Citations

Abstract Introduction Revascularization to prevent limb loss is not feasible or represents a very high risk in a significant proportion of patients with chronic limb-threatening ischaemia (CLTI). No standard definition currently exists to define this population of patients. The aim of this study was to develop a consensus-based, multidomain definition to improve clinical assessment and reporting of studies in people with ‘no option’ (NO) or ‘poor option’ (PO) CLTI. Methods A modified Delphi process was conducted with 164 specialists from 30 countries. Two iterative survey rounds were used to reach consensus, defined as ≥70% agreement with a score of ≥7 on a nine-point scale. Results Some 164 international vascular specialists participated in the study, averaging 19 years of experience. A multidomain framework including arterial disease anatomy, biology, risk, function, and context (ABRFC) achieved 83% consensus. A ‘desert foot’ was defined as the absence of distal arterial revascularization targets on advanced non-invasive imaging, invasive digital subtraction angiography, and at least one failed endovascular revascularization attempt (81.6% agreement). Inadequate autogenous bypass conduit was defined as the lack of usable autologous vein across all four limbs (85% agreement). Patients were classified as NO for revascularization if they present with ‘desert foot’, prohibitive medical risk, a non-functional limb, or in those patients who refused arterial revascularization. PO revascularization patients combined factors such as severe infection, lack of autologous vein, or treatment non-compliance (72.1% agreement). Conclusion This consensus study established a structured, expert-validated definition of no option or poor option for revascularisation of patients with CLTI. The multidomain ABRFC framework provides a foundation for standardized clinical assessment, trial design, and future guideline development.

ABSTRACT Background This exploratory analysis of the NEURO‐TTRansform Phase 3 trial evaluated the efficacy of eplontersen in patients with hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy by genetic variant. Methods Changes from baseline in NEURO‐TTRansform primary endpoints serum transthyretin (TTR) at Week 65, modified Neuropathy Impairment Score+7 (mNIS+7) composite score, and Norfolk Quality of Life‐Diabetic Neuropathy (Norfolk QoL‐DN) total score at Week 66 were evaluated in patients with early‐onset (aged < 50 years) and late‐onset (aged ≥ 50 years) Val30Met (p.Val50Met) or non‐Val30Met ATTRv amyloidosis with polyneuropathy. Secondary endpoints from NEURO‐TTRansform were also evaluated by genetic variant. Results In total, 144 patients with early‐onset ( n = 54) or late‐onset ( n = 31) Val30Met or non‐Val30Met ( n = 59), ATTRv amyloidosis with polyneuropathy were randomized to eplontersen. A further 60 patients from NEURO‐TTR with early‐onset ( n = 16) or late‐onset ( n = 17) Val30Met or non‐Val30Met ( n = 27), served as a historical placebo group. The mean percentage difference (95% confidence interval) in serum TTR was −79.9 (−87.8, −72.0), −85.0 (−93.3, −76.6), and −70.6 (−77.7, −63.5) with eplontersen versus placebo in the early‐ and late‐onset Val30Met, and non‐Val30Met groups, respectively. Across subgroups, the change from baseline to Week 66 in mNIS+7 composite score was generally well maintained, and the Norfolk QoL‐DN total score improved with eplontersen versus worsening with placebo. The Polyneuropathy Disability score was maintained in most patients. From baseline to Week 65, the modified body mass index was maintained with eplontersen compared to a marked reduction (worsening) for placebo. Conclusions Findings were suggestive of consistent benefits in reducing neuropathy impairment and improving QoL with eplontersen versus historical placebo, across TTR variants. Trial Registration ClinicalTrials.gov: NCT04136184, NCT01737398

Abstract Latin America is undergoing rapid population aging alongside a rising burden of dementia. While the region holds substantial potential for dementia risk reduction, challenges remain, such as delayed diagnoses, limited access to specialized care and biomarker testing, persistent stigma, and deep‐rooted structural inequities. To address these gaps and foster regionally informed solutions, the Alzheimer's Association convened the 2025 Alzheimer's Association International Conference (AAIC) Satellite Symposium in Lima, Peru, on May 14–15, in collaboration with the Global Brain Health Institute (GBHI) and the Atlantic Fellows for Equity in Brain Health. The meeting aimed to bring core elements of the global AAIC meeting to regional Latin American settings, recognizing that national and cultural contexts demand tailored approaches to dementia prevention, risk reduction, treatment and care all aimed at promoting brain health in the region. This manuscript synthesizes the symposium's key discussions, scientific advances, and opportunities for collaboration across the region.

Introduction: Ubiquinol–cytochrome c reductase core protein II (UQCRC2) encodes a core subunit of the mitochondrial electron transport chain (ETC) complex III (CIII). Biallelic pathogenic variants in UQCRC2 have been associated with mitochondrial disease characterized by lactic acidosis, developmental delay, hepatopathy, and episodic metabolic decompensation. Methods: We reviewed the biochemical phenotypes of 14 individuals possessing UQCRC2 variants, including two novel cases. We performed biochemical studies of mitochondrial respiration and oxidative phosphorylation (OXPHOS) complex measurements in patient-derived fibroblasts. Results: We report reduced CIII activity in a majority of individuals possessing variants in UQCRC2, as well as biochemical findings consistent with impaired mitochondrial energy metabolism, though impairments in mitochondrial respiration were variable. The two previously unreported, unrelated patients possessing the likely pathogenic missense variant c.361T>C, p.Tyr121His in UQCRC2 in trans with a 16p12.2 microdeletion encompassing UQCRC2 showed milder phenotypes, less severe metabolic decompensations, and no long-term neurological impairments. Both individuals display reduced CIII activity and mitochondrial respiratory dysfunction. Discussion: These data expand the current understanding of genotypes associated with UQCRC2-associated mitochondrial disease to include the novel 16p12.2 microdeletion. These data also highlight the consistent biochemical phenotype associated with UQCRC2-associated mitochondrial disease, and the need for consistent biochemical and respiratory assessment of individuals possessing UQCRC2 variants to further our understanding of this phenotype.

ABSTRACT Background Sunlight has profound impacts on physical and mental health, beyond vision, including effects on circadian rhythms, alertness, mood, and sleep. A family history of any mood disorders is strongly associated with psychiatric disorders including bipolar disorder. The purpose of this study was to evaluate the association between a family history of any mood disorder in patients with bipolar I disorder and solar insolation at varied international onset locations. Methods Data for this analysis were available from 5842 patients with a diagnosis of bipolar I disorder obtained at 83 collection sites in both hemispheres. This included 4752 patients from 71 collection sites in the northern hemisphere and 1090 patients from 12 collection sites in the southern hemisphere. Patient data variables were obtained from records or interviews. Solar insolation data were obtained from The National Aeronautics and Space Administration (NASA) Power database for each onset location, and the ratio of the mean monthly minimum/mean monthly maximum solar insolation was calculated. Typically, the ratio is largest near the equator (little yearly change in solar insolation) and smallest near the poles (large yearly change in solar insolation). Results A significant relationship was found between a family history of any mood disorder, the ratio of the mean monthly minimum/mean monthly maximum solar insolation, and gender. The odds of a family history of mood disorder increased as patient location nears the poles and decreased near the equator. Female gender also increased the odds of having a family history of a mood disorder. Conclusions This study highlighted the association between family history, solar insolation, and gender in international patients with bipolar I disorder. Given the profound effects of sunlight on human health, the family of patients with bipolar disorder who live in the same location with the same solar insolation, and especially females, may be at increased risk for a mood disorder.

ABSTRACT Background: Obesity is considered a global epidemic and has shown a progressive increase in recent decades. Bariatric surgery, such as Roux-en-Y gastric bypass (RYGB), is the most effective sustainable weight loss option. However, weight regain is one of the challenges facing patients and is attributed to several factors, including dilatation of the gastrojejunal anastomosis (GJA). Objectives: The central objective of this study is to correlate the influence of time on GJA widening in patients undergoing RYGB over a 7-year period. Methods: Prospective and longitudinal study conducted over 7 years in patients undergoing RYGB. Surgical and endoscopic procedures were performed in a medium hospital in the same city. Weight, body mass index (BMI) and GJA size were assessed at intervals of 2, 6, 12, 24, 30, 48, 60, and 72 months after the surgical procedure. Results: The highest mean value in the distribution of anastomosis diameter was 20±2.27 mm at 72 months after surgery. The lowest mean value was 10.2±1.70 mm at 2 months after surgery. The analysis showed that there is a significant effect of time on anastomosis diameter, with statistically significant differences in the mean value between 2, 6, 12, 24, 60, and 72 months after surgery (F(1,724,5,172)=9.555, P<0.05). Conclusion: Multiple comparative analysis showed that there are statistically significant differences between the mean lengths of anastomosis across the times studied, with a greater influence of the time factor 24 months after surgery.

Abstract Background: The current standard of care for first-line (1L) treatment of human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) consists of induction chemotherapy combined with trastuzumab (TRAS) and pertuzumab (PERT) followed by maintenance therapy with TRAS + PERT. Although this regimen has been associated with sustained disease control, most patients eventually experience disease progression. The HER2CLIMB-05(NCT05132582) study is investigating the efficacy and safety of adding tucatinib to TRAS + PERT as maintenance therapy in patients with HER2+ MBC after completion of 1L chemotherapy-based induction therapy. Methods: Patients with centrally confirmed HER2+MBC without evidence of progression after 1L induction therapy with 4 to 8cycles of a taxane combined with TRAS + PERT, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, and no or asymptomatic brain metastases (BM) were enrolled in HER2CLIMB-05. Contrast-enhanced brain magnetic resonance imaging was performed at screening and regular intervals during the study. Patients were randomly assigned 1:1 to receive either tucatinib 300 mg or placebo twice daily, in combination with either TRAS (6 mg/kg IV or 600 mg SC) plus PERT (420 mg/kg IV) or a SC fixed-dose combination of TRAS, PERT, and hyaluronidase administered every 21 days. Endocrine therapy was permitted for patients with hormone receptor-positive tumors. The primary endpoint is investigator-assessed progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints include overall survival (OS), PFS by blinded independent central review, investigator-assessed central nervous system (CNS)-PFS, and safety. Results: Between March 2022 and July 2024, 654 patients were randomly assigned to receive tucatinib (n = 326) or placebo (n = 328) with1L maintenance therapy. All patients were female (median age: 54 years [range, 24-83]);45.0% were White, 35.2% were Asian, 2.9% were Black/African American, and 19.3%were Hispanic/Latino(a)/Spanish origin. Most patients had ECOG PS of 0 (64.1%)and de novo metastatic disease (69.3%). At baseline, 12.4% of patients had presence or history of BM and 52.6% had hormone receptor-positive MBC. As of September5, 2025, PFS was statistically significantly improved with the addition of tucatinib versus placebo to 1L maintenance therapy (hazard ratio [HR] = 0.641 [95%confidence interval (CI), 0.514-0.799]; 2-sided P &lt; 0.0001). All prespecified patient subgroups demonstrated a PFS benefit with tucatinib combination 1L maintenance therapy consistent with the overall population and regardless of presence or absence of BM at baseline or hormone-receptor status. OS is still immature (observed number of deaths = 51;tucatinib arm versus control arm HR = 0.539 [95% CI, 0.303-0.957; 2-sided P= 0.032]). In the safety analysis set, the most common treatment-emergent adverse events (TEAEs) in the tucatinib arm (n = 326) were diarrhea (72.7%), nausea (33.1%), and elevated liver enzymes (alanine aminotransferase: 28.2%; aspartate aminotransferase:25.8%), of which 6.1%, 0.9%, 13.5%, and 7.1% were, respectively, grade ≥ 3. In the tucatinib arm, 13.5% of patients discontinued tucatinib due to TEAEs. Conclusions: In the HER2CLIMB-05 trial, the addition of tucatinib to TRAS + PERT as 1L maintenance therapy demonstrated a statistically significant and clinically meaningful improvement in PFS with a manageable safety profile in patients with HER2+ MBC. Citation Format: E. Hamilton, G. Curigliano, M. Martin, F. Lerebours, J. Tsurutani, M. Savard, K. Jerzak, X. Hu, L. Martins de Aquino Pimentel, C. O'Sullivan, E. Tokunaga, A. Okines, C. Huang, W. Jacot, J. Sohn, E. Cronemberger Silva, V. Mueller, S. Yang, G. Granata, Q. Shen, L. Santarpia, V. Dieras Her2climb-05: a randomized, double-blind, phase 3 study of tucatinib versus placebo in combination with trastuzumab and pertuzumab as maintenance therapy for her2+ metastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr GS1-01.

Abstract Introduction High-power short-duration (HPSD) ablation has emerged as a promising alternative to conventional power delivery (CPD) for pulmonary vein isolation (PVI) among patients with atrial fibrillation (AF). However, its efficacy, procedural efficiency, and safety profile remain uncertain. Methods PubMed, Embase, Cochrane Library and ClinicalTrials.Gov databases were systematically searched for randomized controlled trials (RCTs) comparing HPSD with CPD ablation for PVI in patients with AF. Random-effects models were used to pool hazard ratios (HR) and risk ratios (RR) with 95% confidence intervals (CI). Results Seven RCTs with 1,006 patients (514 HPSD, 489 CPD) were included. No significant differences were found in freedom from arrhythmia during the follow-up period (HR 0.77; 95% CI 0.41–1.45; p=0.424). AF recurrence did not differ (RR 0.94; 95% CI 0.65–1.36; p=0.733) between groups. HPSD had a significantly shorter procedural (MD -22.61 min; 95% CI -33.18, -12.04; p&lt;0.001) and RF ablation (MD -15.70 min; 95% CI -20.86, -10.55; p&lt;0.001) times, with comparable fluoroscopy time (MD 0 min; 95% CI -0.44, 0.45; p=0.99) between groups. Conclusion In patients with AF undergoing PVI, HPSD did not increase freedom from arrhythmia as compared with CPD ablation, however it was associated with shorter procedure and RF ablation times. These findings suggest that HPSD may be a more efficient approach without compromising clinical outcomes.

Introduction: Porokeratosis is a group of keratinization disorders characterized by the histopathological presence of the cornoid lamella, a hallmark feature across all subtypes. The clinical diagnosis of porokeratosis can be challenging due to its similarity to other dermatological conditions. While polarized light dermatoscopy (PLD) enhances diagnostic accuracy, certain features remain difficult to identify. Ultraviolet-induced fluorescence dermatoscopy (UVFD) is a novel imaging technique that may improve the visualization of porokeratosis features, particularly the peripheral keratin rim. Objectives: This study aimed to assess the diagnostic utility of UVFD compared with PLD in identifying the dermatoscopic features of porokeratosis. Methods: In this retrospective study, dermatologists from five institutions in Chile, Brazil, Poland, and the United States contributed with dermatoscopic images of porokeratosis cases. Both PLD and UVFD images were obtained for each lesion. Two independent investigators evaluated each lesion in PLD and UVFD for the presence of peripheral keratin rim, rim continuity, central scaling, follicular plugs, vascular structures, and photodamaged surrounding skin. A third investigator reviewed discrepancies. Frequencies and means were calculated. McNemar’s chi-square was used for comparison. Results: A total of 136 lesions from 35 patients with biopsy-proven porokeratosis were analyzed. UVFD significantly improved the visualization of the peripheral keratin rim (95.6% vs. 66.2% in PLD; P<0.001) and increased identification rates for central scaling, follicular plugs, and interrupted rims. PLD remained superior for detecting vascular structures(P<0.001). Conclusions: UVFD enhances the visualization of key dermatoscopic features of porokeratosis, particularly the peripheral keratin rim and other keratin-related structures.