tbuckley/cabot-search huggingface dataset:
EULAR/PReS recommendations for the diagnosis and management of Still’s disease, comprising systemic juvenile idiopathic arthritis and adult-onset Still’s disease
Authors: Bruno Fautrel, Stéphane Mitrovic, Arianna De Matteis, Sara Bindoli, Jordi Antón, Alexandre Belot, Claudia Bracaglia, Tamàs Constantin, Lorenzo Dagna, Alessandro Di Bartolo, Eugen Feist, Dirk Foell, Marco Gattorno, Sophie Georgin-Lavialle, Roberto Giacomelli, Alexei A Grom, Yvan Jamilloux, Katerina Laskari, Calin Lazar, Francesca Minoia, Peter A Nigrovic, Filipa Oliveira Ramos, Seza Ozen, Pierre Quartier, Piero Ruscitti, Erdal Sag, Sinisa Savic, Marie-Elise Truchetet, Sebastiaan J Vastert, Tanita-Christina Wilhelmer, Carine Wouters, Loreto Carmona, Fabrizio De Benedetti
Journal: Annals of the Rheumatic Diseases (2024)

Systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD) are considered the same disease, but a common approach for diagnosis and management is still missing. In May 2022, EULAR and PReS endorsed a proposal for a joint task force (TF) to develop recommendations for the diagnosis and management of sJIA and AOSD. The TF agreed during a first meeting to address four topics: similarity between sJIA and AOSD, diagnostic biomarkers, therapeutic targets and strategies and complications including macrophage activation syndrome (MAS). Systematic literature reviews were conducted accordingly. The TF based their recommendations on four overarching principles, highlighting notably that sJIA and AOSD are one disease, to be designated by one name, Still's disease.Fourteen specific recommendations were issued. Two therapeutic targets were defined: clinically inactive disease (CID) and remission, that is, CID maintained for at least 6 months. The optimal therapeutic strategy relies on early use of interleukin (IL-1 or IL-6 inhibitors associated to short duration glucocorticoid (GC). MAS treatment should rely on high-dose GCs, IL-1 inhibitors, ciclosporin and interferon-γ inhibitors. A specific concern rose recently with cases of severe lung disease in children with Still's disease, for which T cell directed immunosuppressant are suggested. The recommendations emphasised the key role of expert centres for difficult-to-treat patients. All overarching principles and recommendations were agreed by over 80% of the TF experts with a high level of agreement. These recommendations are the first consensus for the diagnosis and management of children and adults with Still's disease.
Implications of the 2022 lung function update and GLI global reference equations among patients with interstitial lung disease
Authors: Andrew Li, Alan Teoh, Lauren Troy, Ian Glaspole, Margaret L Wilsher, Sally de Boer, Jeremy Wrobel, Yuben P Moodley, Francis Thien, Henry Gallagher, Michelle Galbraith, Daniel C Chambers, John Mackintosh, Nicole Goh, Yet Hong Khor, Adrienne Edwards, Karen Royals, Christopher Grainge, Benjamin Kwan, Gregory J Keir, Chong Ong, Paul N Reynolds, Elizabeth Veitch, Gin Tsen Chai, Ziqin Ng, Geak Poh Tan, Dan Jackson, Tamera Corte, Helen Jo
Journal: Thorax (2024)

Lung function testing remains a cornerstone in the assessment and management of interstitial lung disease (ILD) patients. The clinical implications of the Global Lung function Initiative (GLI) reference equations and the updated interpretation strategies remain uncertain.
The Effects of APOEe4 Allele on Cerebral Structure, Function, and Related Interactions with Cognition in Young Adults
Authors: Ludmila Kucikova, Xiong Xiong, Patricia Reinecke, Jessica Madden, Elizabeth Jackson, Oliver Tappin, Weijie Huang, Maria-Eleni Dounavi, Li Su
Journal: Ageing Research Reviews (2024)
Pharmacological regeneration of sensory hair cells restores afferent innervation and vestibular function
Authors: Hanae Lahlou, Hong Zhu, Wu Zhou, Albert Sb Edge
Journal: Journal of Clinical Investigation (2024)

The sensory cells that transduce the signals for hearing and balance are highly specialized mechanoreceptors called hair cells that reside in the sensory epithelia of the inner ear. Loss of hair cells from toxin exposure and age can cause balance disorders and is essentially irreversible due to the inability of mammalian vestibular organs to regenerate physiologically active hair cells. Here, we show substantial regeneration of hair cells in a mouse model of vestibular damage by treatment with a combination of glycogen synthase kinase 3β and histone deacetylase inhibitors. The drugs stimulated supporting cell proliferation and differentiation into hair cells. The new hair cells were reinnervated by vestibular afferent neurons, rescuing otolith function by restoring head translation-evoked otolith afferent responses and vestibuloocular reflexes. Drugs that regenerate hair cells thus represent a potential therapeutic approach to the treatment of balance disorders.
Efficacy and safety of therapies for Still’s disease and macrophage activation syndrome (MAS): a systematic review informing the EULAR/PReS guidelines for the management of Still’s disease
Authors: Sara Bindoli, Arianna De Matteis, Stéphane Mitrovic, Bruno Fautrel, Loreto Carmona, Fabrizio De Benedetti
Journal: Annals of the Rheumatic Diseases (2024)

Objectives To analyse the efficacy and safety of treatments for Still’s disease and macrophage activation syndrome (MAS). Methods Medline, Embase and Cochrane Library were searched for clinical trials (randomised, randomised controlled trial (RCT), controlled and clinical controlled trial (CCT)), observational studies (retrospective, longitudinal observational retrospective (LOR), prospective and longitudinal observational prospective (LOP)) and systematic reviews (SRs), in which the populations studied were patients with Still’s disease and MAS. The intervention was any pharmacological treatment (approved or under evaluation) versus any comparator drug or placebo, and as outcomes, any relevant efficacy and safety event. The risk of bias (RoB) was assessed with the Cochrane RoB and AMSTAR-2 (Assessing the Methodological Quality of Systematic Reviews-2, version 2) for SRs. Results 128 full texts were included: 25 RCTs, 1 CCT, 11 SRs published after 2013 and 91 LOP/LOR studies. In Still’s disease, interleukin (IL)-1 inhibitors (IL-1i) and IL-6R inhibitors (IL-6i) were the most studied drugs. Two meta-analyses on RCTs showed an OR, to achieve an ARC50 response rate, of 6.02 (95% CI 2.24 to 21.36) and 8.08 (95% CI 1.89 to 34.57) for IL-1i and IL-6Ri, respectively. Retrospective studies showed that early initiation of IL-1i or IL-6i was associated with high rates of clinically inactive disease. In MAS, GCs were employed in all patients, often associated with ciclosporin and/or anakinra. Rates of complete response were reported, with a range from 53% to 100%. Emapalumab was the only drug tested in a CCT, with a complete response of 93%. Conclusion IL-1i and IL-6Ri show the highest level of efficacy in the treatment of Still’s disease. For MAS, IL-1 and interferon-γ inhibition appear to be effective on a background of high-dose glucocorticoids.
GDF15 antagonism limits severe heart failure and prevents cardiac cachexia
Authors: Minoru Takaoka, John A Tadross, Ali B A K Al-Hadithi, Xiaohui Zhao, Rocío Villena-Gutiérrez, Jasper Tromp, Shazia Absar, Marcus Au, James Harrison, Anthony P Coll, Stefan J Marciniak, Debra Rimmington, Eduardo Oliver, Borja Ibáñez, Adriaan A Voors, Stephen O’Rahilly, Ziad Mallat, Jane C Goodall
Journal: Cardiovascular Research (2024)

Abstract Aims Heart failure and associated cachexia is an unresolved and important problem. This study aimed to determine the factors that contribute to cardiac cachexia in a new model of heart failure in mice that lack the integrated stress response (ISR) induced eIF2α phosphatase, PPP1R15A. Methods and results Mice were irradiated and reconstituted with bone marrow cells. Mice lacking functional PPP1R15A, exhibited dilated cardiomyopathy and severe weight loss following irradiation, whilst wild-type mice were unaffected. This was associated with increased expression of Gdf15 in the heart and increased levels of GDF15 in circulation. We provide evidence that the blockade of GDF15 activity prevents cachexia and slows the progression of heart failure. We also show the relevance of GDF15 to lean mass and protein intake in patients with heart failure. Conclusion Our data suggest that cardiac stress mediates a GDF15-dependent pathway that drives weight loss and worsens cardiac function. Blockade of GDF15 could constitute a novel therapeutic option to limit cardiac cachexia and improve clinical outcomes in patients with severe systolic heart failure.
An inhalable nanoparticle enabling virulence factor elimination and antibiotics delivery for pneumococcal pneumonia therapy
Authors: Huiyue Dong, Yuxin Zhao, Shihong Li, Qiongwei Wang, Mengli Li, Kaikai Zhao, Zhenzhong Zhang, Jinjin Shi, Xiu Zhao, Junjie Liu
Journal: Journal of Controlled Release (2024)
EspH utilizes phosphoinositide and Rab binding domains to interact with plasma membrane infection sites and Rab GTPases*
Authors: Ipsita Nandi, Rachana Pattani Ramachandran, Deborah E. Shalev, Dina Schneidman-Duhovny, Raisa Shtuhin-Rahav, Naomi Melamed-Book, Efrat Zlotkin-Rivkin, Alexander Rouvinski, Ilan Rosenshine, Benjamin Aroeti
Journal: Gut Microbes (2024)

Enteropathogenic
What defines a healthy gut microbiome?
Authors: Matthias Van Hul, Patrice D Cani, Camille Petitfils, Willem M De Vos, Herbert Tilg, Emad M El-Omar
Journal: Gut (2024)

The understanding that changes in microbiome composition can influence chronic human diseases and the efficiency of therapies has driven efforts to develop microbiota-centred therapies such as first and next generation probiotics, prebiotics and postbiotics, microbiota editing and faecal microbiota transplantation. Central to microbiome research is understanding how disease impacts microbiome composition and vice versa, yet there is a problematic issue with the term 'dysbiosis', which broadly links microbial imbalances to various chronic illnesses without precision or definition. Another significant issue in microbiome discussions is defining 'healthy individuals' to ascertain what characterises a healthy microbiome. This involves questioning who represents the healthiest segment of our population-whether it is those free from illnesses, athletes at peak performance, individuals living healthily through regular exercise and good nutrition or even elderly adults or centenarians who have been tested by time and achieved remarkable healthy longevity.This review advocates for delineating 'what defines a healthy microbiome?' by considering a broader range of factors related to human health and environmental influences on the microbiota. A healthy microbiome is undoubtedly linked to gut health. Nevertheless, it is very difficult to pinpoint a universally accepted definition of 'gut health' due to the complexities of measuring gut functionality besides the microbiota composition. We must take into account individual variabilities, the influence of diet, lifestyle, host and environmental factors. Moreover, the challenge in distinguishing causation from correlation between gut microbiome and overall health is presented.The review also highlights the resource-heavy nature of comprehensive gut health assessments, which hinders their practicality and broad application. Finally, we call for continued research and a nuanced approach to better understand the intricate and evolving concept of gut health, emphasising the need for more precise and inclusive definitions and methodologies in studying the microbiome.
Efficacy and Safety of Crisugabalin (HSK16149) in Adults with Postherpetic Neuralgia
Authors: Daying Zhang, Tiechi Lei, Lanying Qin, Chenyu Li, Xuewu Lin, Huiping Wang, Guoqiang Zhang, Shoumin Zhang, Kemei Shi, Linfeng Li, Zhenling Yang, Xiumin Yang, Xiaohong Ba, Ying Gao, Zhuobo Zhang, Guonian Wang, Liming Wu, Yaping Wang, Yu Wang, Shoumin Zhu, Jihai Shi, Zhijian Ye, Chunjun Yang, Changyi Liu, Tong Zhang, Shousi Lu, Nan Yu, Xiangkui Li, Xiuping Han, Xiaoyan Chen, Li Wan, Zhigang Cheng, Nianyue Bai, Zhehu Jin, Chunshui Yu, Weiyi Zhang, Jianyun Lu, Dongmei Wang, Hui Sun, Wenzhong Wu, Pingping Qin, Zhiying Feng, Rixin Chen, Tangde Zhang, Dong Yang, Wenhao Yin, Jianglin Zhang, Xin Li, Fangqiong Li, Tingting Wu, Qianjin Lu
Journal: JAMA Dermatology (2024)

Importance China carries a heavy burden of postherpetic neuralgia, with an unmet need for novel drugs with greater efficacy and less prominent neurotoxic effects than existing calcium channel ligands. Objective To investigate the efficacy and safety of crisugabalin, an oral calcium channel α2δ-1 subunit ligand, for postherpetic neuralgia. Design, Setting, and Participants This randomized clinical trial, carried out between November 9, 2021, and January 5, 2023, at 48 tertiary care centers across China had 2 parts. Part 1 was a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study consisting of a 2-week screening period, a 7-day run-in period, and a 12-week double-blind treatment period. Part 2 was a 14-week open-label extension study. Investigators, statisticians, trial clinicians, and patients were blinded to trial group assignments. Participants included adults with postherpetic neuralgia with an average daily pain score (ADPS) of at least 4 on the 11-point Numeric Pain Rating Scale over the preceding week, with the exclusion of patients with pain not controlled by prior therapy with pregabalin (≥300 mg/d) or gabapentin (≥1200 mg/d). Interventions Patients were randomized 1:1:1 to receive crisugabalin, 20 mg twice daily (ie, 40 mg/d), and crisugabalin, 40 mg twice daily (ie, 80 mg/d), or placebo for 12 weeks. Eligible patients received crisugabalin, 40 mg, twice daily during extension. Main Outcome and Measure The primary efficacy end point was the change from baseline in ADPS at week 12. Results The study enrolled 366 patients (121 patients receiving crisugabalin, 40 mg/d; 121 patients receiving crisugabalin, 80 mg/d; 124 patients receiving placebo; median [IQR] age, 63.0 [56.0-69.0] years; 193 men [52.7%]). At week 12, the least squares mean (SD) change from baseline in ADPS was −2.2 (0.2) for crisugabalin, 40 mg/d, and −2.6 (0.2) for crisugabalin, 80 mg/d, vs −1.1 (0.2) for placebo, with a least squares mean difference of −1.1 (95% CI, −1.6 to −0.7; P &amp;amp;lt; .001) and −1.5 (−95% CI, −2.0 to −1.0; P &amp;amp;lt; .001) vs placebo, respectively. No new safety concerns emerged. Conclusions and Relevance Crisugabalin, 40 mg/d, or crisugabalin, 80 mg/d, was well tolerated and demonstrated a statistically significant improvement in ADPS over placebo. Trial Registration ClinicalTrials.gov Identifier: NCT05140863
Impact of soluble BCMA and non-T-cell factors on refractoriness to BCMA-targeting T-cell engagers in multiple myeloma
Authors: Holly Lee, Michael A. Durante, Sheri Skerget, Deeksha Vishwamitra, Sacha Benaoudia, Sungwoo Ahn, Mansour Poorebrahim, Elie Barakat, David Jung, Noémie Leblay, Bachisio Ziccheddu, Benjamin T. Diamond, Marios Papadimitriou, Adam D. Cohen, Ola Landgren, Paola Neri, Francesco Maura, Nizar J. Bahlis
Journal: Blood (2024)

Adoptive T cell therapy is a promising therapy for multiple myeloma (MM), but its efficacy hinges on understanding relevant biological and predictive markers of response. B cell maturation antigen (BCMA) is a key target antigen in MM, with active development of multiple anti-BCMA T cell engagers (TCE) and chimeric antigen receptor T cell (CAR T) therapies. The regulation of surface BCMA expression by MM cells, resulting in the shedding of soluble BCMA (sBCMA), has triggered debate surrounding the significance of sBCMA as a predictive marker and its potential impact on treatment outcomes. In order to address this, we leveraged whole genome sequencing and in vitro assays to demonstrate that sBCMA may independently predict primary refractoriness to anti-BCMA therapies. In addition to sBCMA, tumor burden and surface BCMA antigen density collectively influence anti-BCMA TCE cytotoxic efficacy. Correlative analyses of 163 patients treated with anti-BCMA TCE teclistamab validated and further underscored the association between elevated baseline sBCMA (&amp;gt;400 ng/mL) and refractoriness. Importantly, increasing TCE dose, the use of TCE against alternative targets (e.g.,GPRC5D), or gamma secretase inhibitors were able to overcome high sBCMA. These findings highlight the importance of accounting for baseline sBCMA levels, disease burden, and TCE dose intensity when administering anti-BCMA TCEs, offering critical insights for optimizing therapeutic strategies to overcome specific high-risk features and primary anti-BCMA TCE refractoriness.
Avalanche Survival Rates in Switzerland, 1981-2020
Authors: Simon Rauch, Hermann Brugger, Markus Falk, Benjamin Zweifel, Giacomo Strapazzon, Roland Albrecht, Urs Pietsch
Journal: JAMA Network Open (2024)

Importance Survival probability among individuals critically buried by avalanche is highly time dependent, which was demonstrated 30 years ago. However, it remains unclear whether avalanche survival probability has changed over time. Objective To assess the avalanche survival rate and probability as well as the rescue probability over the past 4 decades. Design, Setting, and Participants In this cohort study, avalanche data from Switzerland that were collected by the WSL Institute for Snow and Avalanche Research (SLF) in Davos were analyzed from the winter beginning in 1981 to that beginning in 2020 and compared with data from the period 1981 to 1990. Data were analyzed from January to April 2024. Exposure Critical avalanche burial (ie, burial involving the head and chest). Main Outcomes and Measures Survival rate among individuals critically buried by avalanche, survival probability, and rescue probability in relation to time buried under the avalanche. Results The study included 1643 individuals critically buried by avalanche (mean [SD] age, 37 [13.7] years; 1090 of 1342 with known sex [81.2%] were male) among 3805 avalanches involving 7059 persons. Compared with the period from 1981 to 1990, the total survival rate over the full study period increased from 43.5% (95% CI, 38.8%-48.3%) to 53.4% (95% CI, 51.0%-55.8%). Survival probability remained high at 91% (95% CI, 80%-100%) for rescue during the first 10 minutes but then decreased to 31% (95% CI, 11%-51%) for rescue between 10 and 30 minutes. The survival rate among those buried long term (&amp;amp;gt;130 minutes) increased from 2.6% (95% CI, 0.7%-6.9%) to 7.3% (95% CI, 4.8%-10.7%). The median rescue time decreased from 45 (IQR, 15-148) minutes to 25 (IQR, 10-85) minutes. Survival rates among individuals rescued from avalanche by organized rescue teams increased from 14.0% (28 of 200) to 22.9% (161 of 704). Conclusions and Relevance This cohort study of 1643 individuals critically buried by avalanche found that over the past 4 decades, total survival rates considerably increased and rescue times decreased. Survival rates among those buried long term (&amp;amp;gt;130 minutes) also increased. These findings are likely attributable to collaborative efforts among stakeholders to enhance avalanche search-and-rescue techniques and medical interventions.
Predicting Suicides Among US Army Soldiers After Leaving Active Service
Authors: Chris J. Kennedy, Jaclyn C. Kearns, Joseph C. Geraci, Sarah M. Gildea, Irving H. Hwang, Andrew J. King, Howard Liu, Alex Luedtke, Brian P. Marx, Santiago Papini, Maria V. Petukhova, Nancy A. Sampson, Jordan W. Smoller, Charles J. Wolock, Nur Hani Zainal, Murray B. Stein, Robert J. Ursano, James R. Wagner, Ronald C. Kessler
Journal: JAMA Psychiatry (2024)

Importance The suicide rate of military servicemembers increases sharply after returning to civilian life. Identifying high-risk servicemembers before they leave service could help target preventive interventions. Objective To develop a model based on administrative data for regular US Army soldiers that can predict suicides 1 to 120 months after leaving active service. Design, Setting, and Participants In this prognostic study, a consolidated administrative database was created for all regular US Army soldiers who left service from 2010 through 2019. Machine learning models were trained to predict suicides over the next 1 to 120 months in a random 70% training sample. Validation was implemented in the remaining 30%. Data were analyzed from March 2023 through March 2024. Main outcome and measures The outcome was suicide in the National Death Index. Predictors came from administrative records available before leaving service on sociodemographics, Army career characteristics, psychopathologic risk factors, indicators of physical health, social networks and supports, and stressors. Results Of the 800 579 soldiers in the cohort (84.9% male; median [IQR] age at discharge, 26 [23-33] years), 2084 suicides had occurred as of December 31, 2019 (51.6 per 100 000 person-years). A lasso model assuming consistent slopes over time discriminated as well over all but the shortest risk horizons as more complex stacked generalization ensemble machine learning models. Test sample area under the receiver operating characteristic curve ranged from 0.87 (SE = 0.06) for suicides in the first month after leaving service to 0.72 (SE = 0.003) for suicides over 120 months. The 10% of soldiers with highest predicted risk accounted for between 30.7% (SE = 1.8) and 46.6% (SE = 6.6) of all suicides across horizons. Calibration was for the most part better for the lasso model than the super learner model (both estimated over 120-month horizons.) Net benefit of a model-informed prevention strategy was positive compared with intervene-with-all or intervene-with-none strategies over a range of plausible intervention thresholds. Sociodemographics, Army career characteristics, and psychopathologic risk factors were the most important classes of predictors. Conclusions and relevance These results demonstrated that a model based on administrative variables available at the time of leaving active Army service can predict suicides with meaningful accuracy over the subsequent decade. However, final determination of cost-effectiveness would require information beyond the scope of this report about intervention content, costs, and effects over relevant horizons in relation to the monetary value placed on preventing suicides.