tbuckley/cabot-search huggingface dataset:
Two Phase 3 Trials of Baricitinib for Alopecia Areata
Authors: Brett King, Manabu Ohyama, Ohsang Kwon, Abraham Zlotogorski, Justin Ko, Natasha A. Mesinkovska, Maria Hordinsky, Yves Dutronc, Wen-Shuo Wu, Jill McCollam, Chiara Chiasserini, Guanglei Yu, Sarah Stanley, Katrin Holzwarth, Amy M. DeLozier, Rodney Sinclair
Journal: New England Journal of Medicine (2022)

Alopecia areata is an autoimmune condition characterized by rapid hair loss in the scalp, eyebrows, and eyelashes, for which treatments are limited. Baricitinib, an oral, selective, reversible inhibitor of Janus kinases 1 and 2, may interrupt cytokine signaling implicated in the pathogenesis of alopecia areata.We conducted two randomized, placebo-controlled, phase 3 trials (BRAVE-AA1 and BRAVE-AA2) involving adults with severe alopecia areata with a Severity of Alopecia Tool (SALT) score of 50 or higher (range, 0 [no scalp hair loss] to 100 [complete scalp hair loss]). Patients were randomly assigned in a 3:2:2 ratio to receive once-daily baricitinib at a dose of 4 mg, baricitinib at a dose of 2 mg, or placebo. The primary outcome was a SALT score of 20 or less at week 36.We enrolled 654 patients in the BRAVE-AA1 trial and 546 in the BRAVE-AA2 trial. The estimated percentage of patients with a SALT score of 20 or less at week 36 was 38.8% with 4-mg baricitinib, 22.8% with 2-mg baricitinib, and 6.2% with placebo in BRAVE-AA1 and 35.9%, 19.4%, and 3.3%, respectively, in BRAVE-AA2. In BRAVE-AA1, the difference between 4-mg baricitinib and placebo was 32.6 percentage points (95% confidence interval [CI], 25.6 to 39.5), and the difference between 2-mg baricitinib and placebo was 16.6 percentage points (95% CI, 9.5 to 23.8) (P<0.001 for each dose vs. placebo). In BRAVE-AA2, the corresponding values were 32.6 percentage points (95% CI, 25.6 to 39.6) and 16.1 percentage points (95% CI, 9.1 to 23.2) (P<0.001 for each dose vs. placebo). Secondary outcomes for baricitinib at a dose of 4 mg but not at a dose of 2 mg generally favored baricitinib over placebo. Acne, elevated levels of creatine kinase, and increased levels of low- and high-density lipoprotein cholesterol were more common with baricitinib than with placebo.In two phase 3 trials involving patients with severe alopecia areata, oral baricitinib was superior to placebo with respect to hair regrowth at 36 weeks. Longer trials are required to assess the efficacy and safety of baricitinib for alopecia areata. (Funded by Eli Lilly under license from Incyte; BRAVE-AA1 and BRAVE-AA2 ClinicalTrials.gov numbers, NCT03570749 and NCT03899259.).
Allergen immunotherapy for asthma prevention: A systematic review and meta‐analysis of randomized and non‐randomized controlled studies
Authors: Mariana Farraia, Inês Paciência, Francisca Castro Mendes, João Cavaleiro Rufo, Mohamed Shamji, Ioana Agache, André Moreira
Journal: Allergy (2022)

Allergen immunotherapy (AIT) is a disease-modifying treatment for IgE-mediated diseases. Randomized controlled trials (RCTs) support AIT's potential role in asthma prevention but evidence from non-randomized studies of interventions (NRSI) and longitudinal observational studies has been poorly addressed. Therefore, we aimed to conduct a systematic review and meta-analysis to assess clinical data from all study types to evaluate quantitatively the preventive role of AIT in asthma onset.We search three databases. Studies were screened, selected and evaluated for quality using risk-of-bias (ROB) tools. Data were descriptively summarized and meta-analysed using random effects. We performed a sensitivity, influence and subgroup analyses. Publication bias and heterogeneity were assessed.From the 4549 identified studies, 24 (12 RCTs and 12 NRSI) were included in the qualitative synthesis and 18 underwent meta-analysis. One study was at low ROB, seven had moderate ROB, and 15 were proven of high ROB. Random-effects analysis showed a significant decrease in the risk of developing asthma following AIT by 25% (RR, 95% CI: 0.75, 0.64-0.88). This effect was not significant in the sensitivity analysis. Publication bias raised concerns, together with the moderate heterogeneity between studies (I2 = 58%). Subgroup analysis showed a remarkable preventive effect of AIT in children (RR, 95% CI: 0.71, 0.53-0.96), when completing 3 years of therapy (RR, 95% CI: 0.64, 0.47-0.88), and in mono-sensitized patients (RR, 95% CI: 0.49, 0.39-0.61).Our findings support a possible preventive effect of AIT in asthma onset and suggest an enhanced effect when administered in children, mono-sensitized, and for at least 3 years, independently of allergen type.
DEVELOPMENT OF A NOVEL SCORE TO PREDICT URGENT MECHANICAL CIRCULATORY SUPPORT IN CHRONIC TOTAL OCCLUSION PERCUTANEOUS CORONARY INTERVENTION
Authors: Judit Karacsonyi, Brynn Okeson, Khaldoon Alaswad, Farouc A. Jaffer, Paul Poomipanit, Jaikirshan J. Khatri, Mitul P. Patel, Robert F. Riley, Abdul Sheikh, Jason R. Wollmuth, Robert W. Yeh, Raj H. Chandwaney, Ahmed M. Elguindy, Khalid Tammam, Nidal Abi Rafeh, Daniel R. Schimmel, M. Nicholas Burke, Spyridon Kostantinis, Bahadir Simsek, Karen Deffenbacher, Keith H. Benzuly, James D. Flaherty, Bavana V. Rangan, Imre Ungi, Emmanouil S. Brilakis
Journal: Journal of the American College of Cardiology (2022)
WHOSE DOSE IS IT ANYWAY? INDIVIDUAL PATIENT DOSE-RESPONSE CURVES FROM THE REMOTE-CARE PERSONAL-COVIDBP TRIAL
Authors: Mike Taylor, Tom Godec, Julian Shiel, Rebecca James, Yasmin Chowdury, Patrizia Ebano, Vivienne Monk, Mital Patel, Jane Pheby, Enamuna Enobakhare, Amanda Foubister, Clovell David, Manish Saxena, James Siddle, Gregor Timlin, Paul Goldsmith, Nick Deeming, Neil R. Poulter, Rhian Gabe, Richard McManus, David J. Collier
Journal: Journal of the American College of Cardiology (2022)
Abstract MS1-2: Genomics of DNA repair defects in breast cancer
Authors: S Nik-Zainal
Journal: Cancer Research (2022)

Abstract While driver mutations in cancer genomes were the focus of cancer research for a long time, passenger mutational signatures - the imprints of DNA damage and DNA repair processes that have been operative during tumorigenesis - are also biologically informative. In this lecture, I provide an update of what has been uncovered in breast cancers in relation to genomic imprints of DNA repair defects and showcase how we have developed computational applications that we hope to translate toward clinical utility. Citation Format: S Nik-Zainal. Genomics of DNA repair defects in breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr MS1-2.
DAYS ALIVE OUT OF HOSPITAL FOR PATIENTS WITH LEFT VENTRICULAR DYSFUNCTION AND CORONARY ARTERY DISEASE TREATED WITH CORONARY ARTERY BYPASS SURGERY OR MEDICAL THERAPY: FINDINGS FROM THE STICH TRIAL
Authors: Kamil Faridi, Haocheng Huang, Helen Parise, Tariq Ahmad, Makoto Mori, Mabel Chung, Robert W. Yeh, Eric J. Velazquez
Journal: Journal of the American College of Cardiology (2022)
PREDICTORS OF ANTIPLATELET CESSATION IN A REAL-WORLD PATIENT POPULATION WITH CORONARY STENTS UNDERGOING NONCARDIAC SURGERY
Authors: Anoop Ninan Koshy, Davide Cao, Samantha Sartori, Annapoorna Subhash Kini, Zhongjie Zhang, Bimmer Claessen, Matteo Nardin, Carlo Andrea Pivato, Rishi Chandiramani, Gennaro Giustino, Mauro Chiarito, Johny Nicolas, Samin K. Sharma, Roxana Mehran
Journal: Journal of the American College of Cardiology (2022)
CRISPR based therapeutics: a new paradigm in cancer precision medicine
Authors: Sumit Das, Shehnaz Bano, Prachi Kapse, Gopal C. Kundu
Journal: Molecular Cancer (2022)

Clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated protein (Cas) systems are the latest addition to the plethora of gene-editing tools. These systems have been repurposed from their natural counterparts by means of both guide RNA and Cas nuclease engineering. These RNA-guided systems offer greater programmability and multiplexing capacity than previous generation gene editing tools based on zinc finger nucleases and transcription activator like effector nucleases. CRISPR-Cas systems show great promise for individualization of cancer precision medicine.The biology of Cas nucleases and dead Cas based systems relevant for in vivo gene therapy applications has been discussed. The CRISPR knockout, CRISPR activation and CRISPR interference based genetic screens which offer opportunity to assess functions of thousands of genes in massively parallel assays have been also highlighted. Single and combinatorial gene knockout screens lead to identification of drug targets and synthetic lethal genetic interactions across different cancer phenotypes. There are different viral and non-viral (nanoformulation based) modalities that can carry CRISPR-Cas components to different target organs in vivo.The latest developments in the field in terms of optimization of performance of the CRISPR-Cas elements should fuel greater application of the latter in the realm of precision medicine. Lastly, how the already available knowledge can help in furtherance of use of CRISPR based tools in personalized medicine has been discussed.
Use of evidence‐based therapy in heart failure with reduced ejection fraction across age strata
Authors: Davide Stolfo, Lars H. Lund, Peter Moritz Becher, Nicola Orsini, Tonje Thorvaldsen, Lina Benson, Camilla Hage, Ulf Dahlström, Gianfranco Sinagra, Gianluigi Savarese
Journal: European Journal of Heart Failure (2022)

Aims In older patients, guideline‐directed medical therapy (GDMT) for heart failure (HF) with reduced ejection fraction (&lt;40%; HFrEF) is not contraindicated, but adherence to guidelines is limited. We investigated the implementation of GDMT in HFrEF across different age strata in a large nationwide cohort. Methods and results Patients with HFrEF and HF duration ≥3 months registered in the Swedish HF Registry between 2000–2018 were analysed according to age. Multivariable logistic and multinomial regressions were fitted to investigate factors associated with underuse/underdosing. Of 27 430 patients, 31% were &lt;70 years old, 34% 70–79 years old, and 35% ≥80 years old. Use of treatments progressively decreased with increasing age. Use of renin–angiotensin system/angiotensin receptor–neprilysin inhibitors, beta‐blockers and mineralocorticoid receptor antagonists was 80%, 88% and 35% in age ≥80 years; 90%, 93% and 47% in age 70–79 years; and 95%, 95% and 54% in age &lt;70 years, respectively. Among patients with an indication, use of implantable cardioverter defibrillator and cardiac resynchronization therapy (CRT) was 7% and 23% in age ≥ 80 years; 22% and 42% in age 70–79 years; and 29% and 50% in age &lt;70 years, respectively. Older patients were less likely treated with target doses or combinations of HF medications. Except for CRT, after extensive adjustments, age was inversely associated with the likelihood of GDMT use and target dose achievement. Conclusion In HFrEF, gaps persist in the use of medications and devices. In disagreement with current recommendations, older patients remain undertreated. Improving strategies and a more individualized approach for implementing use of GDMT in HFrEF are required, particularly in older patients.
TET2 Clonal Hematopoiesis Is Associated With Anthracycline-Induced Cardiotoxicity in Patients With Lymphoma
Authors: Kiwamu Hatakeyama, Michinari Hieda, Yuichiro Semba, Shohei Moriyama, Yuqing Wang, Takahiro Maeda, Koji Kato, Toshihiro Miyamoto, Koichi Akashi, Yoshikane Kikushige
Journal: JACC CardioOncology (2022)
Abstract BS1-2: A new perspective on androgen receptor action in estrogen receptor-α positive breast cancer
Authors: W Tilley
Journal: Cancer Research (2022)

Abstract Resistance to estrogen receptor alpha (ER) target therapies is the major cause of breast cancer death. Therapeutic engagement of steroid receptors that impinge on, but do not ablate, ER signalling is an emerging new treatment strategy. The AR is expressed in the majority of breast tumors and represents an exceptional therapeutic target, especially as a range of drugs including AR agonists, antagonists and selective AR modulators (SARMs) are available. Interest in targeting AR for treatment of breast cancer has escalated over the past decade. Despite clinical correlations and preclinical studies supporting a protective role for AR in breast cancer, especially in ER-positive disease, enthusiasm was largely directed toward antagonizing AR with anti-androgenic drugs used to treat men with prostate cancer, a disease definitively driven by oncogenic AR activity. While some pre-clinical studies supported use of an AR antagonist for ER-positive breast cancer, this strategy has had minimal success in clinical trials. Our most recent preclinical studies using a diverse range of in vivo breast cancer models (Hickey et al, Nature Medicine 2021) provides compelling evidence for (i) AR being a tumor suppressor in ER+ breast cancer, and (ii) an AR agonist, not an antagonist, treatment strategy being the optimal therapeutic approach. Citation Format: W Tilley. A new perspective on androgen receptor action in estrogen receptor-α positive breast cancer. [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr BS1-2.
Association of Music Interventions With Health-Related Quality of Life
Authors: J. Matt McCrary, Eckart Altenmüller, Clara Kretschmer, Daniel S. Scholz
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Increasing evidence supports the ability of music to broadly promote well-being and health-related quality of life (HRQOL). However, the magnitude of music's positive association with HRQOL is still unclear, particularly relative to established interventions, limiting inclusion of music interventions in health policy and care. <h3>Objective</h3> To synthesize results of studies investigating outcomes of music interventions in terms of HRQOL, as assessed by the 36- and 12-Item Health Survey Short Forms (SF-36 and SF-12). <h3>Data Sources</h3> MEDLINE, Embase, Web of Science, PsycINFO, ClinicalTrials.gov, and International Clinical Trials Registry Platform (searched July 30, 2021, with no restrictions). <h3>Study Selection</h3> Inclusion criteria were randomized and single-group studies of music interventions reporting SF-36 data at time points before and after the intervention. Observational studies were excluded. Studies were reviewed independently by 2 authors. <h3>Data Extraction and Synthesis</h3> Data were independently extracted and appraised using GRADE criteria (Grading of Recommendations, Assessment, Development, and Evaluations) by multiple authors. Inverse-variance random-effects meta-analyses quantified changes in SF-36 mental and physical component summary (respectively, MCS and PCS) scores from preintervention to postintervention and vs common control groups. <h3>Main Outcomes and Measures</h3> SF-36 or SF-12 MCS and PCS scores, defined a priori. <h3>Results</h3> Analyses included 779 participants from 26 studies (mean [SD] age, 60 [11] years). Music interventions (music listening, 10 studies; music therapy, 7 studies; singing, 8 studies; gospel music, 1 study) were associated with significant improvements in MCS scores (total mean difference, 2.95 points; 95% CI, 1.39-4.51 points;<i>P</i> &lt; .001) and PCS scores (total mean difference, 1.09 points; 95% CI, 0.15-2.03 points;<i>P</i> = .02). In subgroup analysis (8 studies), the addition of music to standard treatment for a range of conditions was associated with significant improvements in MCS scores vs standard treatment alone (mean difference, 3.72 points; 95% CI, 0.40-7.05 points;<i>P</i> = .03). Effect sizes did not vary between music intervention types or doses; no evidence of small study or publication biases was present in any analysis. Mean difference in MCS scores met SF-36 minimum important difference thresholds (mean difference 3 or greater). <h3>Conclusions and Relevance</h3> In this systematic review and meta-analysis, music interventions were associated with clinically meaningful improvements in HRQOL; however, substantial individual variation in intervention outcomes precluded conclusions regarding optimal music interventions and doses for distinct clinical and public health scenarios.
ACE-I AND ARBS DO NOT INFLUENCE THE CHEST CT PRESENTATION AND 1-YEAR SURVIVAL OF COVID-19 PATIENTS: ITALIAN MULTICENTER REGISTRY
Authors: Lucia Ilaria Birtolo, Fabio Infusino, Alessandro Depaoli, Sara Cimino, Silvia Porsperi, Fabrizio D'Ascenzo, Maria Chiara Colaiacomo, Chiara Andreoli, Giovanni Battista Forleo, Marco Schiavone, Chiara Valentina Lario, Sara Monosilio, Paolo Ricci, Carlo Catalano, Giancarlo Ceccarelli, Gabriella D'Ettorre, Gioacchino Galardo, Francesco Pugliese, Gaetano Maria De Ferrari, Viviana Maestrini, Massimo Mancone, Francesco Fedele
Journal: Journal of the American College of Cardiology (2022)
Shared computational principles for language processing in humans and deep language models
Authors: Ariel Goldstein, Zaid Zada, Eliav Buchnik, Mariano Schain, Amy Price, Bobbi Aubrey, Samuel A. Nastase, Amir Feder, Dotan Emanuel, Alon Cohen, Aren Jansen, Harshvardhan Gazula, Gina Choe, Aditi Rao, Catherine Kim, Colton Casto, Lora Fanda, Werner Doyle, Daniel Friedman, Patricia Dugan, Lucia Melloni, Roi Reichart, Sasha Devore, Adeen Flinker, Liat Hasenfratz, Omer Levy, Avinatan Hassidim, Michael Brenner, Yossi Matias, Kenneth A. Norman, Orrin Devinsky, Uri Hasson
Journal: Nature Neuroscience (2022)

Departing from traditional linguistic models, advances in deep learning have resulted in a new type of predictive (autoregressive) deep language models (DLMs). Using a self-supervised next-word prediction task, these models generate appropriate linguistic responses in a given context. In the current study, nine participants listened to a 30-min podcast while their brain responses were recorded using electrocorticography (ECoG). We provide empirical evidence that the human brain and autoregressive DLMs share three fundamental computational principles as they process the same natural narrative: (1) both are engaged in continuous next-word prediction before word onset; (2) both match their pre-onset predictions to the incoming word to calculate post-onset surprise; (3) both rely on contextual embeddings to represent words in natural contexts. Together, our findings suggest that autoregressive DLMs provide a new and biologically feasible computational framework for studying the neural basis of language.
Global urban temporal trends in fine particulate matter (PM2·5) and attributable health burdens: estimates from global datasets
Authors: Veronica A Southerland, Michael Brauer, Arash Mohegh, Melanie S Hammer, Aaron van Donkelaar, Randall V Martin, Joshua S Apte, Susan C Anenberg
Journal: The Lancet Planetary Health (2022)

With much of the world's population residing in urban areas, an understanding of air pollution exposures at the city level can inform mitigation approaches. Previous studies of global urban air pollution have not considered trends in air pollutant concentrations nor corresponding attributable mortality burdens. We aimed to estimate trends in fine particulate matter (PM2·5) concentrations and associated mortality for cities globally.We use high-resolution annual average PM2·5 concentrations, epidemiologically derived concentration response functions, and country-level baseline disease rates to estimate population-weighted PM2·5 concentrations and attributable cause-specific mortality in 13 160 urban centres between the years 2000 and 2019.Although regional averages of urban PM2·5 concentrations decreased between the years 2000 and 2019, we found considerable heterogeneity in trends of PM2·5 concentrations between urban areas. Approximately 86% (2·5 billion inhabitants) of urban inhabitants lived in urban areas that exceeded WHO's 2005 guideline annual average PM2·5 (10 μg/m3), resulting in an excess of 1·8 million (95% CI 1·34 million-2·3 million) deaths in 2019. Regional averages of PM2·5-attributable deaths increased in all regions except for Europe and the Americas, driven by changes in population numbers, age structures, and disease rates. In some cities, PM2·5-attributable mortality increased despite decreases in PM2·5 concentrations, resulting from shifting age distributions and rates of non-communicable disease.Our study showed that, between the years 2000 and 2019, most of the world's urban population lived in areas with unhealthy levels of PM2·5, leading to substantial contributions to non-communicable disease burdens. Our results highlight that avoiding the large public health burden from urban PM2·5 will require strategies that reduce exposure through emissions mitigation, as well as strategies that reduce vulnerability to PM2·5 by improving overall public health.NASA, Wellcome Trust.
A visual circuit related to the periaqueductal gray area for the antinociceptive effects of bright light treatment
Authors: Zhengfang Hu, Yiman Mu, Lu Huang, Yuqing Hu, Zhiqing Chen, Yan Yang, Xiaodan Huang, Yunwei Fu, Yue Xi, Song Lin, Qian Tao, Fuqiang Xu, Kwok-Fai So, Chaoran Ren
Journal: Neuron (2022)
Germline biomarkers predict toxicity to anti-PD1/PDL1 checkpoint therapy
Authors: Joanne Weidhaas, Nicholas Marco, Aaron W Scheffler, Anusha Kalbasi, Kirk Wilenius, Emily Rietdorf, Jaya Gill, Mara Heilig, Caroline Desler, Robert K Chin, Tania Kaprealian, Susan McCloskey, Ann Raldow, Naga P Raja, Santosh Kesari, Jose Carrillo, Alexandra Drakaki, Mark Scholz, Donatello Telesca
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background There is great interest in finding ways to identify patients who will develop toxicity to cancer therapies. This has become especially pressing in the era of immune therapy, where toxicity can be long-lasting and life-altering, and primarily comes in the form of immune-related adverse effects (irAEs). Treatment with the first drugs in this class, anti-programmed death 1 (anti-PD1)/programmed death-ligand 1 (PDL1) checkpoint therapies, results in grade 2 or higher irAEs in up to 25%–30% of patients, which occur most commonly within the first 6 months of treatment and can include arthralgias, rash, pruritus, pneumonitis, diarrhea and/or colitis, hepatitis, and endocrinopathies. We tested the hypothesis that germline microRNA pathway functional variants, known to predict altered systemic stress responses to cancer therapies, would predict irAEs in patients across cancer types. Methods MicroRNA pathway variants were evaluated for an association with grade 2 or higher toxicity using four classifiers on 62 patients with melanoma, and then the panel’s performance was validated on 99 patients with other cancer types. Trained classifiers included classification trees, LASSO-regularized logistic regression, boosted trees, and random forests. Final performance measures were reported on the training set using leave-one-out cross validation and validated on held-out samples. The predicted probability of toxicity was evaluated for its association, if any, with response categories to anti-PD1/PDL1 therapy in the melanoma cohort. Results A biomarker panel was identified that predicts toxicity with 80% accuracy (F1=0.76, area under the curve (AUC)=0.82) in the melanoma training cohort and 77.6% accuracy (F1=0.621, AUC=0.778) in the pan-cancer validation cohort. In the melanoma cohort, the predictive probability of toxicity was not associated with response categories to anti-PD1/PDL1 therapy (p=0.70). In the same cohort, the most significant biomarker of toxicity in RAC1 , predicting a greater than ninefold increased risk of toxicity (p&lt;0.001), was also not associated with response to anti-PD1/PDL1 therapy (p=0.151). Conclusions A germline microRNA-based biomarker signature predicts grade 2 and higher irAEs to anti-PD1/PDL1 therapy, regardless of tumor type, in a pan-cancer manner. These findings represent an important step toward personalizing checkpoint therapy, the use of which is growing rapidly.