tbuckley/cabot-search huggingface dataset:
Response to: Correspondence on ‘Current myositis clinical trials and tribulations’ by Saygin<i>et al</i>
Authors: Didem Saygin, Victoria Werth, Julie J Paik, Jin Kyun Park, Merrilee Needham, Ingrid E Lundberg, Lisa Christopher-Stine
Journal: Annals of the Rheumatic Diseases (2024)

of our viewpoint entitled 'Myositis Clinical Trials and Tribulations'. 2 The authors eloquently discuss additional clinical trial designs and analytical approaches that can increase the likelihood of participants being assigned to the treatment arm and facilitate drug approval in idiopathic inflammatory myopathies (IIM).At this juncture, we would like to take the opportunity to discuss an additional point.While clinical trials offer the highest-quality evidence for treatment effectiveness, they are expensive, time-consuming and may not always be feasible.Observational comparative effectiveness studies such as target trial emulation can also provide valuable information on quantifying the effect of a treatment. 3However, this approach requires large prospective observational databases with robust follow-up information.In a rare disease such as myositis, this can be accomplished by establishing a global myositis registry leveraging common data elements and common data models in an effort to harmonise existing databases.We also agree with the authors that the scarcity of IIM clinical trials that enroll children with juvenile myositis is concerning.Close collaboration between paediatric and adult providers is key to conduct 'age-inclusive' trials in IIM.As stated by the authors, theMyositis International Health and Research Collaborative Alliance (MIHRA) will be instrumental in overcoming these challenges by (1) establishing a clinical trial network, (2) developing a global myositis database and ( 3) bringing together all the relevant stakeholders including patients, paediatric and adult clinicians, researchers and industry partners from around the world.This will increase efficiency, reduce redundancy and maximise benefit for patients with IIM.
Extracellular Matrix Interactome in Modulating Vascular Homeostasis and Remodeling
Authors: Yi Fu, Yuan Zhou, Kai Wang, Zhuofan Li, Wei Kong
Journal: Circulation Research (2024)

The ECM (extracellular matrix) is a major component of the vascular microenvironment that modulates vascular homeostasis. ECM proteins include collagens, elastin, noncollagen glycoproteins, and proteoglycans/glycosaminoglycans. ECM proteins form complex matrix structures, such as the basal lamina and collagen and elastin fibers, through direct interactions or lysyl oxidase-mediated cross-linking. Moreover, ECM proteins directly interact with cell surface receptors or extracellular secreted molecules, exerting matricellular and matricrine modulation, respectively. In addition, extracellular proteases degrade or cleave matrix proteins, thereby contributing to ECM turnover. These interactions constitute the ECM interactome network, which is essential for maintaining vascular homeostasis and preventing pathological vascular remodeling. The current review mainly focuses on endogenous matrix proteins in blood vessels and discusses the interaction of these matrix proteins with other ECM proteins, cell surface receptors, cytokines, complement and coagulation factors, and their potential roles in maintaining vascular homeostasis and preventing pathological remodeling.
Management and outcome of patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era – analysis of the European LeukemiaNet Blast Phase Registry
Authors: Annamaria Brioli, Elza Lomaia, Christian Fabisch, Tomasz Sacha, Hana Klamova, Elena Morozova, Aleksandra Golos, Philipp Ernst, Ulla Olsson-Stromberg, Daniela Zackova, Franck E. Nicolini, Han Bao, Fausto Castagnetti, Elzbieta Patkowska, Jiri Mayer, Klaus Hirschbühl, Helena Podgornik, Edyta Paczkowska, Anne Parry, Thomas Ernst, Astghik Voskanyan, Elzbieta Szczepanek, Susanne Saussele, Georg-Nikolaus Franke, Alexander Kiani, Edgar Faber, Stefan Krause, Luis Felipe Casado, Krzysztof Lewandowski, Matthias Eder, Peter Anhut, Justyna Gil, Thomas Südhoff, Holger Hebart, Sonja Heibl, Markus Pfirrmann, Andreas Hochhaus, Michael Lauseker
Journal: Leukemia (2024)

Abstract Blast phase (BP) of chronic myeloid leukemia (CML) still represents an unmet clinical need with a dismal prognosis. Due to the rarity of the condition and the heterogeneity of the biology and clinical presentation, prospective trials and concise treatment recommendations are lacking. Here we present the analysis of the European LeukemiaNet Blast Phase Registry, an international collection of the clinical presentation, treatment and outcome of blast phases which had been diagnosed in CML patients after 2015. Data reveal the expected heterogeneity of the entity, lacking a clear treatment standard. Outcomes remain dismal, with a median overall survival of 23.8 months (median follow up 27.8 months). Allogeneic stem cell transplantation (alloSCT) increases the rate of deep molecular responses. De novo BP and BP evolving from a previous CML do show slightly different features, suggesting a different biology between the two entities. Data show that outside clinical trials and in a real-world setting treatment of blast phase is individualized according to disease- and patient-related characteristics, with the aim of blast clearance prior to allogeneic stem cell transplantation. AlloSCT should be offered to all patients eligible for this procedure.
Devalued: doctors’ real terms purchasing power has declined substantially over 15 years, independent economic analysis confirms
Journal: BMJ (2024)

Devalued: doctors' real terms purchasing power has declined substantially over 15 years, independent economic analysis confirms This article (BMJ 2024;384:q666, doi:) has been corrected to change a misleading sentence about how the decline in real terms value of doctors' salaries relates to cost of living.The sentence now reads: "This fall, which aligns with a 25% increase in the cost of living in the UK over the same period, is disproportionately affecting the purchasing power of lower grade doctors, the analysis found.
Rebalancing risks in favour of benefits
Authors: Kamran Abbasi
Journal: BMJ (2024)

Balancing risks is life, the universe, and everything.One classic challenge is applying population based data to individuals.A related row over use of statins-the most prescribed drug class in England-shifted in favour of even greater prescription of statins last year, when NICE issued updated guidelines that lowered cardiovascular risk thresholds.Yet the benefits of statins may not outweigh the harms in people at low risk, and population risk thresholds may oversimplify matters.
Use of progestogens and the risk of intracranial meningioma: national case-control study
Authors: Noémie Roland, Anke Neumann, Léa Hoisnard, Lise Duranteau, Sébastien Froelich, Mahmoud Zureik, Alain Weill
Journal: BMJ (2024)

ABSTRACT Objective To assess the risk of intracranial meningioma associated with the use of selected progestogens. Design National case-control study. Setting French National Health Data System (ie, Système National des Données de Santé ). Participants Of 108 366 women overall, 18 061 women living in France who had intracranial surgery for meningioma between 1 January 2009 and 31 December 2018 (restricted inclusion periods for intrauterine systems) were deemed to be in the case group. Each case was matched to five controls for year of birth and area of residence (90 305 controls). Main outcome measures Selected progestogens were used: progesterone, hydroxyprogesterone, dydrogesterone, medrogestone, medroxyprogesterone acetate, promegestone, dienogest, and intrauterine levonorgestrel. For each progestogen, use was defined by at least one dispensation within the year before the index date (within three years for 13.5 mg levonorgestrel intrauterine systems and five years for 52 mg). Conditional logistic regression was used to calculate odds ratio for each progestogen meningioma association. Results Mean age was 57.6 years (standard deviation 12.8). Analyses showed excess risk of meningioma with use of medrogestone (42 exposed cases/18 061 cases (0.2%) v 79 exposed controls/90 305 controls (0.1%), odds ratio 3.49 (95% confidence interval 2.38 to 5.10)), medroxyprogesterone acetate (injectable, 9/18 061 (0.05%) v 11/90 305 (0.01%), 5.55 (2.27 to 13.56)), and promegestone (83/18 061 (0.5%) v 225/90 305 (0.2 %), 2.39 (1.85 to 3.09)). This excess risk was driven by prolonged use (≥one year). Results showed no excess risk of intracranial meningioma for progesterone, dydrogesterone, or levonorgestrel intrauterine systems. No conclusions could be drawn concerning dienogest or hydroxyprogesterone because of the small number of individuals who received these drugs. A highly increased risk of meningioma was observed for cyproterone acetate (891/18 061 (4.9%) v 256/90 305 (0.3%), odds ratio 19.21 (95% confidence interval 16.61 to 22.22)), nomegestrol acetate (925/18 061 (5.1%) v 1121/90 305 (1.2%), 4.93 (4.50 to 5.41)), and chlormadinone acetate (628/18 061 (3.5%) v 946/90 305 (1.0%), 3.87 (3.48 to 4.30)), which were used as positive controls for use. Conclusions Prolonged use of medrogestone, medroxyprogesterone acetate, and promegestone was found to increase the risk of intracranial meningioma. The increased risk associated with the use of injectable medroxyprogesterone acetate, a widely used contraceptive, and the safety of levonorgestrel intrauterine systems are important new findings.
Sided Stimulation of Endothelial Cells Modulates Neutrophil Trafficking in an In Vitro Sepsis Model
Authors: Danial Ahmad, Isabelle Linares, Anthony Pietropaoli, Richard E. Waugh, James L. McGrath
Journal: Advanced Healthcare Materials (2024)

While the role of dysregulated polymorphonuclear leukocyte (PMN) transmigration in septic mediated tissue damage is well documented, strategies to mitigate aberrant transmigration across endothelium have yet to yield viable therapeutics. Recently, microphysiological systems (MPS) have emerged as novel in vitro mimetics that facilitate the development of human models of disease. With this advancement, aspects of endothelial physiology that are difficult to assess with other models can be directly probed. In this study, the role of endothelial cell (EC) apicobasal polarity on leukocyte trafficking response is evaluated with the µSiM-MVM (microphysiological system enabled by a silicon membrane - microvascular mimetic). Here, ECs are stimulated either apically or basally with a cytokine cocktail to model a septic-like challenge before introducing healthy donor PMNs into the device. Basally oriented stimulation generated a stronger PMN transmigratory response versus apical stimulation. Importantly, healthy PMNs are unable to migrate towards a bacterial peptide chemoattractant when ECs are apically stimulated, which mimics the attenuated PMN chemotaxis seen in sepsis. Escalating the apical inflammatory stimulus by a factor of five is necessary to elicit high PMN transmigration levels across endothelium. These results demonstrate that EC apicobasal polarity modulates PMN transmigratory behavior and provides insight into the mechanisms underlying sepsis.
Therapeutic improvement of CFTR function and reversibility of bronchiectasis in cystic fibrosis
Authors: Mark O. Wielpütz, Marcus A. Mall
Journal: European Respiratory Journal (2024)

<h3>Shareable abstract</h3> <b>The study by Cazier and co-workers promotes current efforts to diagnose and treat CF lung disease as early as possible in order to prevent structural lung damage, and to target initially reversible changes before persistent airway damage is established</b>https://bit.ly/42K7tYW
Lung MRI identifies potentially treatable subtypes of long COVID
Authors: Alejandro P. Comellas, Sean B. Fain
Journal: European Respiratory Journal (2024)

<h3>Shareable abstract</h3> <b>Xenon-129 MRI identified different lung phenotypes of long COVID, which could result in the design of new clinical trials to investigate long COVID treatments</b> https://bit.ly/49U9zYz
A Real-time augmented reality robot integrated with artificial intelligence for skin tumor surgery - experimental study and case series
Authors: Kai Huang, Jun Liao, Jishuai He, Sicen Lai, Yihao Peng, Qian Deng, Han Wang, Yuancheng Liu, Lanyuan Peng, Ziqi Bai, Nianzhou Yu, Yixin Li, Zixi Jiang, Juan Su, Jinmao Li, Yan Tang, Mingliang Chen, Lixia Lu, Xiang Chen, Jianhua Yao, Shuang Zhao
Journal: International Journal of Surgery (2024)

Background: Skin tumors affect many people worldwide, and surgery is the first treatment choice. Achieving precise preoperative planning and navigation of intraoperative sampling remains a problem and is excessively reliant on the experience of surgeons, especially for Mohs surgery for malignant tumors. Materials and Methods: To achieve precise preoperative planning and navigation of intraoperative sampling, we developed a real-time augmented reality (AR) surgical system integrated with artificial intelligence (AI) to enhance three functions: AI-assisted tumor boundary segmentation, surgical margin design, and navigation in intraoperative tissue sampling. Non-randomized controlled trials were conducted on manikin, tumor-simulated rabbits, and human volunteers in xxx Laboratory to evaluate the surgical system. Results: The results showed that the accuracy of the benign and malignant tumor segmentation were 0.9556 and 0.9548, respectively, and the average AR navigation mapping error was 0.644 mm. The proposed surgical system was applied in 106 skin tumor surgeries, including intraoperative navigation of sampling in 16 Mohs surgery cases. Surgeons who have used this system highly recognize it. Conclusions: The surgical system highlighted the potential to achieve accurate treatment of skin tumors and to fill the gap in global research on skin tumor surgery systems.
Appropriate thromboprophylaxis strategy for COVID-19 patients on dosage, antiplatelet therapy, outpatient and post-discharge prophylaxis: a meta-analysis of randomized controlled trials
Authors: Jiahao Meng, Hang Tang, Yifan Xiao, Weijie Liu, Yumei Wu, Yilin Xiong, Shuguang Gao
Journal: International Journal of Surgery (2024)

There was controversy surrounding the optimal thromboprophylaxis strategy for coronavirus disease 2019 (COVID-19) patients. This included debates on the dosage of anticoagulants for thromboembolism prophylaxis, the requirement for additional antiplatelet therapy, and the necessity of prophylaxis for outpatients and postdischarge. To explore this, the authors performed a meta-analysis of randomized controlled trials.
Pulsatile Flow Increases METTL14-induced m6A modification and attenuates septic cardiomyopathy: an experimental study
Authors: Shenyu Zhu, Kai Wang, Zhexuan Yu, Wei Tang, Yu Zhang, Shafiu A. umar Shinge, Yongjia Qiang, Hangyu Liu, Jianfeng Zeng, Kun Qiao, Chi Liu, Guanhua Li
Journal: International Journal of Surgery (2024)

Introduction: Septic cardiomyopathy is a sepsis-mediated cardiovascular complication with severe microcirculatory malperfusion. Emerging evidence has highlighted the protective effects of pulsatile flow in case of microcirculatory disturbance, yet the underlying mechanisms are still elusive. The objective of this study was to investigate the mechanisms of N6-methyladenosine (m 6 A) modification in the alleviation of septic cardiomyopathy associated with extracorporeal membrane oxygenation (ECMO)-generated pulsatile flow. Methods: Rat model with septic cardiomyopathy was established and was supported under ECMO either with pulsatile or non-pulsatile flow. Peripheral perfusion index (PPI) and cardiac function parameters were measured using ultrasonography. Dot blot assay was applied to examine the m 6 A level, while qRT-PCR, Western blot, immunofluorescence, and immunohistochemistry were used to measure the expressions of related genes. RNA immunoprecipitation assay was performed to validate the interaction between molecules. Results: The ECMO-generated pulsatile flow significantly elevates microcirculatory PPI, improves myocardial function, protects the endothelium, and prolongs survival in rat models with septic cardiomyopathy. The pulsatile flow mediates the METTL14-mediated m 6 A modification to zonula occludens- (ZO-) 1 mRNA which stabilizes the ZO-1 mRNA depending on the presence of YTHDF2. The pulsatile flow suppresses the PI3K-Akt signaling pathway, of which the downstream molecule Foxo1, a negative transcription factor of METTL14, binds to the METTL14 promoter and inhibits the METTL14-induced m 6 A modification. Conclusion: The ECMO-generated pulsatile flow increases METTL14-induced m 6 A modification in ZO-1 and attenuates the progression of septic cardiomyopathy, suggesting that pulsatility might be a new therapeutic strategy in septic cardiomyopathy by alleviating microcirculatory disturbance.
Opportunities and barriers in omics-based biomarker discovery for steatotic liver diseases
Authors: Maja Thiele, Ida Falk Villesen, Lili Niu, Stine Johansen, Karolina Sulek, Suguru Nishijima, Lore Van Espen, Marisa Keller, Mads Israelsen, Tommi Suvitaival, Andressa de Zawadzki, Helene Bæk Juel, Maximilian Joseph Brol, Sara Elizabeth Stinson, Yun Huang, Maria Camilla Alvarez Silva, Michael Kuhn, Ema Anastasiadou, Diana Julie Leeming, Morten Karsdal, Jelle Matthijnssens, Manimozhiyan Arumugam, Louise Torp Dalgaard, Cristina Legido-Quigley, Matthias Mann, Jonel Trebicka, Peer Bork, Lars Juhl Jensen, Torben Hansen, Aleksander Krag, Torben Hansen, Matthias Mann, Jelle Matthijnssens, Aleksander Krag, Aleksander Krag, Peer Bork, Torben Hansen, Manimozhiyan Arumugam, Jonel Trebicka, Morten Karsdal, Ema Anastasiadou, Hans Israelsen, Hans Olav Melberg, Cristina Legido-Quigley, Maja Thiele
Journal: Journal of Hepatology (2024)

The rising prevalence of liver diseases related to obesity and excessive use of alcohol is fuelling an increasing demand for accurate biomarkers aimed at community screening, diagnosis of steatohepatitis and significant fibrosis, monitoring, prognostication and prediction of treatment efficacy. Breakthroughs in omics methodologies and the power of bioinformatics have created an excellent opportunity to apply technological advances to clinical needs, for instance in the development of precision biomarkers for personalised medicine. Via omics technologies, biological processes from the genes to circulating protein, as well as the microbiome - including bacteria, viruses and fungi, can be investigated on an axis. However, there are important barriers to omics-based biomarker discovery and validation, including the use of semi-quantitative measurements from untargeted platforms, which may exhibit high analytical, inter- and intra-individual variance. Standardising methods and the need to validate them across diverse populations presents a challenge, partly due to disease complexity and the dynamic nature of biomarker expression at different disease stages. Lack of validity causes lost opportunities when studies fail to provide the knowledge needed for regulatory approvals, all of which contributes to a delayed translation of these discoveries into clinical practice. While no omics-based biomarkers have matured to clinical implementation, the extent of data generated has enabled the hypothesis-free discovery of a plethora of candidate biomarkers that warrant further validation. To explore the many opportunities of omics technologies, hepatologists need detailed knowledge of commonalities and differences between the various omics layers, and both the barriers to and advantages of these approaches.
Intradermal delivery of the third dose of the mRNA-1273 SARS-CoV-2 vaccine: safety and immunogenicity of a fractional booster dose
Authors: Geert V.T. Roozen, Manon L.M. Prins, Corine Prins, Jacqueline J. Janse, Heidi L.M. de Gruyter, Cilia R. Pothast, Wesley Huisman, Jan Pieter R. Koopman, Olivia A.C. Lamers, Marjan Kuijer, Sebenzile K. Myeni, Rob S. van Binnendijk, Gerco den Hartog, Mirjam H.M. Heemskerk, Simon P. Jochems, Mariet C.W. Feltkamp, Marjolein Kikkert, Frits R. Rosendaal, Meta Roestenberg, Leo G. Visser, Anna H.E. Roukens
Journal: Clinical Microbiology and Infection (2024)

ObjectivesThe aim of this study was to assess safety and immunogenicity of a dose-sparing fractional intradermal (ID) booster strategy with the mRNA-1273 COVID-19 vaccine.MethodsCOVID-19 naive adults aged 18-30 years were recruited from a previous study on primary vaccination regimens that compared 20 μg ID vaccinations with 100 μg IM vaccinations with mRNA-1273 as the primary vaccination series. Participants previously immunized with ID regimens were randomly assigned (1:1) to receive a fractional ID booster dose (20 μg) or the standard-of-care intramuscular (IM) booster dose (50 μg) of the mRNA-1273 vaccine, six months after completing their primary series (ID-ID and ID-IM group, respectively). Participants that had received a full dose IM regimen as the primary series, received the IM standard-of-care booster dose (IM-IM group). Additionally, COVID-19 naive individuals aged 18-40 years that had received an IM mRNA vaccine as the primary series were recruited from the general population to receive a fractional ID booster dose (IM-ID group). Immunogenicity was assessed using IgG anti-spike antibody responses and neutralizing capacity against SARS-CoV-2. Cellular immune responses were measured in a sub-group. Safety and tolerability were monitored.ResultsIn January 2022, 129 participants were included. Fractional ID boosting was safe and well-tolerated, with fewer systemic adverse events compared to IM boosting. At day 28 post-booster, anti-spike S1 IgG geometric mean concentrations were 9,106 (95% CI: 7,150-11,597) binding antibody units (BAU)/mL in the IM-IM group and 4,357 (3,003-6,322) BAU/mL, 6,629 (4,913-8,946) BAU/mL, and 5,264 (4,032-6,873) BAU/mL in the ID-IM, ID-ID, and IM-ID groups, respectively.ConclusionsID boosting provides robust immune responses and is a viable dose-sparing strategy for mRNA COVID-19 vaccines. The favorable side-effect profile supports its potential in reducing vaccine hesitancy. Fractional dosing strategies should be considered early in the clinical development of future mRNA vaccines to enhance vaccine availability and pandemic preparedness.