiovascular (CV) death, its components, and angioedema by racial group. Results Among 12,097 included participants, 9,451 (78.1%) were White, 2,116 (17.5%) were Asian, and 530 (4.4%) were Black. Asian participants were from 19 countries, with highest enrollment from India, China, and the Philippines. Black participants were from 18 countries, with highest enrollment from the US, South Africa, and Brazil. Black patients had the worst baseline health status (adjusted KCCQ-OSS mean 70.3), while White (71.4) and Asian patients (76.4) had better health status; P<0.001. Over 2.4-years of median follow-up, Black (adjusted HR 1.67; 95% CI 1.37-1.89; P<0.001) and Asian patients (adjusted HR 1.32; 95% CI 1.16-1.50; P<0.001) experienced higher risks of the primary outcome compared with White patients (Figure 1). The treatment effects of sacubitril/valsartan vs. RASi on the primary endpoint were consistent among White (HR 0.84; 95% CI: 0.77-0.91), Asian (HR 0.92; 95% CI: 0.78-1.10), and Black patients (HR 0.79; 95% CI: 0.58-1.07; Pinteraction = 0.39). In light of higher baseline risks, Black patients accrued the greatest absolute risk reduction with sacubitril/valsartan (Figure 2). Consistent treatment benefits by race were also observed for the individual components (CV death alone and first HFH alone). Rates of any adjudicated angioedema were numerically higher with sacubitril/valsartan vs. RASi across race groups (White 0.4% vs. 0.2%; Asian 0.6% vs. 0.2%; Black 2.3% vs. 0.8%), however no patient in either trial experienced airway compromise or required mechanical airway protection. Conclusions In a pooled experience of over 12,000 participants enrolled in 2 trials conducted across 56 countries, Black and Asian patients exhibited a higher risk of CV events than White patients. Rates of non-serious angioedema were numerically higher with sacubitril/valsartan across race groups. The relative CV benefits of sacubitril/valsartan were consistent across races, with greatest absolute benefits observed in Black patients.

Outcomes and effects of sacubitril/valsartan according to NT-proBNP level in patients with heart failure: a patient-level pooled analysis of the PARADIGM-HF and PARAGON-HF trials

Abstract Background NT-proBNP levels are associated with disease severity and outcomes in patients with HF across the spectrum of LVEF. Recently, it has been suggested that the effectiveness of certain treatments may vary by NT-proBNP level with greater benefit from omecamtiv mecarbil, and smaller benefit from vericiguat, in patients with higher NT-proBNP levels. We examined the benefit of sacubitril/valsartan on outcomes across the range of NT-proBNP levels in patients with HFrEF/HFmrEF/HFpEF. Purpose To evaluate clinical outcomes, and the efficacy of sacubitril/valsartan, according to NT-proBNP levels, in patients with HFrEF/HFmrEF/HFpEF, using the pooled dataset of participants in the PARADIGM-HF and PARAGON-HF trials. Methods The PARADIGM-HF (n=8399) and PARAGON-HF (n=4822) trials enrolled patients with HF, functional limitation, and elevated NT-proBNP levels. Patients with LVEF ≤40% were randomized to sacubitril/valsartan 200 mg twice daily or enalapril 10mg twice daily in PARADIGM-HF, and those with LVEF ≥45% to sacubitril/valsartan 200 mg twice daily or valsartan 160mg twice daily in PARAGON-HF. Patients were categorized by quintiles of NT-proBNP level and using NT-proBNP as a continuous variable, analysed using restricted cubic splines. The primary outcome in the present study was the composite of cardiovascular death or HF hospitalization. Results Among the 13195 patients in the pooled PARADIGM-HF and PARAGON-HF dataset, 13142 (99.6%) patients with baseline NT-proBNP were analysed. Patients with higher NT-proBNP levels were more often male, had lower body mass index and LVEF, worse New York Heart Association functional class, worse kidney function, and more atrial fibrillation, while age was similar across NT-proBNP levels. The rate of the primary outcome (per 100 person-years) increased with NT-proBNP level: quintile 1, 5.9 (95%CI 5.3-6.5); quintile 2, 7.5 (95%CI 6.9-8.2); quintile 3, 9.0 (95%CI 8.2-9.7); quintile 4, 12.0 (95%CI 11.1-12.9); and quintile 5, 20.8 (95%CI 19.6-22.2) (Figure 1). Similar trends were observed for other outcomes. The benefit of sacubitril/valsartan was consistent across NT-proBNP levels: the hazard ratio for the primary outcome in NT-proBNP quintile 1 was 0.79 (95%CI 0.65-0.96); quintile 2, 0.87 (95%CI 0.72-1.04); quintile 3, 0.79 (95%CI 0.66-0.93); quintile 4, 0.85 (95%CI 0.73-0.99); and quintile 5, 0.86 (95%CI 0.76-0.97), P-interaction=0.86. The consistent benefit of sacubitril/valsartan was also seen when NT-proBNP was analysed as a continuous variable (Figure 2). The absolute benefit was greatest in quintile 5 of NT-proBNP; the number needed to treat for quintile 5 was 16 versus 37 for the quintile 1 for the primary endpoint. Conclusions Patients with higher NT-proBNP had worse outcomes, but the benefits of sacubitril valsartan were consistent across the range of NT-proBNP levels of participants in PARADIGM-HF and PARAGON-HF.Kaplan-Meier curvesEffect of sac/val across NT-proBNP range

Effect of the culture liquid of Antarctic yeast <i>Nadsoniella nigra</i> on rooting, growth, and biochemical composition of <i>in vitro</i> grapevine (<i>Vitis vinifera</i> L.), cultivar '<i>Karmrahyut</i>'

Background: Grapevine (Vitis vinifera L.) is a globally significant fruit crop known for its nutritional and health benefits, including its role in preventing chronic diseases such as cancer and cardiovascular disorders. The bioactive compounds in grapes contribute to these benefits. Bioactive content changes due to grapevine variety and environmental conditions necessitate ongoing research. In vitro propagation provides a controlled environment for grapevine cultivation, minimizing disease risk and ensuring consistent quality. This study investigates the potential of Nadsoniella nigra (Nn), an Antarctic yeast, as a natural alternative to synthetic auxins like Indole-3-butyric acid (IBA) in grapevine micro cutting propagation. Objective: To evaluate the effectiveness of the culture liquid of Nn as a natural alternative to auxin-class hormones, using IBA as an example, for promoting rooting in grapevine microcuttings and to assess its impact on chlorophyll content, vitamin C levels, and sugar concentrations. Materials and Methods: In vitro propagation of grapevine (Vitis vinifera L.) cultivar 'Karmarhyt' was performed using half-strength Woody Plant Medium (WPM). Nn culture liquid was prepared at concentrations of 0.5, 1.0, 1.5, and 2.0 ml/L, and IBA was used at equivalent concentrations. Microcuttings were cultured on media supplemented with these treatments, with a control group maintained without growth regulators. Rooting was evaluated after 4 weeks by measuring rooting percentage, number of roots per shoot, and root length. Chlorophyll a (Chl a) and Chlorophyll b (Chl b) levels, vitamin C content, and sugar concentrations were assessed. Statistical analysis was performed using standard error and t-tests. Results: Rooting performance of grapevine microcuttings varied with treatment. Nn culture liquid promoted rooting in a dose-dependent manner, with the highest values observed at 2.0 ml/L (97.0% rooting, 7.2 roots, 13.8 cm root length). IBA treatment resulted in peak rooting at 1.0 mg/L (100% rooting) but decreased at higher concentrations, accompanied by callus formation. Chlorophyll content was higher in Nn culture liquid treated microcuttings, with a maximum total chlorophyll of 2.20 mg/g at 2.0 mg/L, compared to a peak of 2.05 mg/g in IBA-treated microcuttings at 1.0 mg/L. Sugar and vitamin C content increased with Nn culture liquid concentrations, whereas IBA showed a less consistent effect. Conclusion: Nn culture liquid was an effective natural alternative to IBA for promoting rooting in grapevine microcuttings. It improved rooting efficiency, chlorophyll content, and increased sugar and vitamin C levels, while IBA led to growth inhibition and callus formation at higher concentrations. Nn culture liquid demonstrated consistent benefits, suggesting potential for sustainable viticulture. As a result of the conducted research, it was established that the mixture of secondary metabolites contained in the liquid culture medium of Nn possesses high biological activity and can be recommended for use in plant biotechnology in vitro to promote the growth of both underground and above-ground parts. Future research could explore its use in propagating other plant species. Keywords: ´Karmrahyut´, grapevine, culture liquid of Nadsoniella nigra. in vitro propagation, functional foods

International cooperation in cardiogenic shock is key to improving outcomes: Cardiogenic Shock Working Group impacts a single-center in a developing country

Abstract Background Management of cardiogenic shock (CS) poses a formidable challenge in healthcare, necessitating innovative approaches and collaborative efforts, not only local, to improve outcomes. Purpose To demonstrate that CSWG international cooperation and research in CS can lower mortality, change practices, and improve outcomes. Methods From our institutional registry 28,054 patients, we selected 9,430 with CS in SCAI CWSG-score B-E 2022-23 CSWG incorporation (n=1112) against previous years (05-21, n=8318). The primary outcome was in-hospital mortality. Univariate and multivariate analyses were performed, and with PAC use as a a priori subgroup. Adjusted analysis was carried out with age, sex, DM, HTN, previous MI, PCI, CABG, or stroke; CKD, CS etiology, PAC, hemodialysis, number of vasoactives; the presence of MCS, use of mechanical ventilation, and SCAI-CSWG stage. Also, propensity score matching was used to explore differences using the a priori selected variables using K-nearest neighbors (K=2), radius of 1:2, caliper 0.2, and exact SCAI stage matching without replacement (Pre-CSWG n=2198, CSWG era n=1106). Results In the CSWG era, there's a increase in mean age (P=0.049) and a higher proportion of men (72.2 vs. 68%, p=0.005). Clinical risk factors show changes, including increased weight (P=0.037), higher smoking (53.3 vs. 48.6%, P=0.003), diabetes (40.1 vs. 34.8%, P=0.001), and hypertension (46.8 vs. 50%, p=0.043). Prior MI and CABG decreased significantly in the CSWG era. Therapeutic shifts are evident, with increased use of PAC (7.9 vs. 4.2%, P<0.001) and significant changes in mechanical circulatory support (p<0.001). Mortality substantially decreases in the CSWG era (15.3 vs. 22.3%, P<0.001). The unadjusted Cox Pre-CSWG era, the HR 1.41 (1.2-1.65, P< 0.001) a restricted mean survival time (RSMT) of 1.73 days (0.92-2.54, P<0.001). In PAC subgroup, the relationship between PAC use and outcomes appears to be consistent across the levels of the interacting variable (Pint=0.918), with a HR Pre-CSWG era 0.51 (0.44-0.59, P <0.001) and CSWG era HR 0.48 (0.33-0.71,P <0.001)(Fig1C) The adjusted analysis, the Pre-CSWG era had a HR 1.21 (1.03-1.42, P=0.019). PAC outcomes were consistent across eras (Pint= 0.923). In the Pre-CSWG era HR 0.71 (0.59-0.84,P<0.001), and similarly in the CSWG era 0.54 (0.34-0.87,P=0.01). (Fig1D) The PS-cohort had a Pre-CSWG era HR 1.21 (1.01-1.45, P=0.034) of the Pre-CSWG era vs CSWG era and a RSMT at 30 days of 1.07 (0.14-2.01 P=0.025). (Fig2) Conclusion Shifts in patient demographics, clinical risk factors, hemodynamic parameters, and therapeutic strategies were observed. Notably, mortality significantly decreased with the CSWG incorporation, with consistent benefits of PAC use in both eras. The PS cohort underscored the impact of CSWG incorporation on outcomes. Overall, these findings highlight the transformative influence of CSWG on CS management, as international cooperation is key to improving outcomes.Figure 1.Mortality through erasFgure 2.Propensity score cohort

Natural Way Of Boosting Immunity: The Role of Echinacea in Cold Prevention and Treatment - A Literature Review

Echinacea, a widely used herbal remedy derived from the purple coneflower, is renowned for its potential benefits in treating and preventing the common cold. This review examines Echinacea’s role in managing cold symptoms, its mechanisms of action, and its efficacy across various species and preparations. Echinacea species, particularly Echinacea purpurea, Echinacea angustifolia, and Echinacea pallida, contain active compounds such as alkamides, caffeic acid derivatives, polysaccharides, and glycoproteins, which contribute to its immunomodulatory, anti-inflammatory, and antiviral properties. Clinical studies demonstrate that Echinacea can modestly reduce the incidence, duration, and severity of colds, though results are variable due to differences in preparation forms (e.g., teas, tinctures, extracts) and study methodologies. Proprietary extracts like Echinaforce® have shown consistent benefits, while other formulations have yielded mixed results. Despite a generally favorable safety profile, including mild gastrointestinal disturbances and rare allergic reactions, the long-term safety, particularly in vulnerable populations, remains under-researched. Future research should focus on standardized formulations, detailed molecular mechanisms, and rigorous clinical trials to better define Echinacea’s role in cold management. Overall, while Echinacea offers a promising option for cold prevention and treatment, its use should be informed by evidence-based practices considering formulation, dosage, and individual patient factors.

Curriculum approaches to strengthening student employability and improving graduate outcomes in the STM disciplines

ABSTRACT In Australia and elsewhere, curriculum improvements are needed to improve the development of Science, Technology and Mathematics (STM) graduates for future work and careers. Several studies document significant STM student attrition, poor graduate preparedness for work, relatively weak employment rates post-graduation, and mismatched expectations of graduate capabilities by employers. The inclusion of work-integrated learning (WIL) activities within curricula can better prepare students for relevant employment by bridging discipline-specific teaching with work practices. Traditionally, access to WIL has been limited for STM Bachelor students and a better understanding of WIL’s benefits and impact is needed to refine and extend STM WIL curricula for different disciplines and cohorts. Through the lens of personal capital resources, this article reports on the perspectives of 34,000 recent Bachelor graduates of Australian STM degrees on their participation in WIL and its impact on their perceived employability and transition to work. Findings indicated differences in engagement in WIL across STM disciplines and underrepresented student groups, yet consistent benefits of WIL on preparedness for work and graduate employment. The study provides valuable insights on gaps in WIL provision and potential ways to improve WIL offerings that support the development of future-capable STM graduates with positive labour market experiences.

The use of dance to improve the health and wellbeing of older adults: A global scoping review of research trials.

Dance is a promising health resource for older adults, but empirical evidence remains inconsistent. The lack of synthesised evidence regarding program design, dose, and delivery limits understanding of factors influencing participation and health outcomes. This scoping review aimed to map the scope, range, and effectiveness of dance programs for older people, and identify gaps and opportunities for future research and practice. Searches across five databases (September 2023) identified 148 studies evaluating 116 dance programs (≥4 weeks) for older adults (≥55 years, N = 8060), Dance interventions delivered to clinical groups were excluded. Intervention design and delivery were charted against the TIDieR reporting checklist. Program outcomes including adherence, safety, and positive tests were charted into established taxonomies. Demographic information, program details, and implementation were often insufficiently reported. Participant groups differed by age range, with underserved communities underrepresented. Programs varied extensively in key factors including dose, prospective 'active ingredients', delivery approach, facilitator expertise, and class size. While dance was physically safe, adherence rates in older adults are comparable to other community exercise programs. Less than 40% of health assessments showed positive change, with more consistent benefits to physical endurance, strength, and function, moderate impacts on psychosocial health, and limited benefits to cognitive and brain health, and falls and falls risk. Dance is a meaningful, safe, adaptable, and low-cost health resource for older adults. Key opportunities for advancing research include improved access for underserved groups, program suitability assessments, strategies to support adherence and engagement including theory-informed approaches, and incorporation of participant and practitioner insights. Identification of key 'active ingredients' and dance program factors may improve understanding of causal pathways and mechanisms to optimise engagement and health impacts. Stronger reporting practices will facilitate comparisons across studies and more robust evidence synthesis. This review provides a critical knowledge foundation to guide future approaches in dance for health and offers reporting recommendations.

Adjuvant Nivolumab in High-Risk Muscle-Invasive Urothelial Carcinoma: Expanded Efficacy From CheckMate 274.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.CheckMate 274 is a phase III, randomized, double-blind trial of adjuvant nivolumab versus placebo for muscle-invasive urothelial carcinoma (MIUC) at high risk of recurrence after radical resection. The primary end points of disease-free survival (DFS) in intent-to-treat (ITT) and tumor PD-L1 expression ≥1% populations were met. We report results at an extended median follow-up of 36.1 months in the ITT population. In addition, we report interim overall survival (OS) data for the first time and an exploratory analysis among patients with bladder primary tumors (muscle-invasive bladder cancer [MIBC]). Consistent DFS benefit with nivolumab versus placebo was observed in both the ITT (hazard ratio [HR], 0.71 [95% CI, 0.58 to 0.86]) and PD-L1 ≥1% (HR, 0.52 [95% CI, 0.37 to 0.72]) patients. The HR for OS with nivolumab versus placebo was 0.76 (95% CI, 0.61 to 0.96) in the ITT population and 0.56 (95% CI, 0.36 to 0.86) in the PD-L1 ≥1 population. Continuous benefit in nonurothelial tract recurrence-free survival and distant metastasis-free survival was also observed in both patient populations. The exploratory analysis of patients with MIBC also showed continued efficacy benefits, irrespective of PD-L1 status. No new safety signals were reported. Overall, these results further support adjuvant nivolumab as a standard of care for high-risk MIUC after radical resection.

Albuminuria-based stratification of end-stage kidney disease progression and mortality with sodium-glucose cotransporter 2 inhibitors (SGLT2i): A retrospective cohort study in type 2 diabetes and chronic kidney disease.

Clinical trials have shown the kidney-protective benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i). However, their real-world impact, particularly across varying levels of albuminuria, remains less well understood. This study aimed to evaluate the association of SGLT2i, compared with other oral glucose-lowering drugs, with end-stage kidney disease (ESKD) progression in patients with type 2 diabetes and chronic kidney disease (CKD) stratified by urine albumin-to-creatinine ratio (UACR) levels. Using data from a national database spanning from 2016 to 2021, the study included patients with type 2 diabetes and CKD with estimated glomerular filtration rates (eGFRs) below 60 mL/min/1.73 m2 and who started on SGLT2i or other oral glucose-lowering drugs. Patients were stratified into groups by UACR ≥300 mg/g and <300 mg/g. Propensity score matching was used to minimize confounding, and progression to ESKD was evaluated using competing risks and Cox proportional-hazards models. All-cause mortality was also analyzed. Following propensity score matching, 18,514 patients in the severely increased albuminuria group (UACR ≥300 mg/g) were tracked, with 2.6% progressing to ESKD over 3 years. In contrast, only 0.3% of the 26,946 patients with UACR <300 mg/g progressed to ESKD. SGLT2i use was associated with a 30% reduction in risk of ESKD progression, compared with the use of other oral glucose-lowering drugs, in the severely increased albuminuria group (hazard ratio[HR]: 0.70, 95% confidence interval [CI]: 0.61-0.80). In the lower albuminuria group, no significant association was evident, though there was a nonsignificant trend toward protection over time. A consistent reduction in mortality risk was observed across all albuminuria levels. SGLT2i are associated with a reduction in the progression to ESKD among patients with severely increased albuminuria, with less pronounced effects observed in those with lower albuminuria levels, suggesting variability in renal outcomes based on albuminuria severity. The consistent survival benefit across all albuminuria levels supports the potential utility of SGLT2i in diabetes and CKD treatment strategies, emphasizing the need for more targeted research.

Animal-assisted services for adults with acquired neurogenic communication disorders: A scoping review.

There is increasing interest in the incorporation of animal-assisted services (AAS) in therapy for adults with acquired neurogenic communication disorders. AAS have the potential to enhance speech and language therapy engagement and outcomes. However, a greater understanding of the nature and potential benefits of these interventions is needed. To describe the existing evidence for the incorporation of AAS in therapy with adults with acquired neurogenic communication disorders and to identify areas for future research. A scoping review was conducted and reported in alignment with the Preferred Reporting Items for Systematic Reviews and Meta-analyses checklist extension for scoping reviews (PRISMA-ScR). Seven databases (PubMed, Embase, CINAHL, PsycINFO, Cochrane, Scopus, Web of Science) and grey literature (Google) were searched. Two reviewers independently screened titles, abstracts and full texts against eligibility criteria using Covidence software. The Template for Intervention Description and Replication (TIDieR) checklist guided extraction of intervention data. A total of 17 studies with adults with aphasia, apraxia of speech and cognitive-communication disorders were included. While terminology varied, most interventions met the definition of animal-assisted therapy or animal-assisted activity and used therapy dogs. Across studies, a range of outcomes were targeted, and positive benefits were reported for participant mood, emotions, motivation and satisfaction. There were mixed, but mostly positive, benefits on social behaviour, communication and participation. AAS has been incorporated in therapy for adults with acquired neurogenic communication disorders, predominately with people with dementia. Across studies, communication impairments and AAS interventions were insufficiently or inconsistently described. Improved reporting would assist understanding of the potential benefits of AAS as an adjunct therapy. A quality appraisal of existing studies, and meta-analysis of findings, is needed to draw conclusions about the effectiveness of AAS as a complementary therapy for people with acquired neurogenic communication disorders. What is already known on this subject There is increasing interest and research in AAS as an adjunct to traditional speech and language therapy. Several clinical populations have been shown to benefit from the incorporation of AAS as a complementary therapy approach, including adults with acquired neurogenic communication disorders. To date there has not been a comprehensive review of literature in the area. What this paper adds to the existing knowledge This review aimed to describe what is known about AAS as an adjunct intervention for adults with acquired neurogenic communication disorders. A total of 17 studies were identified, the majority conducted with people living with dementia. Overall, consistent positive benefits of AAS were reported on participant mood, positive emotions, motivation, and satisfaction. There were mixed, but mostly positive, benefits of AAS on social behaviour, including both verbal and non-verbal communication outcomes, and participation. What are the practical and clinical implications of this work? These results suggest a potential therapeutic benefit for the inclusion of AAS into traditional modalities used by speech-language therapists with people with acquired neurogenic communication disorders. However, clinicians should view these findings with caution. Studies were often insufficiently or inconsistently reported, and a quality appraisal and meta-analysis of existing studies would be needed to draw clear conclusions on the effectiveness of AAS as a complementary approach for people with acquired neurogenic communication disorders.

A phase III trial of adjuvant ribociclib plus endocrine therapy vs endocrine therapy alone in patients with HR+/HER2− early breast cancer: final invasive disease–free survival results from the NATALEE trial

BackgroundNATALEE assessed efficacy and tolerability of 3 years of adjuvant ribociclib plus NSAI compared with a nonsteroidal aromatase inhibitor (NSAI) alone in a broad population of patients with HR+/HER2− early breast cancer, including a select group without nodal involvement. This is the final preplanned analysis of invasive disease–free survival (iDFS). Patients and methodsPremenopausal/postmenopausal women and men were randomized 1:1 to ribociclib (n=2549; 400 mg/day, 3 weeks on/1 week off for 36 months) plus NSAI (letrozole 2.5 mg/day or anastrozole 1 mg/day for 60 months) or NSAI alone (n=2552). Men and premenopausal women also received goserelin (3.6 mg once every 28 days). Patients had anatomical stage IIA (N0 with additional risk factors or N1), IIB, or III disease. The primary endpoint was iDFS. Secondary efficacy endpoints were recurrence-free survival (RFS), distant DFS (DDFS), and overall survival (OS). This final iDFS analysis was planned after ≈500 events. ResultsAt data cutoff (21 July 2023), ribociclib was stopped for 1996 patients (78.3%); 1091 (42.8%) completed 3 years of ribociclib, and ribociclib treatment was ongoing for 528 (20.7%). Median follow-up for iDFS was 33.3 months. Overall, 226 and 283 iDFS events occurred with ribociclib plus NSAI vs NSAI alone, respectively. Ribociclib plus NSAI demonstrated significant iDFS benefit over NSAI alone (Hazard Ratio 0.749, 95% Confidence Interval [CI] 0.628-0.892; P=0.0012). The 3-year iDFS rates were 90.7% (95% CI 89.3%-91.8%) vs 87.6% (95% CI 86.1%-88.9%). A consistent benefit was observed across prespecified subgroups, including stage (II/III) and nodal status (+/−). DDFS and RFS favored ribociclib plus NSAI. OS data were immature. No new safety signals were observed. ConclusionsWith longer follow-up and most patients off ribociclib, NATALEE continues to demonstrate iDFS benefit with ribociclib plus NSAI over NSAI alone in the overall population and across key subgroups. Observed adverse events remained stable.

The Educational Benefits of Plastic Surgery Rotations for Off-Service Residents.

With increasing specialization among surgical divisions, a well-rounded education during a surgical residency is often accomplished by rotating among different subspecialties. Inclusion of specific rotations in the resident curriculum can be considered as a cost-benefit calculation balancing the value of exposure to a subspecialty versus the opportunity cost of potential learning from another rotation. We find that often these decisions are based on anecdotal feedback. Our goal is to supplement these reports with a quantifiable metric of learning achieved on the plastic surgery rotation. Our hypothesis in this prospective study was that residents would demonstrate improved performance on a post-rotation test after their 1-month rotation on plastic surgery compared to the pre-rotation test. A question bank was developed to reflect institutional curriculum objectives and clinical scenarios commonly seen on the service. The questions were developed, validated and vetted in collaboration with medical educators and attending plastic surgeons yielding 20 questions available for use. Postgraduate year 1 residents were given a 10-question test before and after their plastic surgery rotation. A one-tailed paired t-test was used to assess improvement between the pre-rotation test and the post-rotation test. A total of 378 tests were administered with 228 (60%) pre- and post-rotation tests completed meeting inclusion criteria. Average percentage of correct answers for the pre-rotation test was 29% and 88% for the post-rotation test showing a differential improvement of 58% (p < 0.001). Surgical trainee time is a limited commodity. Each clinical rotation needs proven consistent benefit for the trainees. We developed a questionnaire that documents the improvement in clinical knowledge after a one-month rotation on plastic surgery relative to before. The test results were consistent even when comparing trainees who did the rotation early versus late in the PGY-1 year. Clinical exposure reinforces and solidifies specialty learning.

Radiation Therapy in the Management of Head and Neck Mucosal Melanoma.

Mucosal melanoma of the head and neck (HNMM) is a rare but highly aggressive malignancy, often diagnosed at an advanced stage with poor prognosis. This review discusses current treatment strategies, emphasizing the role of radiotherapy in managing this challenging disease. A comprehensive analysis of 33 studies provides updated information on techniques and outcomes, highlighting the consistent benefit of adjuvant radiation in improving local control. Advances in conformal techniques, such as intensity-modulated radiotherapy (IMRT), have significantly reduced toxicity rates. Preliminary data on proton and carbon ion therapies suggest the potential for further enhancement of the therapeutic ratio, despite limited availability. Although recent studies report 3-year local control rates as high as 90%, overall survival within the same time frame remains well below 50-60%, underscoring the need for continued improvement in systemic therapies to address the persistent issue of distant metastases.

Cognitive behavioural therapy for fatigue in patients with multiple sclerosis: A systematic review and meta-analysis

BackgroundTreatment of fatigue is important for many patients with multiple sclerosis (MS). While pharmacological options have not shown consistent benefit, psychological interventions offer another avenue of treatment. Cognitive behavioural therapy (CBT) involves strategies to change maladaptive cognition and illness behaviours that modulate how patients with MS respond to fatigue. The aim of this study was to perform a systematic review and meta-analysis to determine the effectiveness of CBT for the treatment of fatigue in patients with MS. MethodsFive databases (Cochrane Central Register of Controlled Trials, MEDLINE/PubMed, Embase, Emcare and PsycINFO) were searched up until 31 July 2023. Randomised controlled trials involving adult patients with MS and fatigue, comparing CBT with another intervention or usual treatment were included. Studies were required to measure fatigue severity and/or the impact of fatigue as the primary outcome(s). Each study was assessed for bias using the Cochrane Risk of Bias tool version 2. Studies with sufficient data were used for meta-analysis to quantify the short- and long-term effects of CBT on MS-related fatigue. The level of certainty provided by the body of evidence was evaluated using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. ResultsEight studies were included in the review and six studies contributed to the meta-analysis. Most studies had a low overall risk of bias. CBT interventions differed in the number, duration and frequency of sessions, mode of delivery and therapist. There were significant short- (standardised mean difference (SMD) -0.58, 95% confidence interval (95%CI) -0.85 to -0.31, P-value < 0.0001) and long-term (SMD -0.36, 95%CI -0.52 to -0.19, P-value < 0.0001) effects supporting CBT. The evidence provided a low level of certainty for the short-term effect because of heterogeneity of results and possible publication bias, while there was high certainty for the long-term result. ConclusionThe study provides secondary evidence that CBT has moderate short-term and small long-term effects in reducing fatigue in patients with MS. CBT should be regarded as a viable evidence-based intervention, particularly in the absence of established alternatives. Future research should identify the ideal characteristics of a fatigue-specific CBT intervention, patient factors that predict treatment response and strategies to maintain initial improvements over time.

International Variation in Health Status Benefits in Patients Undergoing Initial Invasive Versus Conservative Management for Chronic Coronary Disease: Insights From the ISCHEMIA Trial

BACKGROUND: The ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) demonstrated greater health status benefits with an initial invasive strategy, as compared with a conservative one, for patients with chronic coronary disease and moderate or severe ischemia. Whether these benefits vary globally is important to understand to support global adoption of the results. METHODS: We analyzed participants’ disease-specific health status using the validated 7-item Seattle Angina Questionnaire (SAQ: &gt;5-point differences are clinically important) at baseline and over 1-year follow-up across 37 countries in 6 international regions. The average effect of initial invasive versus conservative strategies on 1-year SAQ scores was estimated using Bayesian proportional odds regression and compared across regions. RESULTS: Considerable regional variation in baseline health status was observed among 4617 participants (mean age=64.4±9.5 years, 24% women), with the mean SAQ summary scores of 67.4±19.5 in Eastern Europe participants (17% of the total), 71.4±15.4 in Asia-Pacific (18%), 74.9±16.7 in Central and South America (10%), 75.5±19.5 in Western Europe (26%), and 78.6±19.2 in North America (28%). One-year improvements in SAQ scores were greater in regions with lower baseline scores with initial invasive management (17.7±20.9 in Eastern Europe and 11.4±19.3 in North America), but similar in the conservative arm. Adjusting for baseline SAQ scores, similar health status benefits of an initial invasive strategy on 1-year SAQ scores were observed (ranging from 2.38 points [95% CI, 0.04–4.50] in North America to 4.66 points [95% CI, 2.46–6.94] in Eastern Europe), with an 88.3% probability that the difference in benefit across regions was &lt;5 points. CONCLUSIONS: In patients with chronic coronary disease and moderate or severe ischemia, initial invasive management was associated with a consistent health status benefit across regions, with modest regional variability, supporting the international generalizability of health status benefits from invasive management of chronic coronary disease. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01471522

Darolutamide in Combination With Androgen-Deprivation Therapy in Patients With Metastatic Hormone-Sensitive Prostate Cancer From the Phase III ARANOTE Trial.

For patients with metastatic hormone-sensitive prostate cancer (mHSPC), delaying progression to castration-resistant disease is important not only for overall survival (OS) but also for patients' quality of life . Darolutamide plus androgen-deprivation therapy (ADT) with docetaxel improved OS versus ADT and docetaxel in patients with mHSPC. The ARANOTE trial evaluated darolutamide and ADT without chemotherapy in patients with mHSPC. In this global phase 3 trial, patients were randomized 2:1 to receive darolutamide 600 mg twice daily or placebo, with concomitant ADT. The primary endpoint was radiological progression-free survival (rPFS). From March 2021 to August 2022, 669 patients were randomized (darolutamide n=446; placebo n=223). At the primary cutoff date (June 7, 2024), darolutamide plus ADT significantly improved rPFS by 46% versus placebo plus ADT (hazard ratio [HR] 0.54; 95% confidence interval [CI], 0.41-0.71; P<0.0001), with consistent benefits across subgroups, including high- and low-volume disease. OS results were suggestive of benefit with darolutamide versus placebo (HR 0.81; 95% CI, 0.59-1.12) and clinical benefits were seen across all other secondary endpoints, including delayed time to castration-resistant prostate cancer (HR 0.40; 95% CI, 0.32-0.51) and time to pain progression (HR 0.72; 95% CI, 0.54-0.96). Adverse events were similar in the two groups. Notably, the incidence of fatigue was lower in patients receiving darolutamide (5.6%) versus those receiving placebo (8.1%), and fewer patients receiving darolutamide (6.1%) versus placebo (9.0%) discontinued treatment due to adverse events. These results confirm the efficacy and tolerability of darolutamide plus ADT in patients with mHSPC, demonstrating clinically and statistically significant improvement in rPFS and a favorable safety profile consistent with prior phase 3 darolutamide trials.