tbuckley/cabot-search huggingface dataset:
Emergency Department Encounters Among Youth With Suicidal Thoughts or Behaviors During the COVID-19 Pandemic
Authors: Kathryn K. Ridout, Mubarika Alavi, Samuel J. Ridout, Maria T. Koshy, Sameer Awsare, Brooke Harris, David R. Vinson, Constance M. Weisner, Stacy Sterling, Esti Iturralde
Journal: JAMA Psychiatry (2021)

Population-level reports of suicide-related emergency department (ED) encounters among youth during the COVID-19 pandemic are lacking, along with youth characteristics and preexisting psychiatric service use.To characterize population-level and relative change in suicide-related ED encounters among youth during the COVID-19 pandemic compared with 2019.This cross-sectional study evaluated ED encounters in 2019 and 2020 at Kaiser Permanente Northern California-a large, integrated, community-based health system. Youth aged 5 to 17 years who presented to the ED with suicidal thoughts or behaviors were included.The COVID-19 pandemic.Population-level incidence rate ratios (IRRs) and percent relative effects for suicide-related ED encounters as defined by the US Centers for Disease Control and Prevention-recommended International Statistical Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes in 4 periods in 2020 compared with the same periods in 2019.There were 2123 youth with suicide-related ED encounters in 2020 compared with 2339 in 2019. In the 2020 group, 1483 individuals (69.9%) were female and 1798 (84.7%) were aged 13 to 17 years. In the 2019 group, 1542 (65.9%) were female, and 1998 (85.4%) were aged 13 to 17 years. Suicide-related ED encounter incidence rates were significantly lower in March through May 2020 compared with this period in 2019 (IRR, 0.57; 95% CI, 0.51-0.63; P < .001), then returned to prepandemic levels. However, suicide-related ED visits among female youth from June 1 to August 31, 2020, and September 1 through December 15, 2020, were significantly higher than in the corresponding months in 2019 (IRR, 1.19; 95% CI, 1.04-1.35; P = .04 and IRR, 1.22; 95% CI, 1.11-1.35; P < .001, respectively), while suicide-related ED visits for male youth decreased from September 1 through December 15, 2020 (IRR, 0.81; 95% CI, 0.69 to 0.94). Youth with no history of outpatient mental health or suicide encounters (129.4%; 95% CI, 41.0-217.8) and those with comorbid psychiatric conditions documented at the ED encounter (6.7%; 95% CI, 1.0-12.3) had a higher risk of presenting with suicide-related problems from September to December 2020 vs the same period in 2019.In this cross-sectional study of youth experiencing suicidal thoughts and behaviors, suicide-related presentations to the ED initially decreased during the COVID-19 pandemic, likely owing to shelter-in-place orders, then were similar to 2019 levels. However, a greater number of female youth, youth with no psychiatric history, and youth with psychiatric diagnoses at the time of the ED encounter presented for suicide-related concerns during the pandemic, suggesting these may be vulnerable groups in need of further interventions. Adjustments in care may be warranted to accommodate these groups during periods of crisis.
Intratumoral injection of TLR9 agonist promotes an immunopermissive microenvironment transition and causes cooperative antitumor activity in combination with anti-PD1 in pancreatic cancer
Authors: Carmine Carbone, Geny Piro, Antonio Agostini, Pietro Delfino, Francesco De Sanctis, Vincenzo Nasca, Francesco Spallotta, Claudio Sette, Maurizio Martini, Stefano Ugel, Vincenzo Corbo, Paola Cappello, Emilio Bria, Aldo Scarpa, Giampaolo Tortora
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Complex tumor and immune microenvironment render pancreatic ductal adenocarcinoma (PDAC) resistant to immune checkpoint inhibitors (ICIs). Therefore, a strategy to convert the immune hostile into an immunopermissive tumor is required. Recent studies showed that intratumoral injection of Toll-like receptor 9 agonist IMO-2125 primes the adaptive immune response. Phase I and II trials with intratumoral IMO-2125 demonstrated its safety and antitumoral activity. Methods We generated an array of preclinical models by orthotopically engrafting PDAC-derived cell lines in syngeneic mice and categorized them as high, low and no immunogenic potential, based on the ability of tumor to evoke T lymphocyte or NK cell response. To test the antitumor efficacy of IMO-2125 on locally treated and distant sites, we engrafted cancer cells on both flanks of syngeneic mice and treated them with intratumoral IMO-2125 or vehicle, alone or in combination with anti-PD1 ICI. Tumor tissues and systemic immunity were analyzed by transcriptomic, cytofluorimetric and immunohistochemistry analysis. Results We demonstrated that intratumoral IMO-2125 as single agent triggers immune system response to kill local and distant tumors in a selected high immunogenic subtype affecting tumor growth and mice survival. Remarkably, intratumoral IMO-2125 in combination with systemic anti-PD1 causes a potent antitumor effect on primary injected and distant sites also in pancreatic cancer models with low immunogenic potential, preceded by a transition toward an immunopermissive microenvironment, with increase in tumor-infiltrating dendritic and T cells in tumor and lymph nodes. Conclusion We demonstrated a potent antitumor activity of IMO-2125 and anti-PD1 combination in immunotherapy-resistant PDAC models through the modulation of immune microenvironment, providing the rationale to translate this strategy into a clinical setting.
The STE20 kinase TAOK3 controls the development of house dust mite–induced asthma in mice
Authors: Bastiaan Maes, Ursula Smole, Matthias Vanderkerken, Kim Deswarte, Justine Van Moorleghem, Karl Vergote, Manon Vanheerswynghels, Caroline De Wolf, Sofie De Prijck, Nincy Debeuf, Benjamin Pavie, Wendy Toussaint, Sophie Janssens, Savvas Savvides, Bart N. Lambrecht, Hamida Hammad
Journal: Journal of Allergy and Clinical Immunology (2021)
Big Data and Glomerular Disease: Uncovering Common Outcomes of Rare Disease
Authors: Dorey A. Glenn, Susan L. Hogan
Journal: Journal of the American Society of Nephrology (2021)

In 1899, when Sir William Osler advised the students of Albany Medical College to "care more particularly for the individual patient than for the special features of the disease," he probably could not have imagined a scenario in which millions of patient records could be analyzed en masse to
YBX1 mediates translation of oncogenic transcripts to control cell competition in AML
Authors: Florian Perner, Tina M. Schnoeder, Yijun Xiong, Ashok Kumar Jayavelu, Nomusa Mashamba, Nuria Tubio Santamaria, Nicolas Huber, Kristina Todorova, Charles Hatton, Birgit Perner, Theresa Eifert, Ciara Murphy, Maximilian Hartmann, Jessica I. Hoell, Nicolas Schröder, Sabine Brandt, Andreas Hochhaus, Peter R. Mertens, Matthias Mann, Scott A. Armstrong, Anna Mandinova, Florian H. Heidel
Journal: Leukemia (2021)

Abstract Persistence of malignant clones is a major determinant of adverse outcome in patients with hematologic malignancies. Despite the fact that the majority of patients with acute myeloid leukemia (AML) achieve complete remission after chemotherapy, a large proportion of them relapse as a result of residual malignant cells. These persistent clones have a competitive advantage and can re-establish disease. Therefore, targeting strategies that specifically diminish cell competition of malignant cells while leaving normal cells unaffected are clearly warranted. Recently, our group identified YBX1 as a mediator of disease persistence in JAK2 -mutated myeloproliferative neoplasms. The role of YBX1 in AML, however, remained so far elusive. Here, inactivation of YBX1 confirms its role as an essential driver of leukemia development and maintenance. We identify its ability to amplify the translation of oncogenic transcripts, including MYC, by recruitment to polysomal chains. Genetic inactivation of YBX1 disrupts this regulatory circuit and displaces oncogenic drivers from polysomes, with subsequent depletion of protein levels. As a consequence, leukemia cells show reduced proliferation and are out-competed in vitro and in vivo, while normal cells remain largely unaffected. Collectively, these data establish YBX1 as a specific dependency and therapeutic target in AML that is essential for oncogenic protein expression.
Trial of Intensive Blood-Pressure Control in Older Patients with Hypertension
Authors: Weili Zhang, Shuyuan Zhang, Yue Deng, Shouling Wu, Jie Ren, Gang Sun, Jinfeng Yang, Yinong Jiang, Xinjuan Xu, Tzung-Dau Wang, Youren Chen, Yufeng Li, Lianchen Yao, Dianfang Li, Lixin Wang, Xiaomei Shen, Xinhua Yin, Wei Liu, Xiaoyang Zhou, Bingpo Zhu, Zihong Guo, Hualing Liu, Xiaoping Chen, Yingqing Feng, Gang Tian, Xiuyin Gao, Kazuomi Kario, Jun Cai
Journal: New England Journal of Medicine (2021)

The appropriate target for systolic blood pressure to reduce cardiovascular risk in older patients with hypertension remains unclear.
The emerging roles of the gut microbiome in allogeneic hematopoietic stem cell transplantation
Authors: Lam T. Khuat, Maneesh Dave, William J. Murphy
Journal: Gut Microbes (2021)

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is used for the treatment of hematologic cancers and disorders. However, graft-versus-host disease (GVHD) in which the donor immune cells attack the genetically-disparate recipient is a significant cause of morbidity. Acute GVHD is an inflammatory condition and the gastrointestinal system is a major organ affected but is also tied to beneficial graft-versus-tumor (GVT) effects. There is increasing interest on the role of the microbiome on immune function as well as on cancer progression and immunotherapy outcomes. However, there are still significant unanswered questions on the role the microbiome plays in GVHD progression or how to exploit the microbiome in GVHD prevention or treatment. In this review, concepts of HSCT with the focus on GVHD pathogenesis as well as issues in preclinical models used to study GVHD will be discussed with an emphasis on the impact of the microbiome. Factors affecting the microbiome and GVHD outcome such as obesity are also examined. The bridging of preclinical models and clinical outcomes in relation to the role of the microbiome will also be discussed along with possibilities for therapeutic exploitation.
Identification and prioritization of myeloid malignancy germline variants in a large cohort of adult patients with AML
Authors: Fei Yang, Nicola Long, Tauangtham Anekpuritanang, Daniel Bottomly, Jonathan C. Savage, Tiffany Lee, Jose Solis-Ruiz, Uma Borate, Beth Wilmot, Cristina Tognon, Allison M. Bock, Daniel A. Pollyea, Saikripa Radhakrishnan, Srinidhi Radhakrishnan, Prapti Patel, Robert H. Collins, Srinivas Tantravahi, Michael W. Deininger, Guang Fan, Brian Druker, Ujwal Shinde, Jeffrey W. Tyner, Richard D. Press, Shannon McWeeney, Anupriya Agarwal
Journal: Blood (2021)
Adherence to National Guidelines on Cervical Screening: A Population-Based Evaluation From a Statewide Registry
Authors: Philip E Castle, Walter K Kinney, Lu Chen, Jane J Kim, Steven Jenison, Giovanna Rossi, Huining Kang, Jack Cuzick, Cosette M Wheeler, Nancy E Walter Joste, Cosette M Kinney, Charles L Wheeler, Michael Wiggins, Ruth M Robertson, Alan McDonald, Steven Waxman, Jean Jenison, Debbie Howe, Jane J Saslow, Mark H Kim, Jack Stoler, Philip E Cuzick, Rebecca B Castle, Janice L Perkins, Salina Gonzales, Giovanna Torres, Kevin Rossi, None English
Journal: JNCI Journal of the National Cancer Institute (2021)

Abstract In 2012, national recommendations for cervical cancer screening of women aged 30-64 years were quinquennial human papillomavirus and cytology cotesting or triennial cytology. Data from a statewide surveillance program in New Mexico demonstrated 65.2% (95% confidence interval [95% CI] = 64.6% to 65.7%) of women screened in 2019 had a negative cotest within the last 3 years. Percentages of women screened in 2013, 2016, and 2019 with a prior negative cotest more than 5 years and up to 7 years ago were 2.6% (95% CI = 2.2% to 2.9%), 2.1% (95% CI = 1.9% to 2.2%), and 6.5% (95% CI = 6.2% to 6.8%), respectively (2-sided Ptrend &amp;lt; .001). Percentages of women screened in 2013, 2016, and 2019 with a prior negative cytology more than 5 years and up to 7 years ago were 3.8% (95% CI = 3.7% to 3.9%), 9.0% (95% CI = 8.7% to 9.3%), and 14.9% (95% CI = 14.4% to 15.4%), respectively (2-sided Ptrend &amp;lt; .001). Thus, in 2019, only 12.7% (95% CI = 12.4% to 13.1%) of the 30 215 women aged 30-64 years underwent cotesting and 27.7% (95% CI = 27.1% to 28.3%) of the 18 733 underwent cytology at the recommended interval. The observed under- and overscreening could result in increases in cervical cancer incidence and harms and costs, respectively.
The misunderstood link between SARS-CoV-2 and angiogenesis. A narrative review
Authors: G. Madureira, R. Soares
Journal: Pulmonology (2021)

Novel Coronavirus Disease 2019 (Covid-19) is associated with multi-systemic derangement, including circulatory dysfunction with features of endothelial dysfunction, microangiopathic thrombosis and angiocentric inflammation. Recently, intussusceptive angiogenesis has been implicated in the pathogenesis of the disease. Herein, we conducted a narrative review according to the SANRA guidelines to review and discuss data regarding splitting angiogenesis including mechanisms, drivers, regulators and putative roles. Relevant angiogenic features in Covid-19, including their potential role in inflammation, endothelial dysfunction and permeability, as well as their use as prognostic markers and therapeutic roles are reviewed. Splitting angiogenesis in Covid-19 involve hypoxia, hypoxia-inducible factors, classic angiogenic mediators, such as the Vascular Endothelial Growth Factor (VEGF), Angiopoietins, hyperinflammation and cytokine storm, and dysregulation of the Renin-Angiotensin-Aldosterone System, which combined, interact to promote intussusception. Data regarding the use of angiogenic mediators as prognostic tools is summarized and suggest that angiopoietins and VEGF are elevated in Covid-19 patients and predictors of adverse outcomes. Finally, we reviewed the scarce data regarding angiogenic mediators as therapeutic targets. These preliminary findings suggest a potential benefit of bevacizumab as an add-on therapy.
Novel vancomycin resistance gene cluster in Enterococcus faecium ST1486, Belgium, June 2021
Authors: Basil Britto Xavier, Jasmine Coppens, Sien De Koster, Sahaya Glingston Rajakani, Sam Van Goethem, Samy Mzougui, Ahalieyah Anantharajah, Christine Lammens, Katherine Loens, Youri Glupczynski, Herman Goossens, Veerle Matheeussen
Journal: Eurosurveillance (2021)

We identified a novel van gene cluster in a clinical Enterococcus faecium isolate with vancomycin minimum inhibitory concentration (MIC) of 4 µg/mL. The ligase gene, vanP , was part of a van operon cluster of 4,589 bp on a putative novel integrative conjugative element located in a ca 98 kb genomic region presumed to be acquired by horizontal gene transfer from Clostridium scidens and Roseburia sp. 499. Screening for van genes in E. faecium strains with borderline susceptibility to vancomycin is important.
Acute Consumption of Alcohol and Discrete Atrial Fibrillation Events
Authors: Gregory M. Marcus, Eric Vittinghoff, Isaac R. Whitman, Sean Joyce, Vivian Yang, Gregory Nah, Edward P. Gerstenfeld, Joshua D. Moss, Randall J. Lee, Byron K. Lee, Zian H. Tseng, Vasanth Vedantham, Jeffrey E. Olgin, Melvin M. Scheinman, Henry Hsia, Rachel Gladstone, Shannon Fan, Emily Lee, Christina Fang, Kelsey Ogomori, Robin Fatch, Judith A. Hahn
Journal: Annals of Internal Medicine (2021)

Patients' self-reports suggest that acute alcohol consumption may trigger a discrete atrial fibrillation (AF) event.To objectively ascertain whether alcohol consumption heightens risk for an AF episode.A prospective, case-crossover analysis.Ambulatory persons in their natural environments.Consenting patients with paroxysmal AF.Participants were fitted with a continuous electrocardiogram (ECG) monitor and an ankle-worn transdermal ethanol sensor for 4 weeks. Real-time documentation of each alcoholic drink consumed was self-recorded using a button on the ECG recording device. Fingerstick blood tests for phosphatidylethanol (PEth) were used to corroborate ascertainments of drinking events.Of 100 participants (mean age, 64 years [SD, 15]; 79% male; 85% White), 56 had at least 1 episode of AF. Results of PEth testing correlated with the number of real-time recorded drinks and with events detected by the transdermal alcohol sensor. An AF episode was associated with 2-fold higher odds of 1 alcoholic drink (odds ratio [OR], 2.02 [95% CI, 1.38 to 3.17]) and greater than 3-fold higher odds of at least 2 drinks (OR, 3.58 [CI, 1.63 to 7.89]) in the preceding 4 hours. Episodes of AF were also associated with higher odds of peak blood alcohol concentration (OR, 1.38 [CI, 1.04 to 1.83] per 0.1% increase in blood alcohol concentration) and the total area under the curve of alcohol exposure (OR, 1.14 [CI, 1.06 to 1.22] per 4.7% increase in alcohol exposure) inferred from the transdermal ethanol sensor in the preceding 12 hours.Confounding by other time-varying exposures that may accompany alcohol consumption cannot be excluded, and the findings from the current study of patients with AF consuming alcohol may not apply to the general population.Individual AF episodes were associated with higher odds of recent alcohol consumption, providing objective evidence that a modifiable behavior may influence the probability that a discrete AF event will occur.National Institute on Alcohol Abuse and Alcoholism.
PRMT5 Prevents Dilated Cardiomyopathy via Suppression of Protein O-GlcNAcylation
Authors: Zhenhua Li, Jingping Xu, Yao Song, Chong Xin, Lantao Liu, Ning Hou, Yan Teng, Xuan Cheng, Tianle Wang, Zhenyang Yu, Jiangping Song, Youyi Zhang, Jian Wang, Xiao Yang
Journal: Circulation Research (2021)

Rationale: Protein O-GlcNAcylation is dynamically regulated by 2 key enzymes, OGT (O-GlcNAc transferase) and OGA (O-GlcNAcase). Excessive protein O-GlcNAcylation contributes to dilated cardiomyopathy (DCM), but its regulatory mechanisms are not fully understood. The PRMT5 (protein arginine methyltransferase 5) is the major type II arginine methyltransferase, which plays critical physiological roles by symmetrically dimethylating various downstream targets including proteins involved in RNA splicing. However, its function in regulating protein O-GlcNAcylation and DCM is unexplored. Objective: To elucidate the physiological function of PRMT5 and the mechanism underlying its role in regulating cardiac O-GlcNAcylation and homeostasis. Methods and Results: Conditional gene knockout was used to study the in vivo function of PRMT5 in regulating cardiac homeostasis. An integrated analysis of transcriptomic and metabolomic profiles was performed to investigate the molecular mechanism. Adeno-associated virus 9-mediated gene delivery in the mouse was used to study the protein O-GlcNAcylation in Prmt5 deficiency-induced DCM. PRMT5 mRNA was decreased in human DCM hearts, and cardiomyocyte-specific Prmt5 deletion in mice resulted in DCM and heart failure. Transcriptomic and metabolomic profiling identified increased O-GlcNAcylation in the hearts of Prmt5 -knockout mice. Mechanistically, Prmt5 deletion suppressed OGA expression by inhibiting the transcription of Oga and triggering its aberrant splicing. Consistently, a positive correlation of PRMT5 and OGA was identified in human DCM hearts. Notably, gene therapy with adeno-associated virus 9 encoding the correctly spliced Oga normalized the cardiac protein O-GlcNAcylation levels and partially rescued the dilation and dysfunction of the hearts in Prmt5 -knockout mice. Conclusions: Our data demonstrate a novel function of PRMT5 in regulating protein O-GlcNAcylation to maintain cardiac homeostasis, suggesting that targeting the PRMT5-OGA axis could be a potential strategy for treating DCM.
Profiling diverse sequence tandem repeats in colorectal cancer reveals co-occurrence of microsatellite and chromosomal instability involving Chromosome 8
Authors: GiWon Shin, Stephanie U. Greer, Erik Hopmans, Susan M. Grimes, HoJoon Lee, Lan Zhao, Laura Miotke, Carlos Suarez, Alison F. Almeda, Sigurdis Haraldsdottir, Hanlee P. Ji
Journal: Genome Medicine (2021)

We developed a sensitive sequencing approach that simultaneously profiles microsatellite instability, chromosomal instability, and subclonal structure in cancer. We assessed diverse repeat motifs across 225 microsatellites on colorectal carcinomas. Our study identified elevated alterations at both selected tetranucleotide and conventional mononucleotide repeats. Many colorectal carcinomas had a mix of genomic instability states that are normally considered exclusive. An MSH3 mutation may have contributed to the mixed states. Increased copy number of chromosome arm 8q was most prevalent among tumors with microsatellite instability, including a case of translocation involving 8q. Subclonal analysis identified co-occurring driver mutations previously known to be exclusive.
The Spectrum of the Prader–Willi-like Pheno- and Genotype: A Review of the Literature
Authors: Alicia F Juriaans, Gerthe F Kerkhof, Anita C S Hokken-Koelega
Journal: Endocrine Reviews (2021)

Abstract Prader–Willi syndrome (PWS) is a rare genetic syndrome, caused by the loss of expression of the paternal chromosome 15q11-q13 region. Over the past years, many cases of patients with characteristics similar to PWS, but without a typical genetic aberration of the 15q11-q13 region, have been described. These patients are often labelled as Prader–Willi-like (PWL). PWL is an as-yet poorly defined syndrome, potentially affecting a significant number of children and adults. In the current clinical practice, patients labelled as PWL are mostly left without treatment options. Considering the similarities with PWS, children with PWL might benefit from the same care and treatment as children with PWS. This review gives more insight into the pheno- and genotype of PWL and includes 86 papers, containing 368 cases of patients with a PWL phenotype. We describe mutations and aberrations for consideration when suspicion of PWS remains after negative testing. The most common genetic diagnoses were Temple syndrome (formerly known as maternal uniparental disomy 14), Schaaf–Yang syndrome (truncating mutation in the MAGEL2 gene), 1p36 deletion, 2p deletion, 6q deletion, 6q duplication, 15q deletion, 15q duplication, 19p deletion, fragile X syndrome, and Xq duplication. We found that the most prevalent symptoms in the entire group were developmental delay/intellectual disability (76%), speech problems (64%), overweight/obesity (57%), hypotonia (56%), and psychobehavioral problems (53%). In addition, we propose a diagnostic approach to patients with a PWL phenotype for (pediatric) endocrinologists. PWL comprises a complex and diverse group of patients, which calls for multidisciplinary care with an individualized approach.
Polymorphic Ventricular Tachycardia: Terminology, Mechanism, Diagnosis, and Emergency Therapy
Authors: Sami Viskin, Ehud Chorin, Dana Viskin, Aviram Hochstadt, Arie Lorin Schwartz, Raphael Rosso
Journal: Circulation (2021)

Polymorphic ventricular tachyarrhythmias are highly lethal arrhythmias. Several types of polymorphic ventricular tachycardia have similar electrocardiographic characteristics but have different modes of therapy. In fact, medications considered the treatment of choice for one form of polymorphic ventricular tachycardia, are contraindicated for the other. Yet confusion about terminology, and thus diagnosis and therapy, continues. We present an in-depth review of the different forms of polymorphic ventricular tachycardia and propose a practical step-by-step approach for distinguishing these malignant arrhythmias.