tbuckley/cabot-search huggingface dataset:
MtDNA genomes reveal relaxed purifying selection during human population expansion after the Last Glacial Maximum
Authors: Hong-Xiang Zheng, Shi Yan, Menghan Zhang, Zhenglong Gu, Jiucun Wang, Li Jin
Journal: Molecular Biology and Evolution (2024)

Modern humans have experienced explosive population growth in the past thousand years. We hypothesized that recent human populations have inhabited environments with relaxation of selective constraints, possibly due to the more abundant food supply after the Last Glacial Maximum. The ratio of nonsynonymous to synonymous mutations (N/S ratio) is a useful and common statistic for measuring selective constraints. In this study, we reconstructed a high-resolution phylogenetic tree using a total of 26,419 East Eurasian mitochondrial DNA genomes, which were further classified into expansion and nonexpansion groups on the basis of the frequencies of their founder lineages. We observed a much higher N/S ratio in the expansion group, especially for nonsynonymous mutations with moderately deleterious effects, indicating a weaker effect of purifying selection in the expanded clades. However, this observation on N/S ratio was unlikely in computer simulations where all individuals were under the same selective constraints. Thus, we argue that the expanded populations were subjected to weaker selective constraints than the nonexpanded populations were. The mildly deleterious mutations were retained during population expansion, which could have a profound impact on present-day disease patterns.
Novel <i>ERBB2</i> Variant Potentially Associated with Resistance against Anti-HER2 Monoclonal Antibody–Based Therapy in <i>ERBB2</i>-Amplified Metastatic Colorectal Cancer
Authors: Naoko Iida, Mitsuho Imai, Wataru Okamoto, Takeshi Kato, Taito Esaki, Ken Kato, Yoshito Komatsu, Satoshi Yuki, Toshiki Masuishi, Tomohiro Nishina, Hiromichi Ebi, Hiroya Taniguchi, Norio Nonomura, Yu Sunakawa, Manabu Shiozawa, Kentaro Yamazaki, Shogen Boku, Hideaki Bando, Yuichi Shiraishi, Maki Kobayashi, Hiroki Goto, Akihiro Sato, Satoshi Fujii, Takayuki Yoshino, Yoshiaki Nakamura
Journal: Clinical Cancer Research (2024)

Abstract Purpose: HER2-targeted therapies in ERBB2-amplified metastatic colorectal cancer (mCRC) are effective; however, a notable portion of patients do not respond to treatment, and secondary resistance occurs in most patients receiving these treatments. The purpose of this study was to investigate determinants of treatment efficacy and resistance in patients with ERBB2-amplified mCRC who received HER2-targeted therapy by analyzing multiomics data. Experimental Design: We investigated genomic data from a nationwide large cancer genomic screening project, the SCRUM-Japan project. We analyzed paired genome and transcriptome data of tissue and genomic data of ctDNA collected pre- and postprogression in patients enrolled in the related trial, TRIUMPH, in ERBB2-amplified mCRC. Results: In 155 patients with ERBB2-amplified solid tumors who received HER2-targeted therapy based on the SCRUM-Japan project, the objective response rate was 50%, 51%, and 35% in ERBB2 wild-type, variant of unknown significance, and pathogenic variant groups, respectively. In the paired genome and transcriptome data analyses in TRIUMPH, we identified the novel splicing-associated variant c.644-66_-2del in one of the 11 patients with paired whole-exome sequencing and whole-transcriptome sequencing data sets, which lacks the binding domain of pertuzumab, in progressed metastatic tumor as a variant with potential pathogenicity. The time-course ctDNA analysis detected c.644-66_-2del as an acquired variant. Conclusions: This study highlighted the importance of ERBB2 genomic status when evaluating the efficacy of HER2-targeted therapies in ERBB2-amplified mCRC. The identification of a novel splicing-associated variant may provide insights into potential mechanisms of treatment resistance. Furthermore, we demonstrated the utility of ctDNA to follow the acquired genomic status of mCRC tumors.
The quality-of-life impact of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) on patients’ lives: An interpretative descriptive qualitative study
Authors: Pauline O’Reilly, Sarah Walsh, Christopher B Bunker, Sheila Ryan, Pierre-André Natella, Audrey Colin, Jacqueline Simpson, Louise A Barry, Pauline Meskell, Roni Dodiuk-Gad, Alice Coffey, Rajamanikandan Savarimalai, Donal G Fortune, Saskia Ingen-Housz-Oro
Journal: British Journal of Dermatology (2024)

Abstract Background Much has been documented about the physical sequelae of Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). While less documented, it is recognized that patients can have long-lasting psychological sequelae. There is a lack of qualitative research on the quality of life (QoL) experiences of adults who have been diagnosed with SJS/TEN. Objectives To explore the experiences of adults who had SJS/TEN and how these experiences relate to their QoL. Methods Using an interpretative descriptive qualitative study, a purposive sample of 18 adults with SJS/TEN were interviewed using in-depth semi-structured interviews. Data were analysed using content analysis. Results Two themes were constructed, each with two categories. Theme 1 (Psychosocial Impacts) included the categories ‘The self and others’ and ‘A changed perspective on life’. Theme 2 (Chronicity of Sequelae) comprised the categories ‘Multi-organ involvement’ and ‘Further consequences of TEN’. Conclusions Findings highlighted that SJS/TEN had a significant impact on the different QoL experiences of participants including psychological, physical, social, educational and occupational. Many expressed challenges they faced following discharge from hospital, including gaps in psychological care, navigating disjointed care pathways and lack of coordinated care. If SJS/TEN is viewed as a chronic condition, it is important that researchers and clinicians study the long-term effects of SJS/TEN on people’s lives to aid in developing a plan of care to enhance the QoL for this cohort. Psychological and QoL assessments following discharge from hospital require consideration.
<i>FGFR3</i> alterations in bladder cancer: Sensitivity and resistance to targeted therapies
Authors: Maxim Noeraparast, Katarina Krajina, Renate Pichler, Dora Niedersüß‐Beke, Shahrokh F Shariat, Viktor Grünwald, Sascha Ahyai, Martin Pichler
Journal: Cancer Communications (2024)

Abstract In this review, we revisit the pivotal role of fibroblast growth factor receptor 3 (FGFR3) in bladder cancer (BLCA), underscoring its prevalence in both non‐muscle‐invasive and muscle‐invasive forms of the disease. FGFR3 mutations in up to half of BLCAs play a well‐established role in tumorigenesis, shaping distinct tumor initiation patterns and impacting the tumor microenvironment (TME). Emphasizing the importance of considering epithelial‐mesenchymal transition profile and TME status, we revisit their relevance in predicting responses to immune checkpoint inhibitors in FGFR3‐mutated BLCAs. This writing highlights the initially promising yet transient efficacy of the FGFR inhibitor Erdafitinib on FGFR3‐mutated BLCA, stressing the pressing need to unravel resistance mechanisms and identify co‐targets for future combinatorial studies. A thorough analysis of recent preclinical and clinical evidence reveals resistance mechanisms, including secondary mutations, epigenetic alterations in pathway effectors, phenotypic heterogeneity, and population‐specific variations within FGFR3 mutational status. Lastly, we discuss the potential of combinatorial treatments and concepts like synthetic lethality for discovering more effective targeted therapies against FGFR3‐mutated BLCA.
Naloxone in Out-of-Hospital Cardiac Arrest—More Than Just Opioid Reversal
Authors: David A. Wampler
Journal: JAMA Network Open (2024)

David G. Dillon, MD, PhD; Juan Carlos C. Montoy, MD, PhD; Daniel K. Nishijima, MD; Sara Niederberger, MD; James J. Menegazzi, PhD; Jeremy Lacocque, DO; Robert M. Rodriguez, MD; Ralph C. Wang, MD
Naloxone and Patient Outcomes in Out-of-Hospital Cardiac Arrests in California
Authors: David G. Dillon, Juan Carlos C. Montoy, Daniel K. Nishijima, Sara Niederberger, James J. Menegazzi, Jeremy Lacocque, Robert M. Rodriguez, Ralph C. Wang
Journal: JAMA Network Open (2024)

The incidence of opioid-associated out-of-hospital cardiac arrest (OA-OHCA) has grown from less than 1% of OHCA in 2000 to between 7% and 14% of OHCA in recent years; American Heart Association (AHA) protocols suggest that emergency medical service (EMS) clinicians consider naloxone in OA-OHCA. However, it is unknown whether naloxone improves survival in these patients or in patients with undifferentiated OHCA.
Chemotherapy drives tertiary lymphoid structures that correlate with ICI-responsive TCF1+CD8+ T cells in metastatic ovarian cancer
Authors: Tereza Lanickova, Michal Hensler, Lenka Kasikova, Sarka Vosahlikova, Artemis Angelidou, Josef Pasulka, Hannah Griebler, Jana Drozenova, Katerina Mojzisova, Ann Vankerckhoven, Jan Laco, Ales Ryska, Pavel Dundr, Roman Kocian, David Cibula, Tomas Brtnicky, Petr Skapa, Francis Jacob, Marek Kovar, Ivan Praznovec, Iain A. McNeish, Michal J. Halaska, Lukas Rob, An Coosemans, Sandra Orsulic, Lorenzo Galluzzi, Radek Spisek, Jitka Fucikova
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Patients with high-grade serous ovarian carcinoma (HGSOC) are virtually insensitive to immune checkpoint inhibitors (ICI) employed as standalone therapeutics, at least in part reflecting microenvironmental immunosuppression. Thus, conventional chemotherapeutics and targeted anticancer agents that not only mediate cytotoxic effects but also promote the recruitment of immune effector cells to the HGSOC microenvironment stand out as promising combinatorial partners for ICIs in this oncological indication. Experimental Design: We harnessed a variety of transcriptomic, spatial, and functional assays to characterize the differential impact of neoadjuvant paclitaxel-carboplatin on the immunological configuration of paired primary and metastatic HGSOC biopsies as compared to neoadjuvant chemotherapy (NACT)-naïve HGSOC samples from five independent patient cohorts. Results: We found NACT-driven endoplasmic reticulum stress and calreticulin exposure in metastatic HGSOC lesions culminates with the establishment of a dense immune infiltrate including follicular T cells (TFH cells), a prerequisite for mature tertiary lymphoid structure (TLS) formation. In this context, TLS maturation was associated with an increased intratumoral density of ICI-sensitive TCF1+PD1+ CD8+ T cells over their ICI-insensitive TIM-3+PD1+ counterparts. Consistent with this notion, chemotherapy coupled with a PD1-targeting ICI provided a significant survival benefit over either therapeutic approach in syngeneic models of HGSOC bearing high (but not low) tumor mutational burden. Conclusions: Altogether, our findings suggest that NACT promotes TLS formation and maturation in HGSOC lesions, de facto preserving an intratumoral ICI-sensitive T-cell phenotype. These observations emphasize the role of rational design, especially relative to the administration schedule, for clinical trials testing chemotherapy plus ICIs in patients with HGSOC.
Screening and Supplementation for Iron Deficiency and Iron Deficiency Anemia During Pregnancy
Authors: Amy G. Cantor, Rebecca Holmes, Christina Bougatsos, Chandler Atchison, Thomas DeLoughery, Roger Chou
Journal: JAMA (2024)

Importance In 2015 the US Preventive Services Task Force (USPSTF) found insufficient evidence to assess the balance of benefits and harms of routine screening and supplementation for iron deficiency anemia during pregnancy. Objective To update the 2015 review on screening for iron deficiency anemia, in addition to iron deficiency during pregnancy, to inform the USPSTF. Data Sources Ovid MEDLINE and Cochrane databases through May 24, 2023; surveillance through May 24, 2024. Study Selection Randomized clinical trials of iron supplementation, screening effectiveness, treatment, and harms; observational studies of screening. Data Extraction and Synthesis Dual review of abstracts, full-text articles, study quality, and data abstraction. Data were pooled using a random-effects model. Main Outcomes and Measures Maternal and infant clinical outcomes, hematologic indices, and harms. Results Seventeen trials (N = 24 023) on maternal iron supplementation were included. Iron supplementation was associated with decreased risk of maternal iron deficiency anemia at term (4 trials, n = 2230; 8.6% vs 19.8%; relative risk, 0.40 [95% CI, 0.26-0.61]; I 2 = 20.5%) and maternal iron deficiency at term (6 trials, n = 2361; 46% vs 70%; relative risk, 0.47 [95% CI, 0.33-0.67]; I 2 = 81.9%) compared with placebo or no iron supplement. There were no statistically significant differences in maternal quality of life, rates of gestational diabetes, maternal hemorrhage, hypertensive disorders of pregnancy, cesarean delivery, preterm birth, infant low birth weight, or infants small for gestational age for maternal iron supplementation compared with placebo or no supplementation. Harms of iron supplementation included transient gastrointestinal adverse effects. No studies evaluated the benefits or harms of screening for iron deficiency or iron deficiency anemia during pregnancy. Data on the association between iron status and health outcomes, such as hypertensive disorders of pregnancy and preterm birth, were very limited. Conclusions and Relevance Routine prenatal iron supplementation reduces the incidence of iron deficiency and iron deficiency anemia during pregnancy, but evidence on health outcomes is limited or indicates no benefit. No studies addressed screening for iron deficiency or iron deficiency anemia during pregnancy. Research is needed to understand the association between changes in maternal iron status measures and health outcomes.
GLP-1 Receptor Agonists and Suicidality—Caution Is Needed
Authors: Francesco Salvo, Jean-Luc Faillie
Journal: JAMA Network Open (2024)

Georgios Schoretsanitis, MD, PhD; Stefan Weiler, MD, PhD; Corrado Barbui, MD; Emanuel Raschi, PhD; Chiara Gastaldon, MD, PhD
Tracheal intubation in critically ill adults with a physiologically difficult airway. An international Delphi study
Authors: Kunal Karamchandani, Prashant Nasa, Mary Jarzebowski, David J. Brewster, Audrey De Jong, Philippe R. Bauer, Lauren Berkow, Calvin A. Brown, Luca Cabrini, Jonathan Casey, Tim Cook, Jigeeshu Vasishtha Divatia, Laura V. Duggan, Louise Ellard, Begum Ergan, Malin Jonsson Fagerlund, Jonathan Gatward, Robert Greif, Andy Higgs, Samir Jaber, David Janz, Aaron M. Joffe, Boris Jung, George Kovacs, Arthur Kwizera, John G. Laffey, Jean-Baptiste Lascarrou, J. Adam Law, Stuart Marshall, Brendan A. McGrath, Jarrod M. Mosier, Daniel Perin, Oriol Roca, Amélie Rollé, Vincenzo Russotto, John C. Sakles, Gentle S. Shrestha, Nathan J. Smischney, Massimiliano Sorbello, Avery Tung, Craig S. Jabaley, Sheila Nainan Myatra, Kariem El-Boghdadly, Anna Budde, Stephen Estime, Kristina Goff, Rachel Kadar, Ashish K. Khanna, Crystal Manohar, Gerald Matchett, Ronald G. Pearl, Robert D. Stevens, Habib Srour
Journal: Intensive Care Medicine (2024)
Anemic Data for Preventive Screening and Supplementation to Address Iron Deficiency Anemia in Pregnancy
Authors: Elaine L. Duryea, Catherine Y. Spong
Journal: JAMA (2024)

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Concurrent chemoradiotherapyof different radiation doses and different irradiation fields for locally advanced thoracic esophageal squamous cell carcinoma: A randomized, multicenter, phase III clinical trial
Authors: Jian Zhang, Minghao Li, Kaixian Zhang, Anping Zheng, Guang Li, Wei Huang, Shaoshui Chen, Xiangming Chen, Xiaomin Li, Yanxing Sheng, Xinchen Sun, Liping Liu, Xiaowei Liu, Jie Li, Jun Wang, Hong Ge, Shucheng Ye, Qingsong Pang, Xianwen Zhang, Shengbin Dai, Richard Yu, Wendong Gu, Mingming Dai, Gaowa Siqin, Yunwei Han, Xiaolin Ge, Xin Yuan, Yongjing Yang, Haiwen Zhu, Juan Pu, Lihua Dong, Xiangdong Sun, Jundong Zhou, Weidong Mao, Fei Gao, Haiqun Lin, Heyi Gong, Tao Zhou, Zhenjiang Li, Hongsheng Li, Zhongtang Wang, Baosheng Li
Journal: Cancer Communications (2024)

Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC). However, the optimal radiotherapy regimen, particularly in terms of total dose and planned range of irradiation field, remains unclear. This phase III clinical trial aimed to compare the survival benefits between different radiation doses and different target fields.
Microbiota and plasticity of antigen-presenting ILC3s: impact on antitumor immune response
Authors: Alessia Calabrò, Fabiana Drommi, Claudia De Pasquale, Giuseppe Navarra, Paolo Carrega, Irene Bonaccorsi, Guido Ferlazzo, Stefania Campana
Journal: Gut Microbes (2024)

Growing evidence highlights the pivotal role of RORγt-innate lymphoid cells (ILCs) in the establishment of antitumor immune response and in enhancing tumor sensitivity to immunotherapy. Noteworthy, type 3 ILCs (ILC3s) have been recently acknowledged as an important class of antigen-presenting cells (APCs) in the context of host–microorganism interactions shaping the adaptive immune response in the intestinal mucosa. Although a broad range of mouse models has led to significant progress in untangling the role of ILC3s as APCs, the outcome of major histocompatibility complex (MHC)-dependent ILC-T cell crosstalk in colorectal cancer (CRC) remains underexplored in human. Moreover, expression of MHCII is confined to ILC3 subset, endowed with lymphoid tissue-inducing properties, that adopts tissue-specific fates and functions. Intestinal microbiota could dictate the plasticity of antigen-presenting ILC3s and we here summarize our current understanding of the functions of these cells in both mouse and human CRC discussing the role of microbiota as a key modulator of their tumor-suppressive activity.
Enhanced Type 1 Interferon Signature in Axial Spondyloarthritis Patients Unresponsive to Secukinumab Treatment
Authors: Addison Pacheco, Sinead Maguire, Zoya Qaiyum, Michael Tang, Adam Bridger, Melissa Lim, Fataneh Tavasolian, Enoch Yau, Sarah Q. Crome, Nigil Haroon, Robert D. Inman
Journal: Arthritis & Rheumatology (2024)

Axial spondyloarthritis (axSpA) is an inflammatory disease in which overactive interleukin (IL)-17A-producing cells are implicated in a central role. Therapeutically, biologics that target IL-17A, such as secukinumab, have demonstrated improved clinical outcomes. Despite this translational success, there is a gap in understanding why some patients with axSpA do not respond to IL-17A-blocking therapy. Our study aims to discriminate immune profiles between secukinumab responders (SEC-R) and nonresponders (SEC-NR).
Infantile colic is associated with development of later constipation and atopic disorders
Authors: Jakob Stokholm, Jonathan Thorsen, Ann‐Marie Malby Schoos, Morten Arendt Rasmussen, Sarah Brandt, Søren Johannes Sørensen, Nilo Vahman, Bo Chawes, Klaus Bønnelykke
Journal: Allergy (2024)

Infantile colic is a common condition with limited knowledge about later clinical manifestations. We evaluated the role of the early life gut microbiome in infantile colic and later development of atopic and gastrointestinal disorders.
Clinical Images: Painless subcutaneous swellings in a middle‐aged man
Authors: Alekhya Amudalapalli, Rasmi Ranjan Sahoo, Ashlesha Shukla, Pradeepta Sekhar Patro
Journal: Arthritis & Rheumatology (2024)

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Validating quantitative pupillometry thresholds for neuroprognostication after out-of-hospital cardiac arrest. A predefined substudy of the Blood Pressure and Oxygenations Targets After Cardiac Arrest (BOX)-trial
Authors: Benjamin Nyholm, Johannes Grand, Laust E. R. Obling, Christian Hassager, Jacob Eifer Møller, Henrik Schmidt, Marwan H. Othman, Daniel Kondziella, Janneke Horn, Jesper Kjaergaard
Journal: Intensive Care Medicine (2024)

Out-of-hospital cardiac arrest (OHCA) survivors face significant risks of complications and death from hypoxic–ischemic brain injury leading to withdrawal of life-sustaining treatment (WLST). Accurate multimodal neuroprognostication, including automated pupillometry, is essential to avoid inappropriate WLST. However, inconsistent study results hinder standardized threshold recommendations. We aimed to validate proposed pupillometry thresholds with no false predictions of unfavorable outcomes in comatose OHCA survivors. In the multi-center BOX-trial, quantitative measurements of automated pupillometry (quantitatively assessed pupillary light reflex [qPLR] and Neurological Pupil index [NPi]) were obtained at admission (0 h) and after 24, 48, and 72 h in comatose patients resuscitated from OHCA. We aimed to validate qPLR < 4% and NPi ≤ 2, predicting unfavorable neurological conditions defined as Cerebral Performance Category 3–5 at follow-up. Combined with 48-h neuron-specific enolase (NSE) > 60 μg/L, pupillometry was evaluated for multimodal neuroprognostication in comatose patients with Glasgow Motor Score (M) ≤ 3 at ≥ 72 h. From March 2017 to December 2021, we consecutively enrolled 710 OHCA survivors (mean age: 63 ± 14 years; 82% males), and 266 (37%) patients had unfavorable neurological outcomes. An NPi ≤ 2 predicted outcome with 0% false-positive rate (FPR) at all time points (0–72 h), and qPLR < 4% at 24–72 h. In patients with M ≤ 3 at ≥ 72 h, pupillometry thresholds significantly increased the sensitivity of NSE, from 42% (35–51%) to 55% (47–63%) for qPLR and 50% (42–58%) for NPi, maintaining 0% (0–0%) FPR. Quantitative pupillometry thresholds predict unfavorable neurological outcomes in comatose OHCA survivors and increase the sensitivity of NSE in a multimodal approach at ≥ 72 h.
Disproportionality Analysis From World Health Organization Data on Semaglutide, Liraglutide, and Suicidality
Authors: Georgios Schoretsanitis, Stefan Weiler, Corrado Barbui, Emanuel Raschi, Chiara Gastaldon
Journal: JAMA Network Open (2024)

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have gained use primarily due to their weight-reduction effects, although a regulatory review was undertaken for potential suicidality concern.
Errors in Results and Figure
Journal: JAMA Network Open (2024)

titled "Variation in Young Driver Training Requirements by State," 1 published June 17, 2024, there were errors in the Results and Figure.Three states were miscategorized as requiring behind-the-wheel training for all individuals aged less than 18 years; 2 states require training only for learners aged less than 16 years, and 1 state allows for replacement of training with adult supervised practice.This article has been corrected.