Citations

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

Abstract The skip phenomenon (SP) is a pattern where blood cultures are intermittently positive before final clearance. We report that one-third of patients with Staphylococcus lugdunensis infective endocarditis experienced the SP. Patients with the SP experienced both a longer duration of bacteremia and hospital stay, with a higher 1-year mortality rate.

ABSTRACT Neurodegenerative pathologies including multiple sclerosis (MS) are consistently associated with energy deficit in the central nervous system (CNS). This might directly impact myelinating oligodendrocytes as these are particularly vulnerable to metabolic insults. Importantly, oligodendroglial dysfunction and myelin alterations occur in most, if not all neurodegenerative diseases, and are associated with axonal pathology/loss. Thus, elucidating metabolic mechanisms required for oligodendroglial myelin maintenance and axonal support might be crucial to identify therapeutic targets to achieve neuroprotection. While monocarboxylates are important energy fuels for the CNS, their role in myelinating oligodendrocyte function remains unclear. Here we show that, just like neurons, myelinating oligodendrocytes express high affinity monocarboxylate transporter 2 (MCT2) both in mice and humans, which is downregulated in progressive MS. While deletion of MCT2 in mouse oligodendrocytes did not affect the survival of these cells, it resulted in downregulation of lipid synthesis-associated enzymes and failure of myelin maintenance. Moreover, axonal upregulation of lactate dehydrogenase A concomitant with axonal damage was observed but could be alleviated by ketogenic diet. We conclude that oligodendroglial MCT2 is required for myelin maintenance and axonal support, which becomes altered in progressive MS, but may be compensated for by specific metabolic therapies. Graphical abstract

OBJECTIVE Cervical spondylotic myelopathy (CSM) shows varying levels of improvement after surgical treatment. While some patients improve soon after surgery, others may take months to years to show any signs of improvement. The goal of this study was to evaluate postoperative improvement, patient-reported outcomes, and patient satisfaction up to 2 years after surgical treatment for CSM, which will help optimize the current treatment strategies and effectively manage patient expectations. METHODS This was a retrospective study of prospectively collected data using the Quality Outcomes Database. The primary outcomes of interest were achievement of the minimal clinically important difference (MCID) for the numeric rating scale for neck and arm pain, modified Japanese Orthopaedic Association, Neck Disability Index, and EQ-5D scores and postoperative satisfaction (North American Spine Society scale). Early and sustained improvement was defined as MCID achievement in at least one patient-reported outcome measure (PROM) at the 3-, 12-, and 24-month follow-ups. Transient improvement was defined as MCID achievement only at the 3-month and/or 12-month follow-up but not at the 24-month follow-up. Late improvement was defined as MCID achievement in at least one PROM only at the 24-month follow-up. RESULTS There were 630 patients included in the comparative analysis. A total of 463 (73.5%) patients achieved early and sustained improvement, 105 (16.7%) patients experienced transient improvement with subsequent decline, 25 (4.0%) patients reported late improvement, and 37 (5.9%) patients did not report any clinically meaningful improvement after surgery. Patients with an anterior approach were more likely to be in the early and sustained improvement group. African American patients (OR 2.98, 95% CI 1.14–7.76; p = 0.03) were more likely to report late improvement when compared with White patients. The overall satisfaction rate at the 24-month follow-up was 87.8%. CONCLUSIONS These findings indicate that 73.5% of patients achieve early and sustained improvement, and 87.8% of patients are satisfied with surgery 24 months postoperatively.

AbstractBackgroundAccumulating evidence indicates that biological sex may influence clinical manifestation within the spectrum of frontotemporal lobar degeneration (FTLD), implying differences in cognitive reserve. Nonetheless, investigations into the impact of biological sex during the preclinical and minimally symptomatic stages of FTLD are lacking.MethodWe included 275 mutation carriers (158 females; 127 with C9orf72, 68 with GRN, and 80 with MAPT mutations) and 161 non‐carrier familial controls (97 females) from the ALLFTD Consortium (Staffaroni et al., Nat Medicine 2022). Participants underwent magnetic resonance imaging (MRI; 348 baseline, 338 longitudinal) and neuropsychological evaluations (394 baseline, 507 longitudinal). Behavioral symptoms were characterized with the Revised Self‐Monitoring Scale (RSMS) and the Neuropsychiatric Inventory (NPI severity scores). MRI‐derived regional volume estimates (RVE) were computed. Cognitive measures and RVE were normalized against sex‐matched controls. Cognitive composites (language, executive function, and visuospatial function) were calculated by averaging raw scores for each domain. Clinical characteristics and RVE comparisons were made between male and female participants. We adopted the residuals approach to explore behavioral and cognitive reserve by fitting a linear regression model for executive z‐scores as the response value and age, education, and RVE as explanatory variables.ResultIn mutation carriers, sex was not a significant differentiator in age, education level, disease severity, or mutation frequency. Most mutation carriers (188, 68%) were asymptomatic or mildly symptomatic at baseline. However, female mutation carriers exhibited significantly lower visuospatial performance at baseline (Cohen's d = ‐0.34, 95% CI[‐0.58, ‐0.09], p=.001). This difference remained significant among asymptomatic GRN mutation carriers (Cohen’s d = ‐0.73, 95% CI[‐1.22, ‐0.23], p=0.003) but not in other mutations. Following the residuals approach, female mutation carriers showed higher executive performance than males for the same amount of both frontotemporal and global atrophy as quantified by RVE (Cohen's d=0.45, 95 % CI[0.22, 0.67], p<.001). The observed higher executive reserve in women was particularly pronounced in C9orf72 carriers (Cohen's d=0.77, 95% CI[0.35, 1.20], p<.001) but not significant in GRN (p=0.48) and MAPT carriers (p=0.07). No differences in behavioral reserve reached statistical significance.ConclusionFemale sex might modulate early cognitive performance and confer higher executive reserve in FTLD mutation carriers.

Abstract Objective To evaluate the effectiveness of multiple decision aid strategies in promoting high quality shared decision making for prevention of stroke in patients with non-valvular atrial fibrillation. Design Cluster randomized controlled trial. Setting Six academic medical centers in the United States. Participants Patient participants were aged ≥18 with a diagnosis of non-valvular atrial fibrillation, at risk for stroke (CHA 2 DS 2 -VASc ≥1 for men, ≥2 for women), and scheduled for a clinical appointment to discuss stroke prevention strategies. Participating clinicians were those who manage stroke prevention strategies for participating patients. Intervention Patients were randomized to use a patient decision aid or usual care; clinicians were randomized to use an encounter decision aid or usual care with all participating patients. Main outcome measures Primary outcome measures were quality of shared decision making measured by OPTION12, knowledge of atrial fibrillation and its management, and decisional conflict. Results 1117 participants across six sites were included in the analysis. Compared with usual care, the combined use of both the patient decision aid and the encounter decision aid improved the quality of shared decision making (adjusted mean difference 12.1 (95% confidence interval (CI) 8.0 to 16.2; P<0.001), improved patients’ knowledge (odds ratio 1.68 (95% CI 1.35 to 2.09; P<0.001), and reduced patients’ decisional conflict (adjusted mean difference −6.3 (95% CI −9.6 to −3.1; P<0.001). Statistically significant improvements were also observed with the encounter decision aid alone versus usual care for all three outcomes and with the patient decision aid alone versus usual care for quality of shared decision making and knowledge. No important differences were observed in treatment choices for stroke prevention or in participants’ satisfaction. No statistically significant difference in the length of visit across study groups was detected. Conclusion Patients who received any decision aid (encounter decision aid, patient decision aid, or both) had lower decisional conflict, better shared decision making, and greater knowledge than those receiving no decision aid, except for the effect of the patient decision aid on decisional conflict, which did not reach statistical significance. The study establishes that use of either pre-visit or in-visit decision aids individually or in combination is advantageous compared with usual care. Trial registration ClinicalTrials.gov NCT04357288 .

AbstractBackgroundThe prognosis in patients with advanced cardiac amyloidosis (CA) remains poor.ObjectivesWe sought to describe survival post heart transplantation (HT) in amyloid compared with non‐amyloid recipients, highlight waitlist times within the new allocation system across three Organ Procurement and Transplantation Network (OPTN) regions, and describe multiorgan transplantation (MOT) in hereditary amyloidosis.MethodsThis is a retrospective review of end‐stage CA patients who underwent HT at Mayo Clinic from January 2007 to December 2020. Wait time was compared in the new versus old OPTN allocation era starting December 18, 2018 by Wilcoxon rank sum test. All‐cause mortality for those with and without CA was compared using Kaplan–Meier estimates with log rank analysis, censoring December 16, 2022.ResultsFifty‐five patients with CA underwent HT between 2007 and 2020, 8 light chain amyloidosis (AL) (14.5%), 28 hereditary transthyretin (ATTRv) (50.9%), 17 wildtype transthyretin (ATTRwt) (30.9%), and 2 hereditary apolipoprotein A1 (AApoA1) amyloidosis patients (3.6%). No significant difference in overall survival post‐transplant was seen in amyloid compared with non‐amyloid (p = 0.816). Median time to HT was shorter in the new system, 45 days (IQR 24, 78) versus 174 days (IQR 76.5, 483.5), p = 0.006. There was a decline in MOT in hereditary amyloidosis over time with the concomitant rise in disease‐targeted therapies.ConclusionsHT survival in CA patients was similar to non‐amyloid patients. The new allocation system benefits this cohort with shorter wait times. There is less MOT in hereditary amyloidosis with increased utilization of disease‐targeted therapy.

Neurogastroenterology and motility disorders are complex gastrointestinal conditions that are prevalent worldwide, particularly affecting women and younger individuals. These conditions significantly impact the quality of life of people suffering from them. There is increasing evidence linking these disorders to cirrhosis, with a higher prevalence compared to the general population. However, the link between neurogastroenterology and motility disorders and cirrhosis remains unclear due to undefined mechanisms. In addition, managing these conditions in cirrhosis is often limited by the adverse effects of drugs commonly used for these disorders, presenting a significant clinical challenge in the routine management of patients with cirrhosis. This review delves into this connection, exploring potential pathophysiological links and clinical interventions between neurogastroenterology disorders and cirrhosis.

PURPOSE In patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), brentuximab vedotin (BV) as monotherapy or combined with either lenalidomide (Len) or rituximab (R) has demonstrated efficacy with acceptable safety. We evaluated the efficacy and safety of BV + Len + R versus placebo + Len + R in patients with R/R DLBCL. METHODS ECHELON-3 is a randomized, double-blind, placebo-controlled, multicenter, phase 3 trial comparing BV + Len + R with placebo + Len + R in patients with R/R DLBCL. Patients received BV or placebo once every 3 weeks, Len once daily, and R once every 3 weeks. The primary end point was overall survival (OS), and secondary end points included investigator-assessed progression-free survival (PFS) and objective response rate (ORR). A prespecified interim analysis was performed after 134 OS events, with two-sided P = .0232 as the efficacy boundary. RESULTS Patients (N = 230) were randomly assigned to receive BV + Len + R (n = 112) or placebo + Len + R (n = 118). Two patients in the placebo arm did not receive treatment. With a median follow-up of 16.4 months, the median OS was 13.8 months with BV + Len + R versus 8.5 months with placebo + Len + R (hazard ratio, 0.63 [95% CI, 0.45 to 0.89]; two-sided P = .009). The median PFS was 4.2 months with BV + Len + R versus 2.6 months with placebo + Len + R (hazard ratio, 0.53 [95% CI, 0.38 to 0.73]; two-sided P < .001). The ORR was 64% ([95% CI, 55 to 73]; two-sided P < .001) with BV + Len + R and 42% (95% CI, 33 to 51) with placebo + Len + R; complete response rates were 40% and 19%, respectively. Treatment-emergent adverse events (AEs) occurred in 97% of patients in both arms. In both arms, the most common treatment-emergent AEs were neutropenia, thrombocytopenia, diarrhea, and anemia. CONCLUSION BV + Len + R demonstrated a statistically significant survival benefit with a manageable safety profile in heavily pretreated patients with R/R DLBCL.