Hui Wang, Yuxin Chen, Jun Lv, Xiaoting Cheng, Qi Cao, Daqi Wang, Longlong Zhang, Biyun Zhu, Min Shen, Chunxin Xu, Mengzhao Xun, Zijing Wang, Honghai Tang, Shaowei Hu, Chong Cui, Luoying Jiang, Yanbo Yin, Luo Guo, Yi Zhou, Lei Han, Ziwen Gao, Jiajia Zhang, Sha Yu, Kaiyu Gao, Jinghan Wang, Bing Chen, Wuqing Wang, Zheng-Yi Chen, Huawei Li, Yilai Shu <<<

AbstractGene therapy is a promising approach for hereditary deafness. We recently showed that unilateral AAV1-hOTOF gene therapy with dual adeno-associated virus (AAV) serotype 1 carrying human OTOF transgene is safe and associated with functional improvements in patients with autosomal recessive deafness 9 (DFNB9). The protocol was subsequently amended and approved to allow bilateral gene therapy administration. Here we report an interim analysis of the single-arm trial investigating the safety and efficacy of binaural therapy in five pediatric patients with DFNB9. The primary endpoint was dose-limiting toxicity at 6 weeks, and the secondary endpoint included safety (adverse events) and efficacy (auditory function and speech perception). No dose-limiting toxicity or serious adverse event occurred. A total of 36 adverse events occurred. The most common adverse events were increased lymphocyte counts (6 out of 36) and increased cholesterol levels (6 out of 36). All patients had bilateral hearing restoration. The average auditory brainstem response threshold in the right (left) ear was >95 dB (>95 dB) in all patients at baseline, and the average auditory brainstem response threshold in the right (left) ear was restored to 58 dB (58 dB) in patient 1, 75 dB (85 dB) in patient 2, 55 dB (50 dB) in patient 3 at 26 weeks, and 75 dB (78 dB) in patient 4 and 63 dB (63 dB) in patient 5 at 13 weeks. The speech perception and the capability of sound source localization were restored in all five patients. These results provide preliminary insights on the safety and efficacy of binaural AAV gene therapy for hereditary deafness. The trial is ongoing with longer follow-up to confirm the safety and efficacy findings. Chinese Clinical Trial Registry registration: ChiCTR2200063181. <<<

Frederic Tremblay, Qiang Xiong, Shrijal S. Shah, Chih-Wei Ko, Kenneth Kelly, Mary S. Morrison, Cristiana Giancarlo, Ricardo N. Ramirez, Erica M. Hildebrand, Sarah B. Voytek, Gabriel K. El Sebae, Shane H. Wright, Liam Lofgren, Scott Clarkson, Christine Waters, Samantha J. Linder, Songlei Liu, Taesun Eom, Shefal Parikh, Yuki Weber, Salette Martinez, Padma Malyala, Sahar Abubucker, Ari E. Friedland, Morgan L. Maeder, Angelo Lombardo, Vic E. Myer, Aron B. Jaffe <<<

Mika Kivimäki, Jaana Pentti, Philipp Frank, Fangyu Liu, Acer Blake, Solja T. Nyberg, Jussi Vahtera, Archana Singh-Manoux, Tony Wyss-Coray, Keenan A. Walker, Linda Partridge, Joni V. Lindbohm <<<

Abstract Social disadvantage, like advanced age, is a risk factor for a broad range of health conditions; however, whether it influences the aging process remains unclear. Here, using a multicohort approach, we investigated the associations of social disadvantage with age-related plasma proteins and age-related diseases. We found proteomic signatures of accelerated immune aging and 14 specific age-related proteins linked to social disadvantage during both early and later life. Individuals experiencing social disadvantage had an increased risk of 66 age-related diseases, with up to 39% of these associations mediated by the 14 age-related proteins (for example, DNAJB9, F2, HSPA1A, BGN). The main enriched pathway involved the upregulation of the pro-inflammatory regulator NF-κB24 and its downstream factor interleukin-8. Our findings support the hypothesis that social disadvantage throughout the life course may accelerate aging, a biological mechanism that could explain why social stratification plays such a fundamental role in determining human health. <<<

Gustaw Eriksson, Congru Li, Tina Gorsek Sparovec, Anja Dekanski, Sara Torstensson, Sanjiv Risal, Claes Ohlsson, Angelica Lindén Hirschberg, Sophie Petropoulos, Qiaolin Deng, Elisabet Stener-Victorin <<<

Abstract Polycystic ovary syndrome (PCOS) has a negative effect on the receptivity of the endometrium to embryo implantation and increases the risk of miscarriage and endometrial cancer. The cellular and molecular heterogeneity of the endometrium in women with PCOS has not been well studied. Our study presents a comprehensive cellular atlas of the endometrium during the proliferative phase in women with PCOS characterized by overweight and obesity, hyperandrogenism and insulin resistance compared with controls of similar age, weight and body mass index. Analysis of 247,791 isolated endometrial nuclei from 27 biopsies (5 controls and 12 PCOS cases at baseline and 7 after 16 weeks of metformin and 3 after lifestyle intervention) revealed cell-type-specific disease signatures and variations in cellular composition and localization. Samples taken after 16 weeks of metformin treatment and lifestyle management showed extensive recovery of disease-specific endometrial signatures. We linked the specific role of each cell type to clinical features such as hyperandrogenism and insulin resistance, and specific cell types to risk of endometrial and metabolic disease. In addition, potential therapeutic targets such as integrin inhibitors were identified and the role of metformin in restoring endometrial health in patients with PCOS was highlighted. Our findings lay the groundwork to significantly advance the understanding of PCOS-specific endometrial dysfunction for future targeted therapies. <<<

Matthias Diebold, Patrick T. Gauthier, Katharina A. Mayer, Martina Mackova, Christian Hinze, Jessica Chang, Uptal D. Patel, Ekkehard Schütz, Bernd Jilma, Eva Schrezenmeier, Klemens Budde, Georg A. Böhmig, Philip F. Halloran <<<

Abstract A recent randomized controlled trial demonstrated that treatment with anti-CD38 monoclonal antibody felzartamab suppressed antibody-mediated rejection (ABMR) in kidney transplant patients but with recurrence after treatment in some patients. Here we examined the molecular effects of 6 months of felzartamab treatment on biopsies from the trial using genome-wide microarray analysis, comparing pretreatment, end-of-treatment (week 24) and posttreatment (week 52) biopsies from ten patients treated with felzartamab and ten patients in the placebo group. Felzartamab reduced molecular ABMR activity scores in all nine patients with baseline ABMR activity, selectively suppressing interferon gamma-inducible and natural killer cell transcripts, with minimal effect on ABMR stage-related endothelial transcripts. Suppression was often incomplete when ABMR activity was intense, and molecular recurrence was nearly universal by week 52. However, we also found that felzartamab had parenchymal benefits at week 52, slowing the trajectories of molecular injury scores beyond the treatment period, suggesting that suppression of ABMR activity could potentially slow future progression to kidney failure. These data provide preliminary molecular insights into the effects of CD38-directed treatment for ABMR, which have the potential to inform future therapeutic strategies. <<<

Anne-Julie Tessier, Fenglei Wang, Andres Ardisson Korat, A. Heather Eliassen, Jorge Chavarro, Francine Grodstein, Jun Li, Liming Liang, Walter C. Willett, Qi Sun, Meir J. Stampfer, Frank B. Hu, Marta Guasch-Ferré <<<

Areeba Patel, Kirsten Göbel, Sebastian Ille, Felix Hinz, Natalie Schoebe, Henri Bogumil, Jochen Meyer, Michelle Brehm, Helin Kardo, Daniel Schrimpf, Artem Lomakin, Michael Ritter, Pauline Göller, Paul Kerbs, Lisa Pfeifer, Stefan Hamelmann, Christina Blume, Franziska M. Ippen, Natalie Berghaus, Philipp Euskirchen, Leonille Schweizer, Claus Hultschig, Nadine Van Roy, Jo Van Dorpe, Joni Van der Meulen, Siebe Loontiens, Franceska Dedeurwaerdere, Henning Leske, Skarphéðinn Halldórsson, Graeme Fox, Simon Deacon, Inswasti Cahyani, Nadine Holmes, Satrio Wibowo, Rory Munro, Dan Martin, Abid Sharif, Mark Housley, Robert Goldspring, Sebastian Brandner, Somak Roy, Jürgen Hench, Stephan Frank, Andreas Unterberg, Violaine Goidts, Natalie Jäger, Simon Paine, Stuart Smith, Christel Herold-Mende, Wolfgang Wick, Stefan M. Pfister, Einar O. Vik-Mo, Andreas von Deimling, Sandro Krieg, David TW Jones, Matthew Loose, Matthias Schlesner, Martin Sill, Felix Sahm <<<

Hesham ElAbd, Mitchell Pesesky, Gabriel Innocenti, Brian K. Chung, Aya K. H. Mahdy, Valeriia Kriukova, Laila Kulsvehagen, Dennis Strobbe, Claudia Stühler, Gabriele Mayr, Damon H. May, Melanie Prinzensteiner, Tim A. Steiert, Florian Tran, Michel V. Hadjihannas, Rainer Günther, Elisa Rosati, Sören Mucha, Wolfgang Lieb, Malte Ziemann, Astrid Dempfle, Felix Braun, Trine Folseraas, Johannes R. Hov, Espen Melum, Petra Bacher, Martina Sterneck, Tobias J. Weismüller, Henrike Lenzen, Bernd Bokemeyer, Bryan Howie, Harlan S. Robins, Christoph Röcken, Stefan Schreiber, Nina Khanna, Anne-Katrin Pröbstel, Christoph Schramm, Thomas Vogl, Tom H. Karlsen, Andre Franke <<<

Abstract Primary sclerosing cholangitis (PSC) is an idiopathic, progressive and incurable liver disease. Here, we aimed for systematic analyses of adaptive immune responses in PSC. By profiling the T cell repertoires of 504 individuals with PSC and 904 healthy controls, we identified 1,008 clonotypes associated with PSC. A substantial fraction of these clonotypes was restricted to known PSC human leukocyte antigen susceptibility alleles and known to target Epstein–Barr virus (EBV) epitopes. We further utilized phage-immunoprecipitation sequencing to determine antibody epitope repertoires of 120 individuals with PSC and 202 healthy controls, which showed a higher burden of anti-EBV responses in PSC than controls. EBV-specific monoclonal antibodies isolated from B cells in PSC livers corroborated convergent B and T cell responses against EBV. By analyzing electronic health records of >116 million people, we identified an association between infectious mononucleosis and PSC (odds ratio, 12; 95% confidence interval, 6.3–22.9), suggesting a link between EBV and PSC. <<<

Isabel Deisenhofer, Jean-Paul Albenque, Sonia Busch, Edouard Gitenay, Stavros E. Mountantonakis, Antoine Roux, Jerome Horvilleur, Babe Bakouboula, Saumil Oza, Selim Abbey, Guillaume Theodore, Antoine Lepillier, Yves Guyomar, Francis Bessiere, Jaap Jan Smit, Theophile Mohr Durdez, Paola Milpied, Anthony Appetiti, Daniel Guerrero, Tom De Potter, Christian De Chillou, Seth Goldbarg, Atul Verma, John D. Hummel, , Jaap Jan Smit, Tom De Potter, Christian De Chillou <<<

Abstract Although pulmonary vein isolation (PVI) has become the cornerstone ablation procedure for atrial fibrillation (AF), the optimal ablation procedure for persistent and long-standing persistent AF remains elusive. Targeting spatio-temporal electrogram dispersion in a tailored procedure has been suggested as a potentially beneficial alternative to a conventional PVI-only procedure. In this multicenter, randomized, controlled, double-blind, superiority trial, patients with drug-refractory persistent AF were randomly assigned to a tailored ablation procedure targeting areas of spatio-temporal dispersion, as detected by an artificial intelligence (AI) algorithm, in addition to PVI (tailored arm, n = 187, 23% women) or to a conventional PVI-only procedure (anatomical arm, n = 183, 19% women). The primary efficacy endpoint was freedom from documented AF with or without antiarrhythmic drugs at 12 months after a single ablation procedure. Secondary endpoints included freedom from any atrial arrhythmic events, and the secondary composite safety endpoint consisted of death, cerebrovascular events, or treatment-related serious adverse events. One year post-procedure, the trial met its primary efficacy endpoint, which was achieved in 88% of patients in the tailored arm compared with 70% of patients in the anatomical arm (log-rank P < 0.0001 for superiority). However, no significant difference between arms was observed for the freedom from any atrial arrhythmia endpoint after one ablation. The safety endpoint did not differ between arms, with procedure and ablation times being twice as long in the tailored arm. These results show that AI-guided ablation of spatio-temporal dispersion areas in addition to PVI is superior to PVI alone in eliminating AF at 1-year follow-up in patients with persistent and long-standing persistent AF. Ablation of subsequent organized atrial tachycardias may be needed to maintain sinus rhythm long term. ClinicalTrials.gov identifier: NCT04702451. <<<