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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

AbstractBackgroundThere is a strong link between tau and progression of Alzheimer’s disease (AD), necessitating an understanding of tau spreading mechanisms. Prior research, predominantly in typical AD, suggested that tau propagates from epicenters (regions with earliest tau) to functionally connected regions. However, given the constrained spatial heterogeneity of tau in typical AD, validating this connectivity‐based tau spreading model in AD variants with distinct tau deposition patterns is crucial.MethodWe included 269 amyloid‐β‐positive (PET/CSF) individuals with clinically diagnosed atypical AD (113 posterior cortical atrophy, PCA‐AD; 83 logopenic variant primary progressive aphasia, lvPPA‐AD; 33 behavioural variant AD, bvAD; 40 corticobasal syndrome, CBS‐AD) and 68 with typical AD from 12 international cohorts, who underwent tau‐PET (54% [18F]AV1451/[18F]flortaucipir/Tauvid, 27% [18F]MK6240, 19% [18F]PI2620). Using Gaussian mixture modeling including amyloid‐β‐negative controls, cross‐sectional tau‐PET standardized uptake value ratios within Schaefer‐200 atlas regions were transformed to tau positivity probabilities. Tau epicenters were defined as the 5% regions with highest tau positivity probabilities. For each variant, the association between functional connectivity‐based distance (using the 30% strongest positive region‐to‐region connections of a group‐average connectivity matrix from ADNI elderly controls) and tau‐PET covariance (group‐average correlation per region pair) was assessed through linear regression, adjusting for age, sex, site, and Euclidean distance. Regions were categorized based on functional proximity to the epicenter (quartiles 1‐4) and tau positivity probabilities were assessed accordingly.ResultTau positivity probabilities matched clinical variants, with a posterior pattern in PCA‐AD, left‐hemispheric dominant pattern in lvPPA‐AD, widespread pattern in bvAD, sensorimotor cortex involvement in CBS‐AD, and temporo‐parietal predominance in typical AD (Figure 1). In line with this, tau epicenters were highly heterogeneous across variants (Figure 1). In all variants, greater tau‐PET covariance was associated with shorter functional connectivity‐based distance (Figure 2). We observed that regions in closer functional proximity to the epicenter exhibited higher tau positivity probabilities than regions functionally further away (p<0.05, Figure 3).ConclusionThis multi‐center study shows that the brain’s functional architecture serves as a universal predictor of tau spreading in AD. Since tau is a key driver of neurodegeneration and cognitive decline in AD, this finding holds potential for personalized medicine and defining participant‐specific endpoints in clinical trials.

AbstractBackgroundThere is a strong link between tau and progression of Alzheimer’s disease (AD), necessitating an understanding of tau spreading mechanisms. Prior research, predominantly in typical AD, suggested that tau propagates from epicenters (regions with earliest tau) to functionally connected regions. However, given the constrained spatial heterogeneity of tau in typical AD, validating this connectivity‐based tau spreading model in AD variants with distinct tau deposition patterns is crucial.MethodWe included 269 amyloid‐ß‐positive (PET/CSF) individuals with clinically diagnosed atypical AD (113 posterior cortical atrophy, PCA‐AD; 83 logopenic variant primary progressive aphasia, lvPPA‐AD; 33 behavioural variant AD, bvAD; 40 corticobasal syndrome, CBS‐AD) and 68 with typical AD from 12 international cohorts, who underwent tau‐PET (54% [18F]AV1451/[18F]flortaucipir/Tauvid, 27% [18F]MK6240, 19% [18F]PI2620). Using Gaussian mixture modeling including amyloid‐ß‐negative controls, cross‐sectional tau‐PET standardized uptake value ratios within Schaefer‐200 atlas regions were transformed to tau positivity probabilities. Tau epicenters were defined as the 5% regions with highest tau positivity probabilities. For each variant, the association between functional connectivity‐based distance (using the 30% strongest positive region‐to‐region connections of a group‐average connectivity matrix from ADNI elderly controls) and tau‐PET covariance (group‐average correlation per region pair) was assessed through linear regression, adjusting for age, sex, site, and Euclidean distance. Regions were categorized based on functional proximity to the epicenter (quartiles 1‐4) and tau positivity probabilities were assessed accordingly.ResultTau positivity probabilities matched clinical variants, with a posterior pattern in PCA‐AD, left‐hemispheric dominant pattern in lvPPA‐AD, widespread pattern in bvAD, sensorimotor cortex involvement in CBS‐AD, and temporo‐parietal predominance in typical AD (Fig.1). In line with this, tau epicenters were highly heterogeneous across variants (Fig.1). In all variants, greater tau‐PET covariance was associated with shorter functional connectivity‐based distance (Fig.2). We observed that regions in closer functional proximity to the epicenter exhibited higher tau positivity probabilities than regions functionally further away (p<0.05, Fig.3).ConclusionThis multi‐center study shows that the brain’s functional architecture serves as a universal predictor of tau spreading in AD. Since tau is a key driver of neurodegeneration and cognitive decline in AD, this finding holds potential for personalized medicine and defining participant‐specific endpoints in clinical trials.

Aging disrupts multiple homeostatic processes, including autophagy, a cellular process for the recycling and degradation of defective cytoplasmic structures. Acute treatment with the autophagy inhibitor chloroquine blunts the maximal forces generated by the diaphragm muscle, but the mechanisms underlying neuromuscular dysfunction in old age remain poorly understood. We hypothesized that chloroquine treatment increases the presynaptic retention of the styryl dye FM 4-64 following high-frequency nerve stimulation, consistent with the accumulation of unprocessed bulk endosomes. Diaphragm-phrenic nerve preparations from 24-month-old male and female C57BL/6 × 129 J mice were incubated with FM 4-64 (5 µM) and either chloroquine (50 µM) or vehicle during 80 Hz phrenic nerve stimulation. Acute chloroquine treatment significantly decreased FM 4-64 intensity at diaphragm neuromuscular junctions following 80 Hz phrenic nerve stimulation, consistent with disrupted synaptic vesicle recycling. A similar reduction was evident in regions with the greatest FM 4-64 fluorescence intensity, which most likely surround synaptic vesicle release sites. In the absence of nerve stimulation, chloroquine treatment significantly increased FM 4-64 intensity at diaphragm neuromuscular junctions. These findings highlight the importance of autophagy in regulating presynaptic vesicle retrieval (including vesicle recycling and endosomal processing) and support the role of autophagy impairments in age-related neuromuscular dysfunction.

ABSTRACT We report a case of acute interstitial nephritis (AIN) in a 68-year-old male with squamous cell carcinoma (SCC) and relapsed/refractory multiple myeloma (RRMM) who developed acute kidney injury (AKI) shortly after starting teclistamab for RRMM. Despite stable renal function on immune checkpoint inhibitor (ICI) therapy for SCC, proton pump inhibitors and trimethoprim-sulfamethoxazole for 3 years, AKI only occurred post-teclistamab initiation. Biopsy-confirmed AIN with serum creatinine improved only after pulse-dose steroids. This case highlights a potential synergistic nephrotoxic effect of teclistamab and ICIs, warranting further investigation into teclistamab's renal safety.

Abstract Nocardiosis is an uncommon yet potentially devastating infection. Nocardia tends to affect individuals with chronic lung disease or immunocompromising conditions, 2 groups increasing in number. Incidence of nocardiosis is likely to increase as well, and it is vital to have an approach to this complex disease. Here, we aim to review the presentation, diagnosis, and management of Nocardia in the modern era. We will also highlight areas of uncertainty in our understanding of nocardiosis and propose a general approach to nocardiosis therapy, accounting for response and tolerance of Nocardia treatment.

ABSTRACTBackgroundMany vascular anomalies harbor postzygotic somatic variants in GNAQ and GNA11; however, the phenotype of specific G‐protein variants has not been well described. We report the clinical characteristics of 17 patients with a GNA11 R183C variant.MethodsThis case series is derived from a multinational cohort of vascular anomaly patients whose pathogenic mutations were identified using high‐depth next generation sequencing. Data include vascular anomaly features, imaging reports, and extracutaneous manifestations of the GNA11 R183C variant.ResultsWe identified 17 subjects (median age 18 years [range 6–67]) with somatic GNA11 R183C variant. All patients had vascular lesions of the skin that presented as pink‐to‐red in children and deeper red in adults. Most lesions were large, poorly demarcated, and reticulated patches that were often bilaterally distributed. Nevus anemicus was observed in 53% (N = 9) and dermal melanocytosis in 13.3% (N = 2) of individuals. 82% (N = 14) of patients had limb growth discrepancies, and 1 patient had marked thoracic hypoplasia. 47% (N = 8) of patients had facial involvement, and 41% (N = 7) had forehead involvement. One patient experienced seizures due to right hemispheric leptomeningeal angiomatosis consistent with Sturge–Weber syndrome. Other findings included glaucoma (29%, N = 5) and psychomotor delay (29%, N = 5).ConclusionThese findings contribute to our understanding of the clinical spectrum of GNA11 R183C capillary malformations (CMs); patients characteristically present with extensive, bilateral, poorly demarcated, pink‐to‐red CMs associated with nevus anemicus. Glaucoma and growth discrepancies (overgrowth or undergrowth) are common. Leptomeningeal angiomatosis and developmental delay can occur, appearing potentially less prevalent and severe than GNAQ‐associated disease.