tbuckley/cabot-search huggingface dataset:
Risk of Major Adverse Cardiovascular Events, Severe Hypoglycemia, and All-Cause Mortality in Postpancreatitis Diabetes Mellitus Versus Type 2 Diabetes: A Nationwide Population-Based Cohort Study
Authors: Søren S. Olesen, Rikke Viggers, Asbjørn M. Drewes, Peter Vestergaard, Morten H. Jensen
Journal: Diabetes Care (2022)

Postpancreatitis diabetes mellitus (PPDM) is a frequent complication of pancreatitis and associates with poor glycemic control. We investigated the risk of adverse diabetes-related outcomes in PPDM compared with type 2 diabetes.In this Danish population-based cohort study, we included adults (>18 years) with incident PPDM or type 2 diabetes between 1998 and 2018 through national health registries. PPDM was further divided into acute (PPDM-A) and chronic (PPDM-C) subtypes. We ascertained risk of major adverse cardiovascular events (MACE), severe hypoglycemia, and all-cause mortality as well as incidence rates of severe hypoglycemia. We compared risk and incidence rates across diabetes subgroups using multivariate Cox and Poisson regression analyses.We identified 383,325 people with incident type 2 diabetes, 3,418 with PPDM-A, and 2,461 with PPDM-C. Compared with type 2 diabetes, PPDM-C was associated with increased risks of severe hypoglycemia (hazard ratio [HR] 5.27, 95% CI 4.62-6.00, P < 0.001) and all-cause mortality (HR 1.54, 95% CI 1.45-1.64, P < 0.001). Similar patterns were observed for people with PPDM-A. Incidence rate ratios (IRRs) for severe hypoglycemia were increased in both PPDM-C (IRR 7.38, 95% CI 6.75-8.08, P < 0.001) and PPDM-A (IRR 3.76, 95% CI 3.36-4.21, P < 0.001) compared with type 2 diabetes. Findings were consistent in an analysis restricted to people on insulin and in an analysis including pancreatitis patients without diabetes as comparator group.Compared with type 2 diabetes, PPDM is associated with excess risk of adverse diabetes-related outcomes. This has important implications for management.
CAN 3-D ECHOCARDIOGRAPHIC VENTRICULAR VOLUMES PREDICT OUTCOMES AFTER BIVENTRICULAR REPAIR IN INFANTS AND CHILDREN WITH BALANCED AND UNBALANCED ATRIOVENTRICULAR CANAL DEFECTS?
Authors: Emily Bucholz, Melinda Shea, Claire Cigarroa, Sitaram M. Emani, Gerald Ross Marx
Journal: Journal of the American College of Cardiology (2022)
Exploring the safety, effect on the tumor microenvironment, and efficacy of itacitinib in combination with epacadostat or parsaclisib in advanced solid tumors: a phase I study
Authors: Aung Naing, John D Powderly, John J Nemunaitis, Jason J Luke, Aaron S Mansfield, Wells A Messersmith, Solmaz Sahebjam, Patricia M LoRusso, Ignacio Garrido-Laguna, Lance Leopold, Ryan Geschwindt, Kai Ding, Michael Smith, Jordan D Berlin
Journal: Journal for ImmunoTherapy of Cancer (2022)

This phase I multicenter study was designed to evaluate the safety, tolerability, efficacy, and translational effects on the tumor microenvironment of itacitinib (Janus-associated kinase 1 (JAK1) inhibitor) in combination with epacadostat (indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor) or parsaclisib (phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor). Patients with advanced or metastatic solid tumors were enrolled and received itacitinib (100-400 mg once a day) plus epacadostat (50-300 mg two times per day; group A), or itacitinib (100-400 mg once a day) plus parsaclisib or parsaclisib monotherapy (0.3-10 mg once a day; group B). A total of 142 patients were enrolled in the study. The maximum tolerated dose was not reached for either the combination of itacitinib plus epacadostat (n=47) or itacitinib plus parsaclisib (n=90). One dose-limiting toxicity of serious, grade 3 aseptic meningitis was reported in a patient receiving itacitinib 300 mg once a day plus parsaclisib 10 mg once a day, which resolved when the study drugs were withdrawn. The most common treatment-related adverse events among patients treated with itacitinib plus epacadostat included fatigue, nausea, pyrexia, and vomiting, and for patients treated with itacitinib plus parsaclisib were fatigue, pyrexia, and diarrhea. In the itacitinib plus epacadostat group, no patient had an objective response. Among patients receiving itacitinib 100 mg once a day plus parsaclisib 0.3 mg once a day, three achieved partial response for an objective response rate (95% CI) of 7.1% (1.50 to 19.48). Treatment with itacitinib plus epacadostat demonstrated some increase in tumor CD8+ T cell infiltration and minor changes in six plasma proteins, whereas treatment with itacitinib plus high-dose parsaclisib resulted in downregulation of 20 plasma proteins mostly involved in immune cell function, with no observed change in intratumoral CD8+ T cell infiltration. Adverse events with JAK1 inhibition combined with either IDO1 or PI3Kδ inhibition were manageable, but the combinations demonstrated limited clinical activity or enhancement of immune activation in the tumor microenvironment. NCT02559492.
Utilization of Filgrastim and Infliximab Biosimilar Products in Medicare Part D, 2015-2019
Authors: S. M. Qasim Hussaini, Arjun Gupta, Kelly E. Anderson, Jeromie M. Ballreich, Lauren Hersch Nicholas, G. Caleb Alexander
Journal: JAMA Network Open (2022)

This cross-sectional study examines utilization trends for filgrastim and infliximab products and their biosimilars to understand whether biosimilars are associated with reduced spending in Medicare Part D.
Cognitive decline and dementia: does delirium matter?
Authors: Geir Selbæk, Bjørn Erik Neerland
Journal: The Lancet Healthy Longevity (2022)

Delirium, an acute change in arousal, attention, and other aspects of cognition, affects more than one in five older inpatients, causes distress for patients and carers, and is associated with in-hospital complications, functional decline, and mortality.1 Delirium is costly for society, and evidence-based preventive measures should be implemented in routine clinical practice.2 Research has indicated that delirium might be associated with long-term cognitive decline and dementia.3
More of less: Novel multi-ome profiling of single human neurons
Authors: Huiwen Che, Bernard Thienpont
Journal: Cell Genomics (2022)

Epigenetic modifications to DNA and chromatin interact to influence gene expression and cellular phenotypes, but defining these omics layers in complex tissues is a daunting task. In this issue of Cell Genomics, Luo et al. describe a novel single-cell multi-omic method, simultaneously profiling transcriptome, DNA methylome, and chromatin accessibility, to shed light on human neurons.
Association between covid-19 vaccination, SARS-CoV-2 infection, and risk of immune mediated neurological events: population based cohort and self-controlled case series analysis
Authors: Xintong Li, Berta Raventós, Elena Roel, Andrea Pistillo, Eugenia Martinez-Hernandez, Antonella Delmestri, Carlen Reyes, Victoria Strauss, Daniel Prieto-Alhambra, Edward Burn, Talita Duarte-Salles
Journal: BMJ (2022)

Abstract Objective To study the association between covid-19 vaccines, SARS-CoV-2 infection, and risk of immune mediated neurological events. Design Population based historical rate comparison study and self-controlled case series analysis. Setting Primary care records from the United Kingdom, and primary care records from Spain linked to hospital data. Participants 8 330 497 people who received at least one dose of covid-19 vaccines ChAdOx1 nCoV-19, BNT162b2, mRNA-1273, or Ad.26.COV2.S between the rollout of the vaccination campaigns and end of data availability (UK: 9 May 2021; Spain: 30 June 2021). The study sample also comprised a cohort of 735 870 unvaccinated individuals with a first positive reverse transcription polymerase chain reaction test result for SARS-CoV-2 from 1 September 2020, and 14 330 080 participants from the general population. Main outcome measures Outcomes were incidence of Bell’s palsy, encephalomyelitis, Guillain-Barré syndrome, and transverse myelitis. Incidence rates were estimated in the 21 days after the first vaccine dose, 90 days after a positive test result for SARS-CoV-2, and between 2017 and 2019 for background rates in the general population cohort. Indirectly standardised incidence ratios were estimated. Adjusted incidence rate ratios were estimated from the self-controlled case series. Results The study included 4 376 535 people who received ChAdOx1 nCoV-19, 3 588 318 who received BNT162b2, 244 913 who received mRNA-1273, and 120 731 who received Ad26.CoV.2; 735 870 people with SARS-CoV-2 infection; and 14 330 080 people from the general population. Overall, post-vaccine rates were consistent with expected (background) rates for Bell’s palsy, encephalomyelitis, and Guillain-Barré syndrome. Self-controlled case series was conducted only for Bell’s palsy, given limited statistical power, but with no safety signal seen for those vaccinated. Rates were, however, higher than expected after SARS-CoV-2 infection. For example, in the data from the UK, the standardised incidence ratio for Bell’s palsy was 1.33 (1.02 to 1.74), for encephalomyelitis was 6.89 (3.82 to 12.44), and for Guillain-Barré syndrome was 3.53 (1.83 to 6.77). Transverse myelitis was rare (&lt;5 events in all vaccinated cohorts) and could not be analysed. Conclusions No safety signal was observed between covid-19 vaccines and the immune mediated neurological events of Bell’s palsy, encephalomyelitis, Guillain-Barré syndrome, and transverse myelitis. An increased risk of Bell’s palsy, encephalomyelitis, and Guillain-Barré syndrome was, however, observed for people with SARS-CoV-2 infection.
Searching for Synergy: Chemotherapy and Checkpoint Inhibitors
Authors: Diane Tseng, Justin F. Gainor
Journal: Clinical Cancer Research (2022)

Continuation of programmed cell death protein 1 (PD-1) inhibitors in combination with chemotherapy did not improve clinical outcomes for patients with non-small cell lung cancer who progressed on prior PD-1/programmed death ligand 1 inhibitor monotherapy. This highlights the need to evaluate the precise mechanisms of resistance to PD-1 axis inhibitors and explore alternative therapeutic strategies to overcome resistance. See related article by Jung et al., p. 2321.
Mesenchymal stromal cells plus basiliximab, calcineurin inhibitor as treatment of steroid-resistant acute graft-versus-host disease: a multicenter, randomized, phase 3, open-label trial
Authors: Ke Zhao, Ren Lin, Zhiping Fan, Xiaoyong Chen, Yu Wang, Fen Huang, Na Xu, Xi Zhang, Xin Zhang, Li Xuan, Shunqing Wang, Dongjun Lin, Lan Deng, Danian Nie, Jianyu Weng, Yonghua Li, Xiaohui Zhang, Yuhua Li, A. P. Xiang, Qifa Liu
Journal: Journal of Hematology & Oncology (2022)

Steroid-resistant (SR) acute graft-versus-host disease (aGVHD) lacks standard second-line treatment. Mesenchymal stromal cells (MSCs) have potential efficacy in SR aGVHD. We aimed to assess the efficacy and safety of MSCs combined with basiliximab and calcineurin inhibitor as second-line therapy for SR aGVHD.
WHEN A TUMOR IS MORE THAN A TUMOR
Authors: Prashanth Singanallur, Robert Kropp, Michael Gleason, Muhammad Adil Sheikh, Zurain Niaz, Luke Schiller, Venkata Missula, Kevin Schrader, Mohamad Sukkari, Raj Patel, Manjari R. Regmi, Daniel Holtz, Abhishek Kalidas Kulkarni
Journal: Journal of the American College of Cardiology (2022)
The CD3ζ adaptor structure determines functional differences between human and mouse CD16 Fc receptor signaling
Authors: Oscar A. Aguilar, Lam-Kiu Fong, Kenichi Ishiyama, William F. DeGrado, Lewis L. Lanier
Journal: The Journal of Experimental Medicine (2022)

Natural killer (NK) cells can detect antibody-coated cells through recognition by the CD16 Fc receptor. The importance of CD16 in human NK cell biology has long been appreciated, but how CD16 functions in mouse NK cells remains poorly understood. Here, we report drastic differences between human and mouse CD16 functions in NK cells. We demonstrate that one of the adaptor molecules that CD16 associates with and signals through, CD3ζ, plays a critical role in these functional differences. Using a systematic approach, we demonstrate that residues in the transmembrane domain of the mouse CD3ζ molecule prevent efficient complex formation with mouse CD16, thereby dampening receptor function. Mutating these residues in mouse CD3ζ to those encoded by human CD3ζ resulted in rescue of CD16 receptor function. We reveal that the mouse CD3ζ transmembrane domain adopts a tightly packed confirmation, preventing association with CD16, whereas human CD3ζ adopts a versatile configuration that accommodates receptor assembly.
The Fragility of Statistically Significant Results in Randomized Clinical Trials for COVID-19
Authors: Takahiro Itaya, Yotsuha Isobe, Sayoko Suzuki, Kanako Koike, Masakazu Nishigaki, Yosuke Yamamoto
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Interpreting results from randomized clinical trials (RCTs) for COVID-19, which have been published rapidly and in vast numbers, is challenging during a pandemic. <h3>Objective</h3> To evaluate the robustness of statistically significant findings from RCTs for COVID-19 using the fragility index. <h3>Design, Setting, and Participants</h3> This cross-sectional study included COVID-19 trial articles that randomly assigned patients 1:1 into 2 parallel groups and reported at least 1 binary outcome as significant in the abstract. A systematic search was conducted using PubMed to identify RCTs on COVID-19 published until August 7, 2021. <h3>Exposures</h3> Trial characteristics, such as type of intervention (treatment drug, vaccine, or others), number of outcome events, and sample size. <h3>Main Outcomes and Measures</h3> Fragility index. <h3>Results</h3> Of the 47 RCTs for COVID-19 included, 36 (77%) were studies of the effects of treatment drugs, 5 (11%) were studies of vaccines, and 6 (13%) were of other interventions. A total of 138 235 participants were included in these trials. The median (IQR) fragility index of the included trials was 4 (1-11). The medians (IQRs) of the fragility indexes of RCTs of treatment drugs, vaccines, and other interventions were 2.5 (1-6), 119 (61-139), and 4.5 (1-18), respectively. The fragility index among more than half of the studies was less than 1% of each sample size, although the fragility index as a proportion of events needing to change would be much higher. <h3>Conclusions and Relevance</h3> This cross-sectional study found a relatively small number of events (a median of 4) would be required to change the results of COVID-19 RCTs from statistically significant to not significant. These findings suggest that health care professionals and policy makers should not rely heavily on individual results of RCTs for COVID-19.
LocoMMotion: a prospective, non-interventional, multinational study of real-life current standards of care in patients with relapsed and/or refractory multiple myeloma
Authors: Maria-Victoria Mateos, Katja Weisel, Valerio De Stefano, Hartmut Goldschmidt, Michel Delforge, Mohamad Mohty, Michele Cavo, Ravi Vij, Joanne Lindsey-Hill, Dominik Dytfeld, Emanuele Angelucci, Aurore Perrot, Reuben Benjamin, Niels W. C. J. van de Donk, Enrique M. Ocio, Christof Scheid, Francesca Gay, Wilfried Roeloffzen, Paula Rodriguez-Otero, Annemiek Broijl, Anna Potamianou, Caline Sakabedoyan, Maria Semerjian, Sofia Keim, Vadim Strulev, Jordan M. Schecter, Martin Vogel, Robert Wapenaar, Tonia Nesheiwat, Jesus San-Miguel, Pieter Sonneveld, Hermann Einsele, Philippe Moreau
Journal: Leukemia (2022)

Despite treatment advances, patients with multiple myeloma (MM) often progress through standard drug classes including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies (mAbs). LocoMMotion (ClinicalTrials.gov identifier: NCT04035226) is the first prospective study of real-life standard of care (SOC) in triple-class exposed (received at least a PI, IMiD, and anti-CD38 mAb) patients with relapsed/refractory MM (RRMM). Patients (N = 248; ECOG performance status of 0-1, ≥3 prior lines of therapy or double refractory to a PI and IMiD) were treated with median 4.0 (range, 1-20) cycles of SOC therapy. Overall response rate was 29.8% (95% CI: 24.2-36.0). Median progression-free survival (PFS) and median overall survival (OS) were 4.6 (95% CI: 3.9-5.6) and 12.4 months (95% CI: 10.3-NE). Treatment-emergent adverse events (TEAEs) were reported in 83.5% of patients (52.8% grade 3/4). Altogether, 107 deaths occurred, due to progressive disease (n = 74), TEAEs (n = 19), and other reasons (n = 14). The 92 varied regimens utilized demonstrate a lack of clear SOC for heavily pretreated, triple-class exposed patients with RRMM in real-world practice and result in poor outcomes. This supports a need for new treatments with novel mechanisms of action.
Durability of transgene expression after rAAV gene therapy
Authors: Manish Muhuri, Daniel I. Levy, Martin Schulz, Douglas McCarty, Guangping Gao
Journal: Molecular Therapy (2022)

Recombinant adeno-associated virus (rAAV) gene therapy has the potential to transform the lives of patients with certain genetic disorders by increasing or restoring function to affected tissues. Following the initial establishment of transgene expression, it is unknown how long the therapeutic effect will last, although animal and emerging human data show that expression can be maintained for more than 10 years. The durability of therapeutic response is key to long-term treatment success, especially since immune responses to rAAV vectors may prevent re-dosing with the same therapy. This review explores the non-immunological and immunological processes that may limit or improve durability and the strategies that can be used to increase the duration of the therapeutic effect.
Bispecific T-cell engagers non-covalently decorated drug-loaded PEGylated nanocarriers for cancer immunochemotherapy
Authors: Wei-Jie Cheng, Kuo-Hsiang Chuang, Yu-Ju Lo, Michael Chen, Yi-Jou Chen, Steve R. Roffler, Hsiu-O Ho, Shyr-Yi Lin, Ming-Thau Sheu
Journal: Journal of Controlled Release (2022)
BETTER LATE THAN NEVER: DEFINITIVE REPAIR OF DEXTRO-TRANSPOSITION OF THE GREAT ARTERIES (D-TGA)/VENTRICULAR SEPTAL DEFECT/PULMONARY STENOSIS (PS) IN A 55 YEAR OLD MALE
Authors: Samuel Dugger, Christopher A. Caldarone, Peter Ryan Ermis, Wilson W. Lam
Journal: Journal of the American College of Cardiology (2022)
Selection Analysis Identifies Clusters of Unusual Mutational Changes in Omicron Lineage BA.1 That Likely Impact Spike Function
Authors: Darren P. Martin, Spyros Lytras, Alexander G. Lucaci, Wolfgang Maier, Björn Grüning, Stephen D. Shank, Steven Weaver, Oscar A. MacLean, Richard J. Orton, Philippe Lemey, Maciej F. Boni, Houriiyah Tegally, Gordon W. Harkins, Cathrine Scheepers, Jinal N. Bhiman, Josie Everatt, Daniel G. Amoako, James Emmanuel San, Jennifer Giandhari, Alex Sigal, Carolyn Williamson, Nei-yuan Hsiao, Anne von Gottberg, Arne De Klerk, Robert W. Shafer, David L. Robertson, Robert J. Wilkinson, B. Trevor Sewell, Richard Lessells, Anton Nekrutenko, Allison J. Greaney, Tyler N. Starr, Jesse D. Bloom, Ben Murrell, Eduan Wilkinson, Ravindra K. Gupta, Tulio de Oliveira, Sergei L. Kosakovsky Pond
Journal: Molecular Biology and Evolution (2022)

Among the 30 nonsynonymous nucleotide substitutions in the Omicron S-gene are 13 that have only rarely been seen in other SARS-CoV-2 sequences. These mutations cluster within three functionally important regions of the S-gene at sites that will likely impact (1) interactions between subunits of the Spike trimer and the predisposition of subunits to shift from down to up configurations, (2) interactions of Spike with ACE2 receptors, and (3) the priming of Spike for membrane fusion. We show here that, based on both the rarity of these 13 mutations in intrapatient sequencing reads and patterns of selection at the codon sites where the mutations occur in SARS-CoV-2 and related sarbecoviruses, prior to the emergence of Omicron the mutations would have been predicted to decrease the fitness of any virus within which they occurred. We further propose that the mutations in each of the three clusters therefore cooperatively interact to both mitigate their individual fitness costs, and, in combination with other mutations, adaptively alter the function of Spike. Given the evident epidemic growth advantages of Omicron overall previously known SARS-CoV-2 lineages, it is crucial to determine both how such complex and highly adaptive mutation constellations were assembled within the Omicron S-gene, and why, despite unprecedented global genomic surveillance efforts, the early stages of this assembly process went completely undetected.
Reproductive health among married and unmarried mothers aged less than 18, 18–19, and 20–24 years in the United States, 2014–2019: A population-based cross-sectional study
Authors: Andrée-Anne Fafard St-Germain, Russell S. Kirby, Marcelo L. Urquia
Journal: PLoS Medicine (2022)

Background Studies in low- and middle-income regions suggest that child marriage (&lt;18 years) is a risk factor for poor reproductive outcomes among women. However, in high-income-country contexts where childbearing before age 18 occurs predominantly outside marriage, it is unknown whether marriage is adversely associated with reproductive health among mothers below age 18. This study examined the joint associations of marriage and adolescent maternal age group (&lt;18, 18–19, and 20–24 years) with reproductive, maternal, and infant health indicators in the United States. Methods and findings Birth registrations with US resident mothers aged ≤24 years with complete information on marital status were drawn from the 2014 to 2019 Natality Public Use Files ( n = 5,669,824). Odds ratios for the interaction between marital status and maternal age group were estimated using multivariable logistic regression, adjusting for covariates such as maternal race/ethnicity and nativity status, federal program participation, and paternal age. Marriage prevalence was 3.6%, 13.2%, and 34.1% among births to mothers aged &lt;18, 18–19, and 20–24 years, respectively. Age gradients in the adjusted odds ratios (AORs) were present for most indicators, and many gradients differed by marital status. Among births to mothers aged &lt;18 years, marriage was associated with greater adjusted odds of prior pregnancy termination (AOR 1.64, 95% CI 1.52–1.77, p &lt; 0.001), repeat birth (AOR 2.84, 95% CI 2.68–3.00, p &lt; 0.001), maternal smoking (AOR 1.24, 95% CI 1.15–1.35, p &lt; 0.001), and infant morbidity (AOR 1.07, 95% CI 1.01–1.14, p = 0.03), but weaker or reverse associations existed among births to older mothers. For all maternal age groups, marriage was associated with lower adjusted odds of late or no prenatal care initiation, sexually transmitted infection, and no breastfeeding at hospital discharge, but these beneficial associations were weaker among births to mothers aged &lt;18 and 18–19 years. Limitations of the study include its cross-sectional nature and lack of information on marriage timing relative to prior pregnancy events. Conclusions Marriage among mothers below age 18 is associated with both adverse and favorable reproductive, maternal, and infant health indicators. Heterogeneity exists in the relationship between marriage and reproductive health across adolescent maternal age groups, suggesting girl child marriages must be examined separately from marriages at older ages.