tbuckley/cabot-search huggingface dataset:
Transposable elements may enhance antiviral resistance in HIV-1 elite controllers
Authors: Manvendra Singh, Sabrina M. Leddy, Luis Pedro Iñiguez, Matthew L. Bendall, Douglas F. Nixon, Cédric Feschotte
Journal: Genome biology (2025)

Less than 0.5% of people living with HIV-1 are elite controllers (ECs)—individuals who maintain undetectable plasma viremia without antiretroviral therapy, despite having replication-competent viral reservoirs. While EC CD4+ T cells have been investigated for gene expression signatures associated with HIV-1 resistance, the expression and regulatory activity of transposable elements (TEs) remain unexplored. TEs can directly impact host immune responses to pathogens, including HIV-1, suggesting their activities could contribute to HIV-1 elite control. To begin testing this hypothesis, we conduct a TE-centric analysis of public multi-omics data from ECs and other populations. We find the CD4+ T cell transcriptome and retrotranscriptome of ECs are distinct from healthy controls, from people living with HIV-1 on antiretroviral therapy, and from viremic progressors. However, there is substantial transcriptomic heterogeneity among ECs. We categorize ECs into four clusters with distinct expression and chromatin accessibility profiles of TEs and antiviral factors. Several TE families with known immuno-regulatory activity are differentially expressed among ECs. Their expression positively correlates with their chromatin accessibility in ECs and negatively correlates with the expression of their KRAB zinc-finger (KZNF) repressors. This coordinated, locus-level variation forms a network of putative cis-regulatory elements for genes involved in HIV-1 restriction. We propose that the EC phenotype is driven in part by reduced KZNF-mediated repression of specific TE-derived cis-regulatory elements for antiviral genes, heightening their resistance against HIV-1. Our study reveals heterogeneity in the EC CD4+ T cell transcriptome, including variable expression of TEs and their KZNF controllers, that must be considered when deciphering HIV-1 control mechanisms.
In-hospital outcomes and 6-month follow-up results of patients supported with extracorporeal membrane oxygenation for COVID-19 from the second wave to the end of the pandemic (EuroECMO-COVID): a prospective, international, multicentre, observational study
Authors: Maria Elena De Piero, Silvia Mariani, Bas C T van Bussel, Dominik Jarczak, Niklas Krenner, Enrique Perez de la Sota, Pedro E Silva, Magdalena Roemmer, Mariusz Kowalewski, Simone Carelli, Lars Mikael Broman, Alain Vuylsteke, Philip Fortuna, Francesco Alessandri, Gennaro Martucci, Brijesh V Patel, Gosta Lotz, Udo Boeken, Sven Maier, Bursa Filip, Bart Meyns, Matthias Haenggi, Severin Puss, Peter Schellongowski, Kaan Kirali, Gil Bolotin, Nicholas Barrett, Jordi Riera, Thomas Mueller, Jan Belohlavek, Roberto Lorusso
Journal: The Lancet Respiratory Medicine (2025)
Characterisation of MRGPRX2<sup>+</sup>mast cells in irritable bowel syndrome
Authors: Lisse Decraecker, María Cuende Estévez, Samuel Van Remoortel, Runze Quan, Nathalie Stakenborg, Zheng Wang, Elisabetta De Marco, Alexandre Denadai-Souza, Maria Francesca Viola, Sonia Garcia Caraballo, Stuart Brierley, Yasuhiro Tsukimi, Gareth Hicks, Wendy Winchester, Jill Wykosky, Andrea Fanjul, Tony Gibson, Mira Wouters, Pieter Vanden Berghe, Hind Hussein, Guy Boeckxstaens
Journal: Gut (2025)

Background Mast cell activation is an important driver of abdominal pain in irritable bowel syndrome (IBS). While evidence supports the role of IgE-mediated mast cell activation in visceral pain development in IBS, the role of pseudoallergic MRGPRX2-mediated mast cell activation in this process remains unknown. Objective We investigated whether MRGPRX2-mediated mast cell activation plays a role in abdominal pain development in patients with IBS. Design MRGPRX2 expression in mast cells and other immune cells was characterised across colon layers using flow cytometry. We evaluated whether MRGPRX2 agonists trigger mast cell degranulation and transient receptor potential vanilloid 1 (TRPV1) sensitisation in healthy human colonic submucosal plexus samples using live imaging. Rectal biopsies were then collected from patients with IBS and healthy volunteers (HV) and MRGPRX2 + mast cell frequency, MRGPRX2 expression per cell, mast cell degranulation kinetics in response to MRGPRX2 agonists, MRGPRX2 agonistic activity and presence of MRGPRX2 agonists in biopsy supernatants were assessed. Results MRGPRX2 + mast cells are enriched in the submucosa and muscularis of the healthy human colon. MRGPRX2 agonists induce mast cell degranulation and TRPV1 sensitisation in the healthy colon submucosa. While the frequency of rectal MRGPRX2 + mast cells was unaltered in IBS, submucosal mast cells showed increased degranulation in response to MRGPRX2 agonists in IBS compared with HV. MRGPRX2 agonistic activity was increased in IBS rectal biopsy supernatant compared with HV, which was associated with increased levels of substance P. Conclusion The MRGPRX2 pathway is functionally upregulated in the colon of patients with IBS, supporting its role in abdominal pain in IBS.
The Kidney Transplant Fast Track (KTFT) Intervention Reduced Time to Kidney Transplant Waitlisting
Authors: Larissa Myaskovsky, Arjun L. Kalaria, Chethan M. Puttarajappa, Yue-Harn Ng, Yuridia Leyva, Yiliang Zhu, Miriam E. Velez-Bermudez, Cindy L. Bryce, Chung-Chou H. Chang, L. Ebony Boulware, Amit D. Tevar, Mary Amanda Dew
Journal: Journal of the American Society of Nephrology (2023)
Impact of Finerenone-Induced Albuminuria Reduction on CKD Outcomes in Type 2 Diabetes: A Causal Mediation Analysis
Authors: Rajiv Agarwal, Wanzhu Tu, Alfredo E. Farjat, Youssef M. Farag, Robert D. Toto, Sanjay Kaul, Robert Lawatscheck, Katja Rohwedder, Luis M. Ruilope, Peter Rossing, Bertram Pitt, Gerasimos Filippatos, Stefan D. Anker, George L. Bakris
Journal: Journal of the American Society of Nephrology (2023)
Hexasodium Fytate (SNF472) for Treatment of Calciphylaxis
Authors: Smeeta Sinha, Sagar U. Nigwekar, Lisa Gould, Thomas E. Serena, Sharon M. Moe, George R. Aronoff, Dinesh K. Chatoth, Jeffrey L. Hymes, Kevin Carroll, Gabriela Alperovich Lehrer, Laurence H. Keller, Joan Perelló, Alex Gold, Glenn Chertow
Journal: Journal of the American Society of Nephrology (2023)
MDR-101-MLK Update: Operational Immune Tolerance Achieved in Living Related HLA-Matched Kidney Transplant Recipients
Authors: Dixon Kaufman, Mark D. Stegall, Sanjeev Akkina, James B. Piper, William S. Asch, Stephan Busque, Ahmed O. Gaber, Martin L. Mai, Michael E. de Vera, Suzon Collette, Anup M. Patel, Ashesh P. Shah, Erik Stites, Lenuta Micsa, Daniel C. Brennan
Journal: Journal of the American Society of Nephrology (2023)
Results of an Exploratory and Randomized Control Study on DAPagliflozin for the Attenuation of Albuminuria in Patients with HEaRt Failure and Type 2 Diabetes Mellitus: DAPPER Study
Authors: Fumiki Yoshihara, Miki Imazu, Ichiro Sakuma, Yukio Hiroi, Hisao Hara, Osamu Okazaki, Chizuru Ishiguro, Chisato Izumi, Teruo Noguchi, Toshihiko Shiraiwa, Norio Nishioka, Kenshi Fujii, Katsuomi Iwakura, Osamu Tomonaga, Koichi Kobayashi, Masahiro Takihata, Kazuhiko Yumoto, Hiroyuki Takase, Toshiharu Himi, Masanori Asakura, Takanori Kawabata, Katsuhiro Omae, Shin Ito, Masafumi Kitakaze
Journal: Journal of the American Society of Nephrology (2023)
Hemodialysis Vascular Access Complications: Insights from the ASCEND-D Trial
Authors: Renato D. Lopes, Aleix Cases, Brian Claggett, Laura M. Dember, Nisha Bhatt, Angela R. Jones-Leone, Amy M. Meadowcroft, Mary O. Muoneke, Prerna Ranganathan, Lin Taft, Ajay K. Singh
Journal: Journal of the American Society of Nephrology (2023)
Efficacy and Safety of Sotagliflozin in Patients with Type 1 Diabetes and CKD
Authors: Vikas Sridhar, Ayodele Odutayo, Satish K. Garg, Thomas Danne, Alessandro Doria, Michael Mauer, Michael J. Davies, Phillip Banks, Manon Girard, David Cherney
Journal: Journal of the American Society of Nephrology (2023)
Short- and Long-Term Effectiveness of Existing Insomnia Therapies for Patients Undergoing Hemodialysis (SLEEP-HD)
Authors: Rajnish Mehrotra, Daniel Cukor, Susan M. Mccurry, Tessa Rue, Maria-Eleni Roumelioti, Patrick J. Heagerty, Mark L. Unruh
Journal: Journal of the American Society of Nephrology (2023)
Exploring the Pharmacokinetics, Pharmacodynamics, and Safety of Apixaban in Hemodiafiltration: Insights from the HEMOCIONA Study
Authors: Miguel Hueso, Aurema Otero, Elena Rosselló-Palmer, Juan Peris Vidal, Sergi Codina Sanchez, Yurema Martínez Vilar, Raúl Rigo-Bonnin, Nuria Lloberas, Sebastián Videla Cés
Journal: Journal of the American Society of Nephrology (2023)
Results of a Randomized Placebo-Controlled Double-Blind Adaptive Phase 2 Study (AKITA) Evaluating RMC-035 for the Prevention of AKI in Patients Undergoing Cardiac Surgery
Authors: Alexander Zarbock, Jay L. Koyner, Andreas Boening, Daniel Engelman, Claudio Ronco, Michael Reusch, Tobias Agervald
Journal: Journal of the American Society of Nephrology (2023)
Graft Function and Other Outcomes in Kidney Transplant Recipients Converting from Immediate-Release to Prolonged-Release Tacrolimus
Authors: Bernhard K. Krämer, Nassim Kamar, László Kóbori, Mathilde Lemoine, Balazs Nemes, Su Hyung Lee, Hai An P. Ha, Yoshihiko Watarai, Jaeseok Yang, Seungyeup Han, Dirk R. Kuypers, Martin Blogg, Alexander Harkavyi, Carola Repetur, Ludmila Scrine, Mohamed Soliman
Journal: Journal of the American Society of Nephrology (2023)
Effect of Curcumin on Vascular and Cognitive Function in CKD: A Randomized Controlled Trial
Authors: Colin J. Gimblet, Nicholas T. Kruse, Katharine M. Geasland, Jeni Michelson, Mingyao Sun, Patrick Ten Eyck, Meenakshi Sambharia, Matthew Rossman, Carinda Linkenmeyer, Manjula Tamura, Michel Chonchol, Douglas R. Seals, Karin Hoth, Diana I. Jalal
Journal: Journal of the American Society of Nephrology (2023)
Multicentre randomised controlled trial of a self-assembling haemostatic gel to prevent delayed bleeding following endoscopic mucosal resection (PURPLE Trial)
Authors: Jan Drews, Markus Zachäus, Tobias Kleemann, Jörg Schirra, Oscar Cahyadi, Oliver Möschler, Christian Schulze, Ingo Steinbrück, Edris Wedi, Oliver Pech, Tobias J Weismüller, Armin Küllmer, Mohamed Abdelhafez, Jochen Wedemeyer, Torsten Beyna, Julian Riedel, Ulrich Paul Halm, Carola Güther, Riccardo Vasapolli, Christian Torres Reyes, Daniel R Quast, Oliver Bachmann, Erini Dedonaki, Jörg Ulrich, Inna Marchuk, Christina Frahm, Tanja Steffen, Peter Wohlmuth, Torsten Bunde, Nele Geßler, Thomas von Hahn
Journal: Gut (2025)

Background Prophylactic application of a haemostatic gel to the resection field may be an easy way to prevent delayed bleeding, a frequent complication after endoscopic mucosal resection (EMR). Objective We aimed to evaluate if the prophylactic application of a haemostatic gel to the resection field directly after EMR can reduce the rate of clinically significant delayed bleeding events. Design We conducted a prospective randomised trial of patients undergoing hot-snare EMR of flat lesions in the duodenum (≥10 mm) and colorectum (≥20 mm) at 15 German centres. Prophylactic clip closure was not allowed, but selective clipping or coagulation could be used prior to randomisation to treat intraprocedural bleeding or for prophylactic closure of visible vessels. Patients were randomised to haemostatic gel application or no prophylaxis. The primary endpoint was delayed bleeding within 30 days. Results The trial was stopped early due to futility after an interim analysis. The primary endpoint was analysed in 232 patients (208 colorectal, 26 duodenal). Both groups were comparable in age, sex, comorbidities and lesion characteristics. Preventive measures, such as selective clipping or coagulation, were applied prior to randomisation in 51.9% of cases, with no difference between groups. Delayed bleeding occurred in 14 cases (11.7%; 95% CI 7.1% to 18.6%) after Purastat and in 7 cases (6.3%; 95% CI 3.1% to 12.3%) in the control group (p=0.227), with no difference between colorectal and duodenal subgroups. Conclusion The application of a haemostatic gel following EMR of large flat lesions in the duodenum and colorectum does not reduce the rate of delayed bleeding.
RNA-based therapies in liver metabolic diseases
Authors: Antonio Fontanellas, Pedro Berraondo, Francesco Urigo, Daniel Jericó, Paolo G V Martini, Fernando Pastor, Matias A Avila
Journal: Gut (2025)

RNA-based therapeutics have rapidly emerged over the past decade, offering a new class of medicines that differ significantly from conventional drugs. These therapies can be programmed to target or restore defective genes, allowing for more personalised treatments and reducing side effects. Notably, RNA therapies have made significant progress in the treatment of genetic liver diseases, exemplified by small interfering RNA treatments for hereditary transthyretin amyloidosis, which use liver-targeting strategies such as GalNAc conjugation to improve efficacy and safety. RNA-based gene-editing technologies, such as base editor and prime editor clustered regularly interspaced short palindromic repeats systems, also show promise with their ability to minimise genomic rearrangements and cancer risk. While RNA therapies offer high precision, challenges remain in optimising delivery methods and ensuring long-term safety and efficacy. Lipid nanoparticle-mRNA therapeutics, particularly for protein replacement in rare diseases, have gained support from preclinical successes. Compared with viral gene therapies, mRNA therapies present a safer profile with reduced risks of genomic integration and oncogene activation. However, clinical trials, especially for rare diseases, face limitations such as small sample sizes and short observation periods. Further preclinical studies, including non-human primates, will be essential for refining trial designs. Despite their potential, the high costs of RNA therapies pose a challenge that will require cost–utility models to guide pricing and accessibility. Here, we discuss the fundamental aspects of RNA-based therapeutics and showcase the most relevant preclinical and clinical developments in genetic liver metabolic diseases.
Repurposing verteporfin and hyaluronic acid gel for ocular surface treatment to prevent corneal scarring
Authors: Fang Chen, Nae-Won Kang, Thitima Wungcharoen, Li Jiang, Chris Basco, Julian Garcia-Sanchez, Danting Lin, Youngyoon Amy Seo, Kyeongwoo Jang, David Myung, Wendy W Liu
Journal: Journal of Controlled Release (2025)
Optimizing peptide nucleic acid-based pretargeting for enhanced targeted radionuclide therapy
Authors: Mohamed Altai, Ábel Nagy, Pauline Granit, Wahed Zedan, Myriam Cerezo-Magaña, Julie Park, Katharina Lückerath, Susanne Geres, Marie Sydoff, Daniel L J Thorek, Kristina Westerlund, David Ulmert, Amelie Eriksson Karlström
Journal: Journal of Controlled Release (2025)
RBM10 loss promotes metastases by aberrant splicing of cytoskeletal and extracellular matrix mRNAs
Authors: Gnana P. Krishnamoorthy, Anthony R. Glover, Brian R. Untch, Nickole Sigcha-Coello, Bin Xu, Dina Vukel, Yi Liu, Vera Tiedje, Jose Mario Bello Pineda, Katherine Berman, Prasanna P. Tamarapu, Adrian Acuña-Ruiz, Mahesh Saqcena, Elisa de Stanchina, Laura Boucai, Ronald A. Ghossein, Jeffrey A. Knauf, Omar Abdel-Wahab, Robert K. Bradley, James A. Fagin
Journal: The Journal of Experimental Medicine (2025)

RBM10 modulates transcriptome-wide cassette exon splicing. Loss-of-function RBM10 mutations are enriched in thyroid cancers with distant metastases. Analysis of transcriptomes and genes mis-spliced by RBM10 loss showed pro-migratory and RHO/RAC signaling signatures. RBM10 loss increases cell velocity. Cytoskeletal and ECM transcripts subject to exon inclusion events included vinculin (VCL), tenascin C (TNC), and CD44. Knockdown of the VCL exon inclusion transcript in RBM10-null cells reduced cell velocity, whereas knockdown of TNC and CD44 exon inclusion isoforms reduced invasiveness. RAC1-GTP levels were increased in RBM10-null cells. Mouse HrasG12V/Rbm1OKO thyrocytes develop metastases that are reversed by RBM10 expression or by combined knockdown of VCL, CD44, and TNC inclusion isoforms. Thus, RBM10 loss generates exon inclusion in transcripts regulating ECM–cytoskeletal interactions, leading to RAC1 activation and metastatic competency. Moreover, a CRISPR-Cas9 screen for synthetic lethality with RBM10 loss identified NFκB effectors as central to viability, providing a therapeutic target for these lethal thyroid cancers.
Germline pathogenic DROSHA variants are linked to pineoblastoma and Wilms tumor predisposition
Authors: Peter N. Fiorica, Lisa Golmard, Jung Kim, Riyue Bao, Frank Y. Lin, Angshumoy Roy, Allison Pribnow, Melissa R. Perrino, Julien Masliah-Planchon, Sophie Michalak-Provost, Jennifer Wong, Mathilde Filser, Dominique Stoppa-Lyonnet, Franck Bourdeaut, Afane Brahimi, Olivier Ingster, Giselle Saulnier Sholler, Sarah A. Jackson, Mark M. Sasaki, Trent Fowler, Anita Ng, Ryan J. Corbett, Rebecca S. Kaufman, Jeremy S. Haley, David J. Carey, Kuan-lin Huang, Sharon J. Diskin, Jo Lynne Rokita, Hussam Al-Kateb, Rose B. McGee, Joshua D. Schiffman, Kenneth S. Chen, Douglas R. Stewart, D. Williams Parsons, Sharon E. Plon, Kris Ann P. Schultz, Kenan Onel
Journal: Clinical Cancer Research (2025)

Abstract Purpose: DROSHA, DGCR8, and DICER1 regulate microRNA biogenesis and are commonly mutated in cancer. Whereas DGCR8 and DICER1 germline pathogenic variants (GPVs) cause autosomal dominant tumor predisposition, no association between DROSHA GPVs and clinical phenotypes has been reported. Experimental Design: After obtaining informed consent, sequencing was performed on germline and tumor samples from all patients. The occurrence of germline DROSHA GPVs was investigated in large pediatric and adult cancer datasets. The population prevalence of DROSHA GPVs was investigated in the UK Biobank and Geisinger DiscovEHR cohorts. Results: We describe nine children from eight families with heterozygous DROSHA GPVs and a diagnosis of pineoblastoma (n=8) or Wilms tumor (WT, n=1). A somatic second hit in DROSHA was detected in all eight tumors analyzed. All pineoblastoma tumors analyzed were classified as miRNA processing altered-1 (PB-miRNA1) subtype. We estimate the population prevalence of germline DROSHA loss-of-function variants to be 1:3,875-1:4,843, but find no evidence for increased adult cancer risk. Conclusions: This is the first report of DROSHA-related tumor predisposition. As pineoblastoma and WT are also associated with DICER1 GPVs, our results suggest the tissues-of-origin for these tumors are uniquely tolerant of general microRNA loss. The PB-miRNA1 pineoblastoma subtype is associated with older age of diagnosis and better outcome than other subtypes, suggesting DROSHA GPV status may have important clinical and prognostic significance. We suggest genetic testing for DROSHA GPVs be considered for patients with pineoblastoma, WT, or other DICER1/DGCR8-related conditions and propose surveillance recommendations through research studies for individuals with DROSHA GPVs.
Plain versus drug balloon and stenting in severe ischaemia of the leg (BASIL-3): open label, three arm, randomised, multicentre, phase 3 trial
Authors: Andrew W Bradbury, Jack A Hall, Matthew A Popplewell, Lewis Meecham, Gareth R Bate, Lisa Kelly, Jon J Deeks, Catherine A Moakes
Journal: BMJ (2025)

Abstract Objective To determine which primary endovascular revascularisation strategy represents the most clinically effective treatment for patients with chronic limb threatening ischaemia who require endovascular femoro-popliteal, with or without infra-popliteal, revascularisation. Design Three arm, open label, pragmatic, multicentre, randomised, phase 3 superiority trial (BASIL-3). Setting 35 UK NHS vascular units. Participants Patients with chronic limb threatening ischaemia who required endovascular femoro-popliteal, with or without infra-popliteal, revascularisation. Interventions Participants were randomly assigned (1:1:1) to femoro-popliteal plain balloon angioplasty with or without bare metal stenting (PBA±BMS), drug coated balloon angioplasty with or without bare metal stenting (DCBA±BMS), or drug eluting stenting (DES) as their first revascularisation strategy. Main outcome measures The primary outcome was amputation free survival defined as time to first major amputation or death from any cause. Secondary outcomes included the composite components of the primary outcome, major adverse limb events, major adverse cardiac events, and other prespecified clinical and patient reported outcome measures. Serious adverse events were collected up to 30 days after the first revascularisation procedure. Results Between 29 January 2016 and 31 August 2021, 481 participants were randomised (167 (35%) women, mean age 71.8 years (standard deviation 10.8)). Major amputation or death occurred in 106 of 160 (66%) participants in the PBA±BMS group, 97 of 161 (60%) in the DCBA±BMS group, and 93 of 159 (58%) in the DES group (adjusted hazard ratios: PBA±BMS v DCBA±BMS: 0.84, 97.5% confidence interval 0.61 to 1.16, P=0.22; PBA±BMS v DES: 0.83, 0.60 to 1.15, P=0.20). No differences in serious adverse events were reported between the groups. Conclusions Neither DCBA±BMS nor DES conferred significant clinical benefit over PBA±BMS in the femoro-popliteal segment in patients with chronic limb threatening ischaemia undergoing endovascular femoro-popliteal, with or without infra-popliteal, revascularisation. Trial registration ISRCTN registry ISRCTN14469736
Presence of tertiary lymphoid structures and exhausted tissue-resident T cells determines clinical response to PD-1 blockade in renal cell carcinoma
Authors: Miya B. Hugaboom, Lena V. Wirth, Kelly Street, Neil Ruthen, Opeyemi A. Jegede, Nicholas R. Schindler, Valisha Shah, Jacob P. Zaemes, Nourhan El Ahmar, Sayed Matar, Varunika Savla, Toni K. Choueiri, Thomas Denize, Destiny J. West, David F. McDermott, Elizabeth R. Plimack, Jeffrey A. Sosman, Naomi B. Haas, Mark N. Stein, Robert Alter, Mehmet A. Bilen, Michael E. Hurwitz, Hans Hammers, Sabina Signoretti, Michael B. Atkins, Catherine J. Wu, David A. Braun
Journal: Cancer Discovery (2025)

Abstract Immune checkpoint inhibitors (ICI) targeting the PD-1 pathway have transformed treatment of advanced renal cell carcinoma (RCC), but mechanisms underlying therapeutic response remain largely unknown. Herein, we perform transcriptomic analysis on RCC biospecimens from 102 patients enrolled in a phase II clinical trial of frontline nivolumab (NCT03117309) to investigate determinants of response to anti-PD1 monotherapy. Through bulk analysis, we identify an enrichment of genes associated with tertiary lymphoid structures (TLS) in responding patients. Using single-cell transcriptomics and external cohort validation, we identify a population of tissue-resident (ZNF683+ SLAMF7+) exhausted CD8+ T cells enriched in patients with poor clinical outcomes. Integrating these findings, we find tumors with high TLS and low tissue-resident exhausted CD8+ T cells have superior clinical outcomes with nivolumab. Altogether, these analyses contribute to a growing understanding of how the tumor microenvironment drives ICI- resistance and propose possible therapeutic targets to rationally overcome resistance to anti-PD1 monotherapy.