tbuckley/cabot-search huggingface dataset:
Impact of extramedullary multiple myeloma on outcomes with idecabtagene vicleucel
Authors: Saurabh Zanwar, Surbhi Sidana, Leyla Shune, Omar Castaneda Puglianini, Oren Pasvolsky, Rebecca Gonzalez, Danai Dima, Aimaz Afrough, Gurbakhash Kaur, James A. Davis, Megan Herr, Hamza Hashmi, Peter Forsberg, Douglas Sborov, Larry D. Anderson Jr, Joseph P. McGuirk, Charlotte Wagner, Alex Lieberman-Cribbin, Adriana Rossi, Ciara L. Freeman, Frederick L. Locke, Shambavi Richard, Jack Khouri, Yi Lin, Krina K. Patel, Shaji K. Kumar, Doris K. Hansen
Journal: Journal of Hematology & Oncology (2024)

Idecabtagene vicleucel (Ide-cel) has demonstrated excellent efficacy and durable responses in patients with relapsed/refractory multiple myeloma (RRMM). However, the outcomes with ide-cel in patients with extramedullary disease (EMD) remain incompletely characterized. We included patients with RRMM treated with ide-cel between May 2021 and April 2023 across 11 US academic institutions. Visceral or soft tissue lesions non-contiguous from bone was classified as EMD. Time-to-event analyses were performed from date of ide-cel infusion. Among 351 patients, 84 (24%) had EMD prior to infusion. The median follow-up from ide-cel infusion was 18.2 months (95% CI: 17-19.3). The day 90 overall response rates (ORR) were 52% vs. 82% for the EMD and non-EMD cohorts, respectively (p < 0.001). The median progression-free survival (PFS) was 5.3 months (95% CI: 4.1-6.9) for the EMD cohort vs. 11.1 months (95% CI: 9.2-12.6; p < 0.0001) for the non-EMD cohort. In a multivariable analysis, EMD was an independent predictor of inferior PFS [hazard ratio 1.5 (1.1-2.2), p = 0.02]. The median overall survival was 14.8 months [95% CI: 9-Not reached (NR)] vs. 26.9 months (26.3 vs. NR, p = 0.006) for the EMD and non-EMD cohorts, respectively. Extramedullary disease represents an independent predictor of inferior day 90 ORR and PFS among patients treated with ide-cel.
Cognitive Impairments in Drug-Naive Patients With First-Episode Negative Symptom–Dominant Psychosis
Authors: TianHong Zhang, YanYan Wei, XiaoChen Tang, HuiRu Cui, YeGang Hu, LiHua Xu, HaiChun Liu, ZiXuan Wang, Tao Chen, Qiang Hu, ChunBo Li, JiJun Wang
Journal: JAMA Network Open (2024)

Importance Available antipsychotic medications are predominantly used to treat positive symptoms, such as hallucinations and delusions, in patients with first-episode psychosis (FEP). However, treating negative and cognitive symptoms, which are closely related to functional outcomes, remains a challenge. Objective To explore the cognitive characteristics of patients with negative symptom–dominant (NSD) psychosis. Design, Setting, and Participants This large-scale cross-sectional study of patients with FEP was led by the Shanghai Mental Health Center in China from 2016 to 2021, with participants recruited from 10 psychiatric tertiary hospitals. A comprehensive cognitive assessment was performed among 788 patients with FEP who were drug-naive. Symptom profiles were determined using the Positive and Negative Symptoms Scale (PANSS), and NSD was defined as a PANSS score for negative symptoms higher than that for positive and general symptoms. Positive symptom–dominant (PSD) and general symptom–dominant (GSD) psychosis were defined similarly. Data were analyzed in 2023. Exposure Psychotic symptoms were categorized into 3 groups: NSD, PSD, and GSD. Main Outcomes and Measures Neurocognitive performance, assessed using the Chinese version of the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery. Results This study included 788 individuals with FEP (median age, 22 [IQR, 17-28] years; 399 men [50.6%]). Patients with NSD exhibited more-pronounced cognitive impairment than did those with PSD or GSD. Specifically, cognitive differences between the NSD and PSD group, as well as between the NSD and GSD group, were most notable in the processing speed and attention domains (Trail Making [ F = 4.410; P = .01], Symbol Coding [ F = 4.957; P = .007], Verbal Learning [ F = 3.198; P = .04], and Continuous Performance [ F = 3.057; P = .05]). Patients with PSD and GSD showed no significant cognitive differences. Cognitive impairment was positively associated with the severity of negative symptoms. Most of the cognitive function tests used were able to differentiate patients with NSD from those with PSD and GSD, with significant differences observed across a range of tests, from Brief Visuospatial Memory Test–Revised ( χ 2 = 3.968; P = .05) to Brief Assessment of Cognition in Schizophrenia symbol coding ( χ 2 = 9.765; P = .002). Conclusions and Relevance The findings of this cross-sectional study of patients with FEP suggest the presence of a clinical subtype characterized by a predominance of negative symptoms and cognitive impairment.
Reply to the Letter to the Editor regarding ‘Overcoming Barriers in Biomarker Testing’ J. García-Foncillas et al.
Authors: A. Bayle, D. Chaltiel, N. Latino, E. Rouleau, S. Peters, M. Galotti, G. Bricalli, B. Besse, R. Giuliani, J. Bonastre
Journal: Annals of Oncology (2024)
Off-target autophagy inhibition by SHP2 allosteric inhibitors contributes to their anti-tumor activity in RAS-driven cancers
Authors: Yiming Miao, Yunpeng Bai, Jinmin Miao, Allison A. Murray, Jianping Lin, Jiajun Dong, Zihan Qu, Ruo-Yu Zhang, Quyen D. Nguyen, Shaomeng Wang, Jingmei Yu, Frederick Nguele Meke, Zhong-Yin Zhang
Journal: Journal of Clinical Investigation (2024)

Aberrant activation of RAS-MAPK signaling is common in cancer, and efforts to inhibit pathway components have yielded drugs with promising clinical activities. Unfortunately, treatment-provoked adaptive resistance mechanisms inevitably develop, limiting their therapeutic potential. As a central node essential for receptor tyrosine kinase mediated RAS activation, SHP2 has emerged as an attractive cancer target. Consequently, many SHP2 allosteric inhibitors are now in clinical testing. Here we discovered a previously unrecognized off-target effect associated with SHP2 allosteric inhibitors. We found that these inhibitors accumulate in the lysosome and block autophagic flux in a SHP2-independent manner. We showed that off-target autophagy inhibition by SHP2 allosteric inhibitors contributes to their anti-tumor activity. We also demonstrated that SHP2 allosteric inhibitors harboring this off-target activity not only suppress oncogenic RAS signaling but also overcome drug resistance such as MAPK rebound and protective autophagy in response to RAS-MAPK pathway blockage. Finally, we exemplified a therapeutic framework that harnesses both the on- and off-target activities of SHP2 allosteric inhibitors for improved treatment of mutant RAS driven and drug resistant malignancies such as pancreatic and colorectal cancers. Brief Summary: SHP2 allosteric inhibitors elicit off-target autophagy blockade that can be exploited for improved treatment of RAS-driven and drug-resistant cancers.
Mpox Surveillance Based on Rash Characteristics — 13 Emergency Departments, United States, June–December 2023
Authors: Carl T. Berdahl, Anusha Krishnadasan, Kavitha Pathmarajah, Gregory J. Moran, Jesus R. Torres, Matthew Waxman, William Mower, Omai B. Garner, Lorenzo P. Duvergne, Anne W. Rimoin, Pamina M. Gorbach, David A. Talan, Brett Faine, Jon K. Femling, James W. Galbraith, Derek Isenberg, Jonathan Jui, Frank LoVecchio, Johanna C. Moore, Utsav Nandi, Richard Rothman, Howard Smithline, Mark T. Steele, Amy M. Stubbs, Sam S. Torbati
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

In 2022, a global mpox outbreak occurred, primarily affecting gay and bisexual men who have sex with men (GBMSM).To screen for mpox's reemergence and investigate potentially unsuspected cases among non-GBMSM, prospective surveillance of patients aged ≥3 months with an mpox-compatible rash (vesicular, pustular, ulcerated, or crusted) was conducted at 13 U.S. emergency departments (EDs) during June-December 2023.Demographic, historical, and illness characteristics were collected using questionnaires and electronic health records.Lesions were tested for monkeypox virus using polymerase chain reaction.Among 196 enrolled persons, the median age was 37.5 years (IQR = 21.0-53.5 years); 39 (19.9%) were aged <16 years, and 108 (55.1%) were male.Among all enrollees, 13 (6.6%)were GBMSM.Overall, approximately one half (46.4%) and one quarter (23.5%) of enrolled persons were non-Hispanic White and non-Hispanic Black or African American, respectively, and 38.8% reported Hispanic or Latino (Hispanic) ethnicity.Unstable housing was reported by 21 (10.7%)enrollees, and 24 (12.2%)lacked health insurance.The prevalence of mpox among ED patients evaluated for an mpox-compatible rash was 1.5% (95% CI = 0.3%-4.4%);all persons with a confirmed mpox diagnosis identified as GBMSM and reported being HIV-negative, not being vaccinated against mpox, and having engaged in sex with one or more partners met through smartphone dating applications.No cases were identified among women, children, or unhoused persons.Clinicians should remain vigilant for mpox and educate persons at risk for mpox about modifying behaviors that increase risk and the importance of receiving 2 appropriately spaced doses of JYNNEOS vaccine to prevent mpox.
Prevalence and Co-Occurrence of Psychiatric Conditions Among Bereaved Adults
Authors: Alyssa A. Rheingold, Joah L. Williams, Jamison S. Bottomley
Journal: JAMA Network Open (2024)

Importance Rates of grief-related psychiatric conditions, such as prolonged grief disorder (PGD), posttraumatic stress disorder (PTSD), and major depressive disorder (MDD), among bereaved adults in the US are largely unknown due to limited studies that leverage national samples. Objective To assess risk factors for and prevalence rates and co-occurrence of PGD, PTSD, and MDD among bereaved adults in the US. Design, Setting, and Participants Data for this survey study were collected from a large US panel sample between October 10 and 28, 2022, using a web-based survey. Participants were aged 18 years or older and were proficient in English. Data analysis was conducted between March and June 2023. Main Outcomes and Measures Probable psychiatric conditions were assessed with validated measures that used conservative cutoff scores, duration, and impairment criteria. These measures included the revised Prolonged Grief Disorder scale for PGD, the PTSD Checklist for DSM-5 for PTSD, and the Patient Health Questionnaire-9 for MDD. Data were analyzed using basic descriptives and logistic regression. Results A total of 2034 adults (n = 1529 and 505 in the bereaved and comparison groups, respectively) completed the study. Respondents had a mean (SD) age of 40.7 (15.9) years; the majority were women (1314 [64.6%]) and had at least some college experience (1394 [68.5%]). With regard to race and ethnicity, 392 respondents (19.3%) were Black, 138 (6.8%) were Hispanic, and 1357 (66.7%) were White. Among bereaved adults, 312 (20.4%), 518 (33.9%), and 461 (30.2%) met criteria for a presumptive diagnosis of PGD, PTSD, and MDD, respectively. Comorbidities were common, with 441 participants (28.8%) meeting criteria for at least 2 co-occurring disorders. Comorbid PGD, PTSD, and MDD were more common than any 2 co-occurring or isolated disorders; the presence of co-occurring conditions was more likely among respondents who reported a traumatic loss. Age and educational attainment were associated with the risk of psychiatric conditions; less time since the index death, loss of a psychologically close other, and a traumatic loss experience were associated with increased risk of PGD, PTSD, and MDD or their co-occurrence. Conclusions and Relevance In this study, the majority of bereaved adults did not meet presumptive criteria for PGD, PTSD, or MDD. Nevertheless, PGD, PTSD, and MDD were highly prevalent and comorbid, particularly among those who experienced traumatic loss. These findings underscore the need for integrated psychological care that leverages transdiagnostic mechanisms of evidence-based practice.
European Respiratory Society Statement on preschool wheezing disorders: updated definitions, knowledge gaps, and proposed future research directions
Authors: Heidi Makrinioti, Valentina Fainardi, Klaus Bonnelykke, Adnan Custovic, Lisa Cicutto, Courtney Coleman, Thomas Eiwegger, Claudia Kuehni, Alexander Moeller, Eva Pedersen, Marielle Pijnenburg, Hilary Pinnock, Sarath Ranganathan, Thomy Tonia, Padmaja Subbarao, Sejal Saglani
Journal: European Respiratory Journal (2024)

Since the publication of the European Respiratory Society (ERS) task force reports on the management of preschool wheezing in 2008 and 2014, a large body of evidence has accumulated suggesting that the clinical phenotypes that were proposed (episodic (viral) wheezing and multiple-trigger wheezing) do not relate to underlying airway pathology and may not help determine response to treatment. Specifically, using clinical phenotypes alone may no longer be appropriate, and new approaches that can be used to inform clinical care are needed for future research. This ERS task force reviewed the literature published after 2008 related to preschool wheezing and has suggested that the criteria used to define wheezing disorders in preschool children should include age of diagnosis (0 to &lt;6 years), confirmation of wheezing on at least one occasion, and more than one episode of wheezing ever. Furthermore, diagnosis and management may be improved by identifying treatable traits, including inflammatory biomarkers (blood eosinophils, aeroallergen sensitisation) associated with type-2 immunity and differential response to inhaled corticosteroids, lung function parameters and airway infection. However, more comprehensive use of biomarkers/treatable traits in predicting the response to treatment requires prospective validation. There is evidence that specific genetic traits may help guide management, but these must be adequately tested. In addition, the task force identified an absence of caregiver-reported outcomes, caregiver/self-management options and features that should prompt specialist referral for this age group. Priorities for future research include a focus on identifying 1) mechanisms driving preschool wheezing; 2) biomarkers of treatable traits and efficacy of interventions in those without allergic sensitisation/eosinophilia; 3) the need to include both objective outcomes and caregiver-reported outcomes in clinical trials; 4) the need for a suitable action plan for children with preschool wheezing; and 5) a definition of severe/difficult-to-treat preschool wheezing.
COVID-19 Vaccination Coverage and Factors Associated With Vaccine Uptake Among People With HIV
Authors: Rulin C. Hechter, Lei Qian, In-Lu Amy Liu, Lina S. Sy, Denison S. Ryan, Stanley Xu, Joshua T. B. Williams, Nicola P. Klein, Robyn M. Kaiser, Elizabeth G. Liles, Jason M. Glanz, Lisa A. Jackson, Maria E. Sundaram, Eric S. Weintraub, Hung Fu Tseng
Journal: JAMA Network Open (2024)

Importance People with HIV (PWH) may be at increased risk for severe outcomes with COVID-19 illness compared with people without HIV. Little is known about COVID-19 vaccination coverage and factors associated with primary series completion among PWH. Objectives To evaluate COVID-19 vaccination coverage among PWH and examine sociodemographic, clinical, and community-level factors associated with completion of the primary series and an additional primary dose. Design, Setting, and Participants This retrospective cohort study used electronic health record data to assess COVID-19 vaccination information from December 14, 2020, through April 30, 2022, from 8 health care organizations of the Vaccine Safety Datalink project in the US. Participants were adults diagnosed with HIV on or before December 14, 2020, enrolled in a participating site. Main Outcomes and Measures The percentage of PWH with at least 1 dose of COVID-19 vaccine and PWH who completed the COVID-19 vaccine primary series by December 31, 2021, and an additional primary dose by April 30, 2022. Rate ratios (RR) and 95% CIs were estimated using Poisson regression models for factors associated with completing the COVID-19 vaccine primary series and receiving an additional primary dose. Results Among 22 058 adult PWH (mean [SD] age, 52.1 [13.3] years; 88.8% male), 90.5% completed the primary series by December 31, 2021. Among 18 374 eligible PWH who completed the primary series by August 12, 2021, 15 982 (87.0%) received an additional primary dose, and 4318 (23.5%) received a booster dose by April 30, 2022. Receipt of influenza vaccines in the last 2 years was associated with completion of the primary series (RR, 1.17; 95% CI, 1.15-1.20) and an additional primary dose (RR, 1.61; 95% CI, 1.54-1.69). PWH with uncontrolled viremia (HIV viral load ≥200 copies/mL) (eg, RR, 0.90 [95% CI, 0.85-0.95] for viral load 200-10 000 copies/mL vs undetected or &amp;amp;lt;200 copies/mL for completing the primary series) and Medicaid insurance (eg, RR, 0.89 [95% CI, 0.87-0.90] for completing the primary series) were less likely to be fully vaccinated. By contrast, greater outpatient utilization (eg, RR, 1.07 [95% CI, 1.05-1.09] for ≥7 vs 0 visits for primary series completion) and residence in counties with higher COVID-19 vaccine coverage (eg, RR, 1.06 [95% CI, 1.03-1.08] for fourth vs first quartiles for primary series completion) were associated with primary series and additional dose completion (RRs ranging from 1.01 to 1.21). Conclusions and Relevance Findings from this cohort study suggest that, while COVID-19 vaccination coverage was high among PWH, outreach efforts should focus on those who did not complete vaccine series and those who have uncontrolled viremia.
Surgically Resectable Non-Small Cell Lung Cancer: A Contemporary Approach
Authors: Marie-Frédérique D'Amours, Florence T.H. Wu, Olivia Theisen-Lauk, Elisa K. Chan, Anna McGuire, Cheryl Ho
Journal: European Respiratory Journal (2024)

New treatment paradigms for resectable nonsmall cell lung cancer (NSCLC), with an emphasis on personalised care and a multidisciplinary approach, have significantly improved patient outcomes. The incorporation of immune checkpoint inhibitors into neoadjuvant, perioperative and adjuvant treatment algorithms is reshaping the standard of care for resectable NSCLC. Adjuvant targeted therapy trials have also paved the way for a much-needed personalised approach for patients with actionable genomic alterations. Innovative surgical techniques and judicious use of postoperative radiotherapy may mitigate the toxicity associated with a multimodality approach. Amid the many new treatment options, questions remain about the best approach to consider for each patient. Measurement of minimal residual disease and achievement of pathological complete response are emerging biomarkers of interest to help further refine treatment selection. This review summarises the current management of resectable NSCLC, focusing on ongoing and recent advances in surgical approaches, the role of postoperative radiotherapy and the rapidly changing field of systemic therapies.
PIK3CA inhibition in models of proliferative glomerulonephritis and lupus nephritis
Authors: Junna Yamaguchi, Pierre Isnard, Noémie Robil, Pierre de la Grange, Clément Hoguin, Alain Schmitt, Aurélie Hummel, Jérôme Megret, Nicolas Goudin, Marine Luka, Mickaël M. Ménager, Cécile Masson, Mohammed Zarhrate, Christine Bôle-Feysot, Michalina Janiszewska, Kornelia Polyak, Julien Dairou, Sara Baldassari, Stéphanie Baulac, Christine Broissand, Christophe Legendre, Fabiola Terzi, Guillaume Canaud
Journal: Journal of Clinical Investigation (2024)

Proliferative glomerulonephritis is a severe condition often leading to kidney failure. There is a significant lack of effective treatment for these disorders. Here, following the identification of a somatic PIK3CA gain-of-function mutation in podocytes of a patient, we demonstrate using multiple genetically engineered mouse models, single-cell RNA sequencing and spatial transcriptomics the crucial role played by this pathway for proliferative glomerulonephritis development by promoting podocyte proliferation, dedifferentiation and inflammation. Additionally, we show that alpelisib, a PI3Kα inhibitor, improves glomerular lesions and kidney function in different mouse models of proliferative glomerulonephritis and lupus nephritis by targeting podocytes. Surprisingly, we determined that pharmacological inhibition of PI3Kα affects B and T lymphocyte population in lupus nephritis mouse models with decrease in the production of proinflammatory cytokines, autoantibodies and glomerular complement deposition, which are all characteristic features of PI3K delta (PI3Kδ) inhibition, the primary PI3K isoform expressed in lymphocytes. Importantly, PI3Kα inhibition does not impact lymphocyte function under normal conditions. These findings were then confirmed in human lymphocytes isolated from patients with active lupus nephritis. In conclusion, we demonstrate the major role played by PI3Kα in proliferative glomerulonephritis and show that in this condition, alpelisib acts on both podocytes and the immune system.
Diagnostic delay and access to care in bronchiectasis: data from the EMBARC/ELF patient survey
Authors: Arietta Spinou, Marta Almagro, Bridget Harris, Jeanette Boyd, Tove Berg, Beatriz Herrero-Cortina, Annette Posthumous, Stefano Aliberti, Barbara Crossley, Thomas F. Ruddy, Nili Stein, Megan L. Crichton, Pieter C. Goeminne, James D. Chalmers, Michal Shteinberg
Journal: European Respiratory Journal (2024)

Bronchiectasis is receiving increased awareness from clinicians, researchers, and stakeholders. However, despite the development of international and national guidelines in bronchiectasis, clinical practice does not necessarily follow quality standards and clinical recommendations. The European Multicenter Bronchiectasis Audit and Research Collaboration (EMBARC) together with the European Lung Foundation (ELF) coordinate patient-initiated activities designed to facilitate bronchiectasis awareness and care [1]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of Interest: A. Spinou has nothing to disclose. Conflict of Interest: M. Almagro has nothing to disclose. Conflict of Interest: B. Harris is a patient with bronchiectasis and a member of the ELF Bronchiectasis Patient Advisory Group. This is an unpaid, voluntary role. Conflict of Interest: J. Boyd has nothing to disclose. Conflict of Interest: T. Berg has nothing to disclose. Conflict of Interest: B. Herrero-Cortina reports payment or honoraria for lectures, presentations, manuscript writing or educational events from SEPAR (Spanish Respiratory Society). Conflict of Interest: A. Posthumous is a patient with bronchiectasis and a member of the ELF Bronchiectasis Patient Advisory Group. This is an unpaid, voluntary role. Conflict of Interest: S. Aliberti has nothing to disclose. Conflict of Interest: B. Crossley is a voluntary member of the European Lung Foundation's Patient Advisory Group, for bronchiectasis. Conflict of Interest: T.F. Ruddy has nothing to disclose. Conflict of Interest: N. Stein has nothing to disclose. Conflict of Interest: M.L. Crichton reports consultancy fees from Boxer Capital LLC, Conflict of Interest: P.C. Goeminne has nothing to disclose. Conflict of Interest: J.D. Chalmers has nothing to disclose. Conflict of Interest: M. Shteinberg reports grants from GSK, Novartis, writing fees from Bohringer Ingelheim, personal fees from GSK, Novartis, AstraZeneca, Kamada, Teva, GSK, Zambon, Airphysio, Bonus Biogroup, Syncrony medical, non-financial support from GSK, Boehringer Ingelheim, Actelion, GSK, Rafa.