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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

AbstractBackgroundCross‐modality translation between MRI and PET presents significant challenges due to the distinct mechanisms underlying those modalities. Currently, the leading method for this translation is CycleGAN. Previous studies have proved a strong correlation between BBBMs and brain amyloid status measured by PET. However, the impact of blood‐based biomarkers (BBBMs) on PET image synthesis has not yet been thoroughly evaluated. In this study, we propose Plasma CycleGAN, a generative model based on CycleGAN to synthesize PET images from MRI, while also incorporating BBBMs and other clinical covariates. We show that Plasma CycleGAN outperforms the state‐of‐the‐art CycleGAN for MRI‐to‐PET translation. Our method is the first to integrate BBBMs in a conditional cross modality translation from MRI to PET.MethodOur model was built on CycleGAN architecture, while the backbone was improved by integrating BBBMs as additional conditions in the input domain. To be specific, we introduce a masked perturbation in the MRI image, whose voxel‐level magnitudes are learnable parameters in the neural network. The dataset we used to evaluate our model is downloaded from the ADNI database. The cohort contains 160 subjects with matching BBBM, T1‐weighted MRI images, amyloid PET, and clinical features, including age, sex, weights, etc. The synthesized PET images are compared with the ground truth PET images for performance evaluation using traditional metrics like structural similarity index (SSIM), peak‐signal‐to‐noise ratio (PSNR) and mean square error (MSE). In addition, the Pearson correlation coefficients (PCCs) of the masked SUVR ratios were calculated.ResultWe evaluated the baseline CycleGAN model using MRI input, as well as combined inputs of MRI+BBBM and other clinical features. Our model achieved an SSIM of 0.72±0.16 and PSNR of 22.8±2.3 in PET image synthesis task using MRI+ Aβ42/40, both yielding the best results among all input combinations. MRI+sex achieved the best result using MSE measurement. PCCs of all experimental results ranged from 0.44 to 0.5.ConclusionWe introduce Plasma CycleGAN, the first generative model to integrate BBBMs and clinical features in PET image synthesis from MRI images. In PET image synthesis task, our proposed integrated model outperforms the baseline CycleGAN model.

Abstract Genetic modifiers are believed to play an important role in the onset and severity of polycystic kidney disease (PKD), but identifying these modifiers has been challenging due to the lack of effective methodologies. In this study, we investigated zebrafish mutants of IFT140 , a newly identified ADPKD gene, and observed phenotypes similar to those seen in mammalian models, including kidney cysts and bone defects. Using efficient microhomology-mediated end joining (MMEJ)-based genome editing technology, we demonstrated that ift140 CRISPRants recapitulate mutant phenotypes while bypassing the early lethality of the mutants to allow for renal cyst analysis in adult fish. In addition to cilia defects, non-cilia phenotypes, such as disrupted cell polarity and aberrant microtubule stabilization in kidney epithelial cells, may also contribute to ift140 -associated cystogenesis. Importantly, the ability to detect ift140 -associated renal cysts with ease allowed us to develop an F0-based genetic screen to identify potential protective modifiers. A pilot screen of sixteen genes previously linked to dysregulated signaling pathways in ADPKD revealed both known and novel modifiers, including mtor and ulk1a . Inhibition of mtor and ulk1a reversed both cilia-related and non-cilia-related abnormalities. In summary, our study underscores the potential of using zebrafish as a model for the efficient discovery of genetic modifiers of kidney cysts.

Abstract As the healthcare burden caused by an increasingly aging population rapidly rises, a pressing need exists for innovative geroscience research that can elucidate aging mechanisms and precipitate the development of therapeutic interventions to support healthy aging. The Fifth Annual Midwest Aging Consortium Aging Research symposium, held from April 28 to 30, 2024, was hosted by The Ohio State University in Columbus, Ohio, and featured presentations from investigators across the Midwestern United States. This report summarizes the research presented at the symposium, whose topics included cellular senescence and the aging brain, metabolism and metabolic interventions, nutrition, redox mechanisms and biomarkers, and stress mechanisms. Abstract presentations and short talks highlighted early-stage and young investigators, whereas 2 keynote presentations anchored the symposium. Overall, this symposium showed the robustness of aging research in the Midwest and underscored the advantages of a collaborative approach to geroscience research.

The hierarchical organization of the connective tissue, more specifically, the musculoskeletal soft tissue, has been extensively studied. With advancements in experimental methodology, investigation of the structure–function relationship has provided more insight into how the mechanical integrity of the tissue is created. Such information is essential in the linking the macroscopic loading environment of the tissue to the microscopic level of the tissue to be experienced by the cell. The flexibility and elastic modulus of gross connective tissue, the fascicle, the fiber and then the collagen molecule are compared based on the data available in the literature.

Abstract INTRODUCTION Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, yet our comprehension predominantly relies on studies within non‐Hispanic White (NHW) populations. Here we provide an extensive survey of the proteomic landscape of AD across diverse racial/ethnic groups. METHODS Two cortical regions, from multiple centers, were harmonized by uniform neuropathological diagnosis. Among 998 unique donors, 273 donors self‐identified as African American, 229 as Latino American, and 434 as NHW. RESULTS While amyloid precursor protein and the microtubule‐associated protein tau demonstrated higher abundance in AD brains, no significant race‐related differences were observed. Further proteome‐wide and focused analyses (specific amyloid beta [Aβ] species and the tau domains) supported the absence of racial differences in these AD pathologies within the brain proteome. DISCUSSION Our findings indicate that the racial differences in AD risk and clinical presentation are not underpinned by dramatically divergent patterns in the brain proteome, suggesting that other determinants account for these clinical disparities. Highlights We present a large‐scale proteome (∼10,000 proteins) of DLPFC (998) and STG (244) across AD cases. About 50% of samples were from racially and ethnically diverse brain donors. Key AD proteins (amyloid and tau) correlated with CERAD and Braak stages. No significant race‐related differences in amyloid and tau protein levels were observed in AD brains. AD‐associated protein changes showed a strong correlation between the brain proteomes of African American and White individuals. This dataset advances understanding of ethnoracial‐specific AD pathways and potential therapies.

Abstract This study reports the first pig-to-human lung xenotransplantation using a six gene-edited pig lung. A left lung from a gene-edited Chinese Bama Xiang pig was transplanted into a 39-year-old brain-dead human recipient. The xenograft maintained viability and functionality for 216 hours without signs of hyperacute rejection. Postoperatively, severe edema resembling primary graft dysfunction (PGD) was observed, potentially due to ischemia-reperfusion injury. Antibody-mediated rejection appeared to contribute to xenograft damage on postoperative days 3 and 6, with partial recovery by day 9 under the current immunosuppressive regimen. This pioneering study suggests that genetically modified pig lungs could potentially be used for future clinical applications in xenotransplantation.