tbuckley/cabot-search huggingface dataset:
The effect of high altitude (2500 m) on incremental cycling exercise in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: a randomised controlled cross-over trial
Authors: Julian Müller, Anna Titz, Simon R. Schneider, Meret Bauer, Laura Mayer, Lea Lüönd, Tanja Ulrich, Michael Furian, Aglaia Forrer, Esther I. Schwarz, Konrad E. Bloch, Mona Lichtblau, Silvia Ulrich
Journal: European Respiratory Journal (2024)

Objective To investigate the effect of a daylong exposure to high altitude on peak exercise capacity and safety in stable patients with pulmonary arterial and chronic thromboembolic pulmonary hypertension (PAH/CTEPH). Methods In a randomised controlled cross-over trial, stable patients with PAH or distal CTEPH without resting hypoxemia at low altitude performed two incremental exercise tests to exhaustion, one after 3–5 h at high (2500 m) and one at low altitude (470 m). Results In 27 patients with PAH/CTEPH (44% women, 61±14 y), maximal work-rate was 110±64 watts at 2500 m and 123±64 watts at 470 m (−11%, 95%CI: −16 to −11, p&lt;0.001). SpO 2 and PaO 2 at end-exercise were 83±6% versus 91±6% and 6.1±1.9 kPa versus 8.6±1.9 kPa (−8%; −29%; both p&lt;0.001) at 2500 m versus 470 m, respectively. Maximal oxygen uptake at high altitude was 17.8±7.5 L·min −1 ·kg −1 versus 20±7.4 L·min −1 ·kg −1 at low altitude (−11%, p&lt;0.001). At end-exercise, the ventilatory equivalent for CO 2 was 43±9 at 2500 m versus 39±9 at 470 m (+9%, 95%CI: 2 to 6; p=0.002). No adverse events occurred during or after exercise. Conclusion Among predominantly low-risk patients with stable PAH/CTEPH, cycling exercise during the first day at 2500 m was well tolerated, but peak exercise capacity, blood oxygenation and ventilatory efficiency were lower compared to 470 m.
Revised ISHAM-ABPA working group clinical practice guidelines for diagnosing, classifying and treating allergic bronchopulmonary aspergillosis/mycoses
Authors: Ritesh Agarwal, Inderpaul Singh Sehgal, Valliappan Muthu, David W. Denning, Arunaloke Chakrabarti, Kathirvel Soundappan, Mandeep Garg, Shivaprakash M. Rudramurthy, Sahajal Dhooria, Darius Armstrong-James, Koichiro Asano, Jean-Pierre Gangneux, Sanjay H. Chotirmall, Helmut J.F. Salzer, James D. Chalmers, Cendrine Godet, Marcus Joest, Iain Page, Parameswaran Nair, P. Arjun, Raja Dhar, Kana Ram Jat, Geethu Joe, Uma Maheswari Krishnaswamy, Joseph L. Mathew, Venkata Nagarjuna Maturu, Anant Mohan, Alok Nath, Dharmesh Patel, Jayanthi Savio, Puneet Saxena, Rajeev Soman, Balamugesh Thangakunam, Caroline G. Baxter, Felix Bongomin, William J. Calhoun, Oliver A. Cornely, Jo A. Douglass, Chris Kosmidis, Jacques F. Meis, Richard Moss, Alessandro C. Pasqualotto, Danila Seidel, Rosanne Sprute, Kuruswamy Thurai Prasad, Ashutosh N. Aggarwal
Journal: European Respiratory Journal (2024)

Background The International Society for Human and Animal Mycology (ISHAM) working group proposed recommendations for managing allergic bronchopulmonary aspergillosis (ABPA) a decade ago. There is a need to update these recommendations due to advances in diagnostics and therapeutics. Methods An international expert group was convened to develop guidelines for managing ABPA (caused by Aspergillus spp.) and allergic bronchopulmonary mycosis (ABPM; caused by fungi other than Aspergillus spp.) in adults and children using a modified Delphi method (two online rounds and one in-person meeting). We defined consensus as ≥70% agreement or disagreement. The terms “recommend” and “suggest” are used when the consensus was ≥70% and &lt;70%, respectively. Results We recommend screening for A. fumigatus sensitisation using fungus-specific IgE in all newly diagnosed asthmatic adults at tertiary care but only difficult-to-treat asthmatic children. We recommend diagnosing ABPA in those with predisposing conditions or compatible clinico-radiological presentation, with a mandatory demonstration of fungal sensitisation and serum total IgE ≥500 IU·mL −1 and two of the following: fungal-specific IgG, peripheral blood eosinophilia or suggestive imaging. ABPM is considered in those with an ABPA-like presentation but normal A. fumigatus -IgE. Additionally, diagnosing ABPM requires repeated growth of the causative fungus from sputum. We do not routinely recommend treating asymptomatic ABPA patients. We recommend oral prednisolone or itraconazole monotherapy for treating acute ABPA (newly diagnosed or exacerbation), with prednisolone and itraconazole combination only for treating recurrent ABPA exacerbations. We have devised an objective multidimensional criterion to assess treatment response. Conclusion We have framed consensus guidelines for diagnosing, classifying and treating ABPA/M for patient care and research.
Dual T-cell constant β chain (TRBC)1 and TRBC2 staining for the identification of T-cell neoplasms by flow cytometry
Authors: Pedro Horna, Matthew J. Weybright, Mathieu Ferrari, Dennis Jungherz, YaYi Peng, Zulaikha Akbar, F. Tudor Ilca, Gregory E. Otteson, Jansen N. Seheult, Janosch Ortmann, Min Shi, Paul M. Maciocia, Marco Herling, Martin A. Pule, Horatiu Olteanu
Journal: Blood Cancer Journal (2024)

Abstract The diagnosis of leukemic T-cell malignancies is often challenging, due to overlapping features with reactive T-cells and limitations of currently available T-cell clonality assays. Recently developed therapeutic antibodies specific for the mutually exclusive T-cell receptor constant β chain (TRBC)1 and TRBC2 isoforms provide a unique opportunity to assess for TRBC-restriction as a surrogate of clonality in the flow cytometric analysis of T-cell neoplasms. To demonstrate the diagnostic utility of this approach, we studied 164 clinical specimens with (60) or without (104) T-cell neoplasia, in addition to 39 blood samples from healthy donors. Dual TRBC1 and TRBC2 expression was studied within a comprehensive T-cell panel, in a fashion similar to the routine evaluation of kappa and lambda immunoglobulin light chains for the detection of clonal B-cells. Polytypic TRBC expression was demonstrated on total, CD4 + and CD8 + T-cells from all healthy donors; and by intracellular staining on benign T-cell precursors. All neoplastic T-cells were TRBC-restricted, except for 8 cases (13%) lacking TRBC expression. T-cell clones of uncertain significance were identified in 17 samples without T-cell malignancy (13%) and accounted for smaller subsets than neoplastic clones (median: 4.7 vs. 69% of lymphocytes, p &lt; 0.0001). Single staining for TRBC1 produced spurious TRBC1-dim subsets in 24 clinical specimens (15%), all of which resolved with dual TRBC1/2 staining. Assessment of TRBC restriction by flow cytometry provides a rapid diagnostic method to detect clonal T-cells, and to accurately determine the targetable TRBC isoform expressed by T-cell malignancies.
Targeted deletion of CD244 on monocytes promotes differentiation into anti-tumorigenic macrophages and potentiates PD-L1 blockade in melanoma
Authors: Jeongsoo Kim, Tae-Jin Kim, Sehyun Chae, Hyojeong Ha, Yejin Park, Sunghee Park, Chul Joo Yoon, Seon Ah Lim, Hyemin Lee, Jiyoung Kim, Jungwon Kim, Kyungtaek Im, Kyunghye Lee, Jeongmin Kim, Daham Kim, Eunju Lee, Min Hwa Shin, Serk In Park, Inmoo Rhee, Keehoon Jung, Jeewon Lee, Keun Hwa Lee, Daehee Hwang, Kyung-Mi Lee
Journal: Molecular Cancer (2024)

In the myeloid compartment of the tumor microenvironment, CD244 signaling has been implicated in immunosuppressive phenotype of monocytes. However, the precise molecular mechanism and contribution of CD244 to tumor immunity in monocytes/macrophages remains elusive due to the co-existing lymphoid cells expressing CD244.
circFAM193B interaction with PRMT6 regulates AML leukemia stem cells chemoresistance through altering the oxidative metabolism and lipid peroxidation
Authors: Xinyu Yang, Jinting Liu, Wancheng Liu, Hanyang Wu, Yihong Wei, Xiaodong Guo, Hexiao Jia, Can Can, Dongmei Wang, Xiang Hu, Daoxin Ma
Journal: Leukemia (2024)
From ether to ethernet: ensuring ethical policy in digital transformation of waitlist triage for cardiovascular procedures
Authors: Mihir A. Kelshiker, Karanjot Chhatwal, Patrik Bachtiger, Josephine Mansell, Nicholas S. Peters, Daniel B. Kramer
Journal: npj Digital Medicine (2024)

Cardiovascular disease remains the leading cause of death in both the United Kingdom (UK) and worldwide 1 .For several coronary and valvular conditions, timely surgical or catheter-based interventions improve survival and quality of life 2,3 .Yet the UK National Health Service (NHS) faces an unprecedented backlog of over 370,000 patients (in a population of 67 million) awaiting critical cardiac procedures, leading to over 30,000 excess deaths 4 .In this Comment, we describe a novel strategy for digitally-supported prioritization for critical cardiovascular procedures.We then examine potential ethical concerns in this new clinical and population health pathway and evaluate programmatic features that may address these hazards while promoting effective technology adoption within the service provision for these most vulnerable patients.
Updated overall survival and circulating tumor DNA analysis of ensartinib for crizotinib‐refractory <i>ALK</i>‐positive NSCLC from a phase II study
Authors: Jing Zheng, Tao Wang, Yunpeng Yang, Jie Huang, Jifeng Feng, Wu Zhuang, Jianhua Chen, Jun Zhao, Wei Zhong, Yanqiu Zhao, Yiping Zhang, Yong Song, Yi Hu, Zhuang Yu, Youling Gong, Yuan Chen, Feng Ye, Shucai Zhang, Lejie Cao, Yun Fan, Gang Wu, Yubiao Guo, Chengzhi Zhou, Kewei Ma, Jian Fang, Weineng Feng, Yunpeng Liu, Zhendong Zheng, Gaofeng Li, Huijie Wang, Shundong Cang, Ning Wu, Wei Song, Xiaoqing Liu, Shijun Zhao, Lieming Ding, Giovanni Selvaggi, Yang Wang, Shanshan Xiao, Qian Wang, Zhilin Shen, Jianya Zhou, Jianying Zhou, Li Zhang
Journal: Cancer Communications (2024)

Abstract Background The initial phase II stuty (NCT03215693) demonstrated that ensartinib has shown clinical activity in patients with advanced crizotinib‐refractory, anaplastic lymphoma kinase ( ALK )‐positive non‐small cell lung cancer (NSCLC). Herein, we reported the updated data on overall survival (OS) and molecular profiling from the initial phase II study. Methods In this study, 180 patients received 225 mg of ensartinib orally once daily until disease progression, death or withdrawal. OS was estimated by Kaplan‒Meier methods with two‐sided 95% confidence intervals (CIs). Next‐generation sequencing was employed to explore prognostic biomarkers based on plasma samples collected at baseline and after initiating ensartinib. Circulating tumor DNA (ctDNA) was detected to dynamically monitor the genomic alternations during treatment and indicate the existence of molecular residual disease, facilitating improvement of clinical management. Results At the data cut‐off date (August 31, 2022), with a median follow‐up time of 53.2 months, 97 of 180 (53.9%) patients had died. The median OS was 42.8 months (95% CI: 29.3‐53.2 months). A total of 333 plasma samples from 168 patients were included for ctDNA analysis. An inferior OS correlated significantly with baseline ALK or tumor protein 53 ( TP53 ) mutation. In addition, patients with concurrent TP53 mutations had shorter OS than those without concurrent TP53 mutations. High ctDNA levels evaluated by variant allele frequency (VAF) and haploid genome equivalents per milliliter of plasma (hGE/mL) at baseline were associated with poor OS. Additionally, patients with ctDNA clearance at 6 weeks and slow ascent growth had dramatically longer OS than those with ctDNA residual and fast ascent growth, respectively. Furthermore, patients who had a lower tumor burden, as evaluated by the diameter of target lesions, had a longer OS. Multivariate Cox regression analysis further uncovered the independent prognostic values of bone metastases, higher hGE, and elevated ALK mutation abundance at 6 weeks. Conclusion Ensartinib led to a favorable OS in patients with advanced, crizotinib‐resistant, and ALK ‐positive NSCLC. Quantification of ctDNA levels also provided valuable prognostic information for risk stratification.
Nucleic acid therapeutics as differentiation agents for myeloid leukemias
Authors: Olivia Kovecses, François E. Mercier, Maureen McKeague
Journal: Leukemia (2024)

Abstract Differentiation therapy has proven to be a success story for patients with acute promyelocytic leukemia. However, the remaining subtypes of acute myeloid leukemia (AML) are treated with cytotoxic chemotherapies that have limited efficacy and a high likelihood of resistance. As differentiation arrest is a hallmark of AML, there is increased interest in developing differentiation-inducing agents to enhance disease-free survival. Here, we provide a comprehensive review of current reports and future avenues of nucleic acid therapeutics for AML, focusing on the use of targeted nucleic acid drugs to promote differentiation. Specifically, we compare and discuss the precision of small interfering RNA, small activating RNA, antisense oligonucleotides, and aptamers to modulate gene expression patterns that drive leukemic cell differentiation. We delve into preclinical and clinical studies that demonstrate the efficacy of nucleic acid-based differentiation therapies to induce leukemic cell maturation and reduce disease burden. By directly influencing the expression of key genes involved in myeloid maturation, nucleic acid therapeutics hold the potential to induce the differentiation of leukemic cells towards a more mature and less aggressive phenotype. Furthermore, we discuss the most critical challenges associated with developing nucleic acid therapeutics for myeloid malignancies. By introducing the progress in the field and identifying future opportunities, we aim to highlight the power of nucleic acid therapeutics in reshaping the landscape of myeloid leukemia treatment.
Risk of flare and damage accrual after tapering glucocorticoids in modified serologically active clinically quiescent patients with systemic lupus erythematosus: a multinational observational cohort study
Authors: Yasuhiro Katsumata, Eisuke Inoue, Masayoshi Harigai, Jiacai Cho, Worawit Louthrenoo, Alberta Hoi, Vera Golder, Chak Sing Lau, Aisha Lateef, Yi-Hsing Chen, Shue-Fen Luo, Yeong-Jian Jan Wu, Laniyati Hamijoyo, Zhanguo Li, Sargunan Sockalingam, Sandra Navarra, Leonid Zamora, Yanjie Hao, Zhuoli Zhang, Madelynn Chan, Shereen Oon, Kristine Ng, Jun Kikuchi, Tsutomu Takeuchi, Fiona Goldblatt, Sean O’Neill, Nicola Tugnet, Annie Hui Nee Law, Sang-Cheol Bae, Yoshiya Tanaka, Naoaki Ohkubo, Sunil Kumar, Rangi Kandane-Rathnayake, Mandana Nikpour, Eric F Morand
Journal: Annals of the Rheumatic Diseases (2024)

To assess the risk of flare and damage accrual after tapering glucocorticoids (GCs) in modified serologically active clinically quiescent (mSACQ) patients with systemic lupus erythematosus (SLE).
Bridging the equity gap towards inclusive artificial intelligence in healthcare diagnostics
Authors: See Chai Carol Chan, Ana Luisa Neves, Azeem Majeed, Aldo Faisal
Journal: BMJ (2024)

Rapid advances in artificial intelligence (AI) are paving the way for innovations in how healthcare is delivered.AI technologies have shown remarkable potential in outperforming humans in diagnosing a range of clinical conditions including cancer, diabetes, cardiac arrhythmias, and Alzheimer's Disease. 1 To date, the UK Department of Health and Social Care has invested £123 million directly into 86 AI technologies and have allocated an additional £21m in October 2023 to 64 NHS hospital trusts in England, aiming to streamline diagnostic procedures, enhance predictive analytics, and ultimately improve healthcare delivery and patient outcomes. 2In addition, AI can help democratise access to world-leading expertise distilled into algorithms, and bring underserved, often rural communities, health and care support that would be difficult to realise otherwise.
Final Results From the Randomized Phase III ASCENT Clinical Trial in Metastatic Triple-Negative Breast Cancer and Association of Outcomes by Human Epidermal Growth Factor Receptor 2 and Trophoblast Cell Surface Antigen 2 Expression
Authors: Aditya Bardia, Hope S. Rugo, Sara M. Tolaney, Delphine Loirat, Kevin Punie, Mafalda Oliveira, Adam Brufsky, Kevin Kalinsky, Javier Cortés, Joyce O' Shaughnessy, Véronique Diéras, Lisa A. Carey, Luca Gianni, Martine Piccart-Gebhart, Sibylle Loibl, Oh Kyu Yoon, Yang Pan, Scott Hofsess, See-Chun Phan, Sara A. Hurvitz
Journal: Journal of Clinical Oncology (2024)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Sacituzumab govitecan (SG), a first-in-class anti–trophoblast cell surface antigen 2 (Trop-2) antibody-drug conjugate, demonstrated superior efficacy over single-agent chemotherapy (treatment of physician's choice [TPC]) in patients with metastatic triple-negative breast cancer (mTNBC) in the international, multicenter, phase III ASCENT study. Patients were randomly assigned 1:1 to receive SG or TPC until unacceptable toxicity/progression. Final efficacy secondary end point analyses and post hoc analyses of outcomes stratified by Trop-2 expression and human epidermal growth factor receptor 2 status are reported. Updated safety analyses are provided. In this final analysis, SG (n = 267) improved median progression-free survival (PFS; 4.8 v 1.7 months; hazard ratio (HR), 0.41 [95% CI, 0.33 to 0.52]) and median overall survival (OS; 11.8 v 6.9 months; HR, 0.51 [95% CI, 0.42 to 0.63]) over TPC (n = 262). SG improved PFS over TPC in each Trop-2 expression quartile (n = 168); a trend was observed for improved OS across quartiles. Overall, SG had a manageable safety profile, with ≤5% of treatment-related discontinuations because of adverse events and no treatment-related deaths. The safety profile was consistent across all subgroups. These data confirm the clinical benefit of SG over chemotherapy, reinforcing SG as an effective treatment option in patients with mTNBC in the second line or later.
Covid-19 taskforce called for a new national vaccine agency to prepare for future pandemics
Authors: Jacqui Wise
Journal: BMJ (2024)

Covid-19 taskforce called for a new national vaccine agency to prepare for future pandemics Jacqui WiseThe UK needs a permanent ecosystem for rapidly developing, manufacturing, and supplying vaccines for future pandemics to ensure domestic resilience and security, a report from the now disbanded Vaccine Taskforce said. 1 The report was originally prepared in December
The Pandemic Treaty: shameful and unjust
Authors: None The Lancet
Journal: The Lancet (2024)

The Intergovernmental Negotiating Body (INB), which is tasked under WHO with drawing up an international instrument on pandemic prevention, preparedness, and response, will sit for the 9th and final time from March 18–29. In the 2 years since it first met, hundreds of hours and unknown costs have been spent, but the political impetus has died. The convention is now at a critical juncture: the final text for countries to ratify is due to be presented at the World Health Assembly in May. With only limited days of negotiation left and a long way to go to secure a meaningful agreement, it is now or never for a treaty that can make the world a safer place.
Remote haemodynamic monitoring in patients with heart failure
Authors: John Kikoïne, Nadia Kilani, Barbara Pitta-Gros, Patrick Yerly
Journal: The Lancet (2024)

In the MONITOR-HF trial, Jasper J Brugts and colleagues1 report that quality of life and heart failure hospitalisation rate improved in patients with New York Heart Association class III heart failure (71% with reduced ejection fraction) haemodynamically monitored with the CardioMEMS (CardioMEMS; Abbott, Abbott Park, IL, USA) system as compared with standard of care. However, key differences in patients' management between the groups limit the conclusions that can be drawn about the value of the device in this study.
Fluctuations in plasma adrenocorticotropic hormone concentration may predict the onset of immune checkpoint inhibitor-related hypophysitis
Authors: Hironori Bando, Masaaki Yamamoto, Shin Urai, Yuma Motomura, Yuriko Sasaki, Yuka Ohmachi, Masaki Kobatake, Yasutaka Tsujimoto, Yuka Oi-Yo, Masaki Suzuki, Naoki Yamamoto, Michiko Takahashi, Hidenori Fukuoka, Genzo Iguchi, Wataru Ogawa
Journal: Journal for ImmunoTherapy of Cancer (2024)

Immune checkpoint inhibitor (ICI)-related hypophysitis (RH) is a common immune-related adverse event. The early detection of ICI-RH prevents life-threatening adrenal insufficiency. However, good predictors of secondary adrenal insufficiency in ICI-RH have not yet been reported. We hypothesized that fluctuations in plasma adrenocorticotropic hormone (ACTH) and cortisol levels occur similarly to those in thyroid-stimulating hormone and thyroid hormone (thyroxine and triiodothyronine) levels in ICI-related thyroiditis. Here, we sought to test this hypothesis. Patients who used ICI and had a history of measurement of plasma ACTH and serum cortisol concentrations were retrieved from electronic medical records, and those with a history of glucocorticoid use were excluded from the analysis. We evaluated fluctuations in plasma ACTH and serum cortisol concentrations and the development of ICI-RH. For patients with ICI-RH, data at three points (before ICI administration (pre), maximum ACTH concentration (peak), and onset of ICI-RH) were analyzed to evaluate hormone fluctuations. A total of 202 patients were retrieved from the medical record. Forty-three patients were diagnosed with ICI-RH. Twenty-six out of 43 patients had sufficient data to evaluate fluctuations in plasma ACTH and serum cortisol concentrations and no history of glucocorticoid use. ACTH concentrations changed from 37.4 (29.9–48.3) (pre) to 64.4 (46.5–106.2) (peak) pg/mL (1.72–fold increase, p=0.0026) in the patients with ICI-RH before the onset. There were no differences in cortisol concentrations between the pre and peak values in patients with ICI-RH. We also evaluated the fluctuations in plasma ACTH and serum cortisol levels in patients who did not receive ICI-RH (62 cases). However, elevation of plasma ACTH levels was not observed in patients without ICI-RH, suggesting that transient elevation of plasma ACTH levels is a unique phenomenon in patients with ICI-RH. In conclusion, plasma ACTH levels were transiently elevated in some patients with ICI-RH before the onset of secondary adrenal insufficiency. Monitoring the ACTH levels and their fluctuations may help predict the onset of ICI-RH.