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ObjectiveThe objective was to determine the mortality rate as well as the causes and predictors of death in antiphospholipid antibody (aPL)–positive patients with and without antiphospholipid syndrome (APS) classification.MethodsThe inclusion criterion for the multicenter international Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION) registry is positive aPLs according to the Revised Sapporo Classification Criteria tested within one year before enrollment. Patients are observed every 12 ± 3 months with clinical data and blood collection. For this prospective analysis, we first analyzed the causes of death for patients reported as “deceased.” Secondly, we analyzed risk factors for death using the adjusted Cox proportional hazards model and calculated survival probability using the Kaplan‐Meier model based on different age groups.ResultsOf 967 patients, 43 (5%) were deceased after a median follow‐up of 5.3 years. Based on the univariate analysis, deceased patients, compared to living patients, were more likely to be older and have a history of arterial thrombosis, catastrophic APS, concomitant systemic autoimmune diseases (SAIDs), and baseline cardiovascular disease (CVD) risk factors. Based on the Cox proportional hazards model adjusted for age and for each of the strongest predictors of death, arterial thrombosis (hazard ratio [HR] 2.94, 95% confidence interval [CI] 1.50–5.76), concomitant SAIDs (HR 2.97, 95% 1.56–5.63), and baseline any CVD risk factor (HR 2.43, 95% CI 1.05–5.71) were significantly associated with mortality.ConclusionIn our cohort of persistently aPL‐positive patients, the mortality rate was 5% after a median follow‐up of five years and was highest for patients ≥60 years old at registry entry. History of arterial thrombosis, concomitant SAIDs, and baseline any CVD risk factor independently predicted future death.

OBJECTIVE Tobacco smoking is among the factors known to significantly augment the risk of untreated intracranial aneurysm (IA) growth and rupture. Smoking appears to have a variable effect on different endovascular treatment modalities. The impact of smoking on the safety, efficacy, and outcomes of Woven EndoBridge (WEB) device use for wide-neck IAs has not been evaluated. This study aimed to investigate the outcomes of WEB devices by smoking status. METHODS A retrospective multicenter analysis was conducted on the data of patients from 36 sites worldwide treated with the WEB device for intracranial saccular aneurysms. Patients were stratified based on smoking status (current, former, and never smokers). The Student t-test and chi-square test were performed for continuous and categorical variables, respectively. Multivariable logistic regression was used to adjust for confounders. RESULTS Of 1376 patients with available smoking status, 504 were current smokers, 358 were former smokers, and 514 were never smokers. Upon adjusting for significant confounders, no association was found between smoking and recurrence outcomes (OR 1.39, 95% CI 0.69–2.80; p = 0.36), thromboembolic and hemorrhagic complications, and mortality among IAs treated with the WEB device. There was no statistically significant difference in outcomes between former and never smokers (OR 1.23, 95% CI 0.70–2.18; p = 0.46). The location of aneurysms differed between smoking groups, with former smokers having more anterior circulation aneurysms compared with current and never smokers (99.0% vs 96.9% vs 95.3%; p = 0.01). In terms of clinical symptoms, headache and dizziness were more common in the never smokers compared with current and former smokers (13.9% vs 8.9% vs 7.7%, p = 0.01). CONCLUSIONS This large-scale study suggests no significant correlation between smoking and the recurrence of IAs treated with the WEB device. Biological studies are warranted to better understand the biological impact of smoking on the growth and rupture of treated IAs.

Abstract Introduction We describe the safety of sotorasib monotherapy in patients with KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC) and discuss practical recommendations for managing key risks. Methods Incidence rates of treatment-related adverse events (TRAEs) were pooled from 4 clinical trials: CodeBreaK 100 (NCT03600883), CodeBreaK 101 (NCT04185883), CodeBreaK 105 (NCT04380753), and CodeBreaK 200 (NCT04303780) and graded according to CTCAE v5.0. Adverse events were deemed sotorasib-related per investigator causality assessment. Results In the pooled population (n = 549), TRAEs were reported in 388 (70.7%) patients (grade 1: 124 [22.6%]; grade 2: 117 [21.3%]; grade ≥ 3: 147 [26.8%]). Gastrointestinal and hepatic TRAEs, including diarrhea (171 [31.1%]), nausea (80 [14.6%]), elevated alanine aminotransferase (ALT; 68 [12.4%]), and elevated aspartate aminotransferase (AST; 67 [12.2%]) were the most common (≥10%). Dose interruption and dose reduction of sotorasib resulted in the resolution of >90% of diarrhea events; median time to resolution were 18.0 days and 22.0 days, respectively. Similar trends were observed for elevated ALT and AST events. Patients who stopped immunotherapy <3 months before initiating sotorasib had a higher incidence of treatment-related hepatotoxicity (80/240 [33.3%]) than those who stopped immunotherapy ≥3 months before initiating sotorasib (26/188 [13.8%]). Treatment-related pneumonitis/interstitial lung disease (ILD) and corrected QT (QTc) prolongation were observed in 9 (1.6%) and 4 (0.7%) patients, respectively. Two (0.4%) patients died with TRAEs, 1 with ILD whose ultimate cause of death was disease progression, and the other with an unknown cause. Conclusions Sotorasib has a well-characterized safety profile in patients with KRAS G12C-mutated advanced NSCLC, and key risks are manageable with dose modification.

Abstract Background Tafamidis is a kinetic stabilizer that binds to the transthyretin (TTR) gene, inhibiting its dissociation. It is the only disease-modifying treatment for hereditary TTR amyloidosis with peripheral neuropathy (ATTRv-PN) available in the National Therapeutic Form (Formulário Terapêutico Nacional, FTN, in Portuguese) of the Brazilian Unified Health System (Sistema Único de Saúde, SUS, in Portuguese). Objective To assess if the efficacy and safety of tafamidis in the Brazilian real-world experience are comparable to the results of clinical trials. Methods We retrospectively studied all patients with ATTRv-PN evaluated at our center from September 2011 to March 2022 (data cut-off) who were initiated on tafamidis and had at least 1 follow up visit 6 months after the initiation of the drug treatment. Neurologic and functional outcomes were compared from day 1 (D1) of the tafamidis treatment (baseline) to the last follow-up. Results In total, 33 patients were included, 18 (55%) of whom were female. All patients were carriers of the V30M mutation of ATTRv-PN, and 20 (61%) presented early onset (EO) ATTRv-PN. At baseline, the median age of the sample was of 40 (interquartile range [IQR]: 36–68) years, the median Neuropathy Impairment Score (NIS) was of 10 (6–24) points, and the median body mass index (BMI) was of 26 (23–28) kg/m2. The mean follow-up time was of 3.4 years. At the last follow-up, the BMI, the neurological impairment, and the level of disability slightly worsened compared with baseline, while the findings of the nerve conduction studies remained stable. These same results were observed across EO and late-onset (LO) ATTRv-PN patients. A total of 25 (75.8%) patients were considered responders, and 8 (24.2%), non-responders. Conclusion The efficacy and safety of tafamidis reported in clinical trials is expandable to the Brazilian real-world scenario in EO and late-onset (LO) ATTRv-PN.

Abstract Limbic predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) is highly prevalent in late life and a common co‐pathology with Alzheimer's disease neuropathologic change (ADNC). LATE‐NC is a slowly progressive, amnestic clinical syndrome. Alternatively, when present with ADNC, LATE‐NC is associated with a more rapid course. With the emergence of anti‐amyloid therapeutics, discrimination of LATE‐NC from ADNC is critical and will lead to greater clinical recognition of amnestic patients without ADNC. Furthermore, co‐pathology with LATE‐NC may influence outcomes of these therapeutics. Thus there is a need to identify patients during life with likely LATE‐NC. We propose criteria for clinical diagnosis of LATE as an initial framework for further validation. In the context of progressive memory loss and substantial hippocampal atrophy, criteria are laid out for probable (amyloid negative) or possible LATE (amyloid biomarkers are unavailable or when amyloid is present, but hippocampal neurodegeneration is out of proportion to expected pure ADNC). Highlights Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) is a highly prevalent driver of neuropathologic memory loss in late life. LATE neuropathologic change (LATE‐NC) is a common co‐pathology with Alzheimer's disease neuropathologic change (ADNC) and may influence outcomes with emerging disease‐modifying medicines. We provide initial clinical criteria for diagnosing LATE during life either when LATE‐NC is the likely primary driver of symptoms or when observed in conjunction with AD. Definitions of possible and probable LATE are provided.

Importance There is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN. Objective To present the long-term efficacy and safety of patisiran in adults with hATTR-PN. Design, Setting, and Participants This global open-label extension (OLE) of the APOLLO randomized clinical trial and phase 2 OLE study enrolled patients from 43 hospitals or clinical centers across 19 countries between July 2015 and August 2017, with follow-up until November 2022. Of 212 eligible patients with hATTR who completed the phase 3 APOLLO or phase 2 OLE parent studies, 211 enrolled in and 138 completed the global OLE. Intervention Patisiran, 0.3 mg/kg, intravenously once every 3 weeks for up to 5 years. Main Outcomes and Measures Outcomes evaluated at year 5 of the global OLE included disability (polyneuropathy disability [PND] score); polyneuropathy severity (Neuropathy Impairment Score [NIS]), nutritional status (modified body mass index [mBMI]), quality of life (Norfolk Quality of Life–Diabetic Neuropathy [Norfolk QOL-DN]), and Rasch-Built Overall Disability Scale (R-ODS), with no statistical hierarchy. Safety, survival probability, and mortality were also assessed. Results At the global OLE baseline, the mean (SD) age was 61.3 (12.3) years, and 156 patients (73.9%) were male. In 138 patients completing the study, PND scores remained stable or improved in 89 patients (65.0%), NISs showed a mean (SD) change of 10.9 (14.7), and mean (SD) mBMI (calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter) increased by 46.4 (120.7) over 5 years from baseline. Norfolk QOL-DN and R-ODS scores showed mean (SD) changes of 4.1 (16.7) and –3.7 (6.2), respectively. Adverse events (AEs) leading to study withdrawal occurred in 47 patients (22.3%). Infusion-related reactions were the most common treatment-related AE (n = 34 [16.1%]). Overall, 41 patients (19.4%) died during the study. Patisiran treatment in the parent study and low familial amyloid polyneuropathy score at parent study baseline were associated with significantly improved survival. Conclusions and Relevance In the longest study of an RNAi therapeutic for any disease, patisiran treatment resulted in modest changes for patients with hATTR-PN with an acceptable safety profile. These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine. Trial Registration ClinicalTrials.gov Identifier: NCT02510261

AbstractBackgroundTau‐PET tracers allow for in vivo Braak staging of individuals in the Alzheimer’s disease (AD) continuum. The impact of tracers’ characteristics for Braak staging using tau‐PET remains unclear. Therefore, we performed a head‐to‐head comparison of Braak staging using first‐ and second‐generation tau‐PET tracers.MethodWe assessed 51 cognitively unimpaired (CU) and 49 cognitively impaired participants (mean [SD] age 69.4 [7.5] years) with at least two tau‐PET ligands ([18F]MK6240, [18F]AV1451, and/or [18F]RO948) at McGill University, as part of the HEAD study. We calculated standardized uptake value ratios (SUVR) in Braak‐like regions of interest (ROI) for each ligand and investigated their association using Spearman’s correlation. Thresholds defined the presence of tauopathy in each Braak ROI, which was used to assign a Braak stage to each participant. Finally, we assessed the agreement between the Braak staging provided by each tracer, both for the traditional (using separate Braak stages – 0, I, II, III, IV, V, and VI) and simplified (using joint Braak stages – 0, I‐II, III‐IV, and V‐VI) frameworks.ResultIn all Braak ROIs, we found positive correlations between the SUVR values of the three tracers (Figure 1). The strongest correlation was between [18F]MK6240 and [18F]RO948 in Braak II (r=0.94), and the weakest between [18F]AV1451 and [18F]RO948 in VI (r=0.51). Inter‐tracer agreement regarding the latest stage of abnormality was substantial or nearly perfect between pairs of tracers but moderate between the three tracers (Figure 2A). The simplified framework presented greater agreement compared to traditional Braak staging, except between [18F]MK6240 and [18F]RO948. At the ROI level, the lowest agreements were observed for Braak II and I‐II, when [18F]MK6240 and [18F]RO948 were compared to [18F]AV1451 (Figure 2B‐C). [18F]AV1451 had the highest probability of overestimating the Braak stage assigned by [18F]MK6240 and by [18F]RO948, especially at earlier stages (Figure 3).ConclusionThe ligands presented moderate to nearly perfect agreement for in vivo staging of AD severity. Off‐target binding of [18F]AV1451 to the choroid plexus might explain disagreements at early stages. Overall, slight improvements in agreements were achieved with the simplified framework, as observed in histopathological staging.

AbstractBackgroundUtilizing PET amyloid‐beta (Aβ) and tau for staging Alzheimer’s Disease (AD) has demonstrated potential in identifying individuals with varying degrees of disease severity, applicable to both clinical trials and practice. However, the diverse binding characteristics of tau tracers pose challenges to the application of this staging across different ligands. In this study, we evaluate a novel staging framework proposed by the AA working group, employing Aβ PET and either [18F]MK6240 or [18F]Flortaucipir in individuals participating in a head‐to‐head study of tau PET tracers. This will provide insights into the robustness of this framework when applied across different tau ligands.MethodWe evaluated 154 people (89 CU and 65 CI), with MK6240, Flortaucipir, Aβ‐PET, MRI. SUVRs used inferior cerebellar gray as reference. Participants were categorized in Aβ positivity(A), using visual read, and tau positivity (T) in medial temporal lobe(MTL) and neocortex(NEO). Tau MTL(TMTL) and NEO positivity were defined as average +3 SD of youngs. NEO moderate(TMOD) and high(THIGH) was defined as below and above median SUVR of NEO‐positive individuals. Individuals were grouped as: A‐T‐, A+T‐, A+TMTL+(early), A+TMOD+(intermediary), and A+THIGH+(advanced).ResultsWe found that the distribution of the number of individuals across the five AD stages was comparable when using both MK6240 and Flortaucipir tracers (Figure 1). However, upon examining the concordance within each group, we found a low concordance of 30% (3/10) between tracers in the early tau stage (A+TMTL+). Concordance increased in the intermediary stage A+TMOD+, with a rate of 65% (9/14), and further increased to 79% (11/14) in the advanced stage (A+THIGH+). The A+T‐ group exhibited the highest concordance between tracer results, at 95% (21/22).ConclusionOur findings indicate that the application of this framework across different populations using different tau tracers can lead to a compatible distribution among groups. However, in a direct comparison, we noted that this did not necessarily result in high concordance between groups, as group shifts were observed that depended on the cutoffs used (data not shown). These results emphasize the necessity for harmonization of tau PET tracers prior to their utilization for stage determination.