tbuckley/cabot-search huggingface dataset:
Genome-wide association study implicates novel loci and reveals candidate effector genes for longitudinal pediatric bone accrual
Authors: Diana L. Cousminer, Yadav Wagley, James A. Pippin, Ahmed Elhakeem, Gregory P. Way, Matthew C. Pahl, Shana E. McCormack, Alessandra Chesi, Jonathan A. Mitchell, Joseph M. Kindler, Denis Baird, April Hartley, Laura Howe, Heidi J. Kalkwarf, Joan M. Lappe, Sumei Lu, Michelle E. Leonard, Matthew E. Johnson, Hakon Hakonarson, Vicente Gilsanz, John A. Shepherd, Sharon E. Oberfield, Casey S. Greene, Andrea Kelly, Deborah A. Lawlor, Benjamin F. Voight, Andrew D. Wells, Babette S. Zemel, Kurt D. Hankenson, Struan F. A. Grant
Journal: Genome biology (2021)

Bone accrual impacts lifelong skeletal health, but genetic discovery has been primarily limited to cross-sectional study designs and hampered by uncertainty about target effector genes. Here, we capture this dynamic phenotype by modeling longitudinal bone accrual across 11,000 bone scans in a cohort of healthy children and adolescents, followed by genome-wide association studies (GWAS) and variant-to-gene mapping with functional follow-up.
St. Jude Cloud: A Pediatric Cancer Genomic Data-Sharing Ecosystem
Authors: Clay McLeod, Alexander M. Gout, Xin Zhou, Andrew Thrasher, Delaram Rahbarinia, Samuel W. Brady, Michael Macias, Kirby Birch, David Finkelstein, Jobin Sunny, Rahul Mudunuri, Brent A. Orr, Madison Treadway, Bob Davidson, Tracy K. Ard, Arthur Chiao, Andrew Swistak, Stephanie Wiggins, Scott Foy, Jian Wang, Edgar Sioson, Shuoguo Wang, J. Robert Michael, Yu Liu, Xiaotu Ma, Aman Patel, Michael N. Edmonson, Mark R. Wilkinson, Andrew M. Frantz, Ti-Cheng Chang, Liqing Tian, Shaohua Lei, S.M. Ashiqul Islam, Christopher Meyer, Naina Thangaraj, Pamella Tater, Vijay Kandali, Singer Ma, Tuan Nguyen, Omar Serang, Irina McGuire, Nedra Robison, Darrell Gentry, Xing Tang, Lance E. Palmer, Gang Wu, Ed Suh, Leigh Tanner, James McMurry, Matthew Lear, Alberto S. Pappo, Zhaoming Wang, Carmen L. Wilson, Yong Cheng, Soheil Meshinchi, Ludmil B. Alexandrov, Mitchell J. Weiss, Gregory T. Armstrong, Leslie L. Robison, Yutaka Yasui, Kim E. Nichols, David W. Ellison, Chaitanya Bangur, Charles G. Mullighan, Suzanne J. Baker, Michael A. Dyer, Geralyn Miller, Scott Newman, Michael Rusch, Richard Daly, Keith Perry, James R. Downing, Jinghui Zhang
Journal: Cancer Discovery (2021)

Abstract Effective data sharing is key to accelerating research to improve diagnostic precision, treatment efficacy, and long-term survival in pediatric cancer and other childhood catastrophic diseases. We present St. Jude Cloud (https://www.stjude.cloud), a cloud-based data-sharing ecosystem for accessing, analyzing, and visualizing genomic data from &amp;gt;10,000 pediatric patients with cancer and long-term survivors, and &amp;gt;800 pediatric sickle cell patients. Harmonized genomic data totaling 1.25 petabytes are freely available, including 12,104 whole genomes, 7,697 whole exomes, and 2,202 transcriptomes. The resource is expanding rapidly, with regular data uploads from St. Jude's prospective clinical genomics programs. Three interconnected apps within the ecosystem—Genomics Platform, Pediatric Cancer Knowledgebase, and Visualization Community—enable simultaneously performing advanced data analysis in the cloud and enhancing the Pediatric Cancer knowledgebase. We demonstrate the value of the ecosystem through use cases that classify 135 pediatric cancer subtypes by gene expression profiling and map mutational signatures across 35 pediatric cancer subtypes. Significance: To advance research and treatment of pediatric cancer, we developed St. Jude Cloud, a data-sharing ecosystem for accessing &amp;gt;1.2 petabytes of raw genomic data from &amp;gt;10,000 pediatric patients and survivors, innovative analysis workflows, integrative multiomics visualizations, and a knowledgebase of published data contributed by the global pediatric cancer community. This article is highlighted in the In This Issue feature, p. 995
Recruitment of inflammatory monocytes by senescent fibroblasts inhibits antigen-specific tissue immunity during human aging
Authors: Emma S. Chambers, Milica Vukmanovic-Stejic, Barbara B. Shih, Hugh Trahair, Priya Subramanian, Oliver P. Devine, James Glanville, Derek Gilroy, Malcolm H. A. Rustin, Tom C. Freeman, Neil A. Mabbott, Arne N. Akbar
Journal: Nature Aging (2021)
Covid-19 vaccination: What’s the evidence for extending the dosing interval?
Authors: Gareth Iacobucci, Elisabeth Mahase
Journal: BMJ (2021)

On 30 December the four UK chief medical officers announced that the second doses of the covid vaccines should be given towards the end of 12 weeks rather than in the previously recommended 3-4 weeks. <b>Gareth Iacobucci</b> and <b>Elisabeth Mahase</b> look at the questions this has raised
Abstract 16886: Wall Stress Profiles in Tricuspid Aortic Valve Associated Ascending Thoracic Aortic Aneurysms: The Effect of Surgical Threshold Diameter ≥5.5cm
Authors: Axel Gomez, Zhongjie Wang, Yue XUAN, Liang Ge, Elaine E Tseng
Journal: Circulation (2020)

Introduction: Ascending thoracic aortic aneurysms (aTAAs) carry a risk of dissection. Elective repair guidelines are designed around size thresholds, but the one-dimensional parameter is insufficient to predict acute events in small aneurysms. Biomechanically, aortic events can occur when wall stress exceeds wall strength. Patient-specific aTAA wall stresses may be a better predictor of complications. Our aim was to compare wall stresses in aTAAs associated with a tricuspid aortic valve (TAV) based on diameter. Methods: Patients with TAV-aTAA and diameter &gt;4.0cm (n=448) were divided into groups by 0.5 cm diameter increments. Pre-stress three-dimensional aneurysm geometries were reconstructed from ECG-gated computer tomography images. A fiber-embedded hyperelastic material model was applied to obtain longitudinal and circumferential wall stress distributions under systolic pressure. Medians with interquartile ranges are reported. The Kruskal-Wallis test is used for comparisons between size groups. Results: Peak longitudinal wall stresses for TAV-aTAA were 308[282-338] kPa for size 4.0-4.4cm vs 341[309-362] kPa for 4.5-4.9cm vs 339[289-370] kPa for 5.0-5.4cm vs 319[297-355] kPa for 5.5-5.9cm vs 373[364-449] for 6.0cm (p=0.003). Peak circumferential wall stresses were 487[448-579] kPa for size 4.0-4.4cm vs 516[473-619] kPa for 4.5-4.9cm vs 506[422-580] kPa for 5.0-5.4cm vs 540[468-591] kPa for 5.5-5.9cm vs 565[506-634] for &gt;6.0cm (p=0.19) (figure). 95th-percentile longitudinal peak stress for TAV-aTAA &lt;5.5cm vs ≥5.5cm is 408 vs 465 kPa. Conclusions: Longitudinal wall stresses are higher as diameter increases. The 95% percentile longitudinal peak stress for diameter ≥5.5cm is ~450 kPa, which correlates with established ~5% dissection risk for size ≥5.5cm. Wall stress thresholds may be a better predictor of patient-specific risk of dissection than diameter and require testing in clinical trials.
Maturation of the neonatal oral mucosa involves unique epithelium-microbiota interactions
Authors: Noam Koren, Khaled Zubeidat, Yasmin Saba, Yael Horev, Or Barel, Anneke Wilharm, Oded Heyman, Sharon Wald, Luba Eli-berchoer, Hagit Shapiro, Chen Nadler, Eran Elinav, Asaf Wilensky, Immo Prinz, Hillel Bercovier, Avi-Hai Hovav
Journal: Cell Host & Microbe (2021)
Illuminating Non-genetic Cellular Heterogeneity with Imaging-Based Spatial Proteomics
Authors: Christian Gnann, Anthony J. Cesnik, Emma Lundberg
Journal: Trends in cancer (2021)

Cellular heterogeneity is an important biological phenomenon observed across space and time in human tissues. Imaging-based spatial proteomic technologies can provide fruitful new readouts of phenotypic states for individual cells at subcellular resolution, which may help unravel the roles of non-genetic cellular heterogeneity in tumorigenesis and drug resistance.
The Frustrating Search for Arrhythmia Risk Stratifiers in Heart Failure Due to Nonischemic Cardiomyopathy: Does T-Wave Alternans Testing Help?⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Richard L. Verrier, Kapil Kumar, Mark E. Josephson
Journal: Journal of the American College of Cardiology (2007)
Vaccination induces maturation in a mouse model of diverse unmutated VRC01-class precursors to HIV-neutralizing antibodies with &gt;50% breadth
Authors: Xuejun Chen, Tongqing Zhou, Stephen D. Schmidt, Hongying Duan, Cheng Cheng, Gwo-Yu Chuang, Ying Gu, Mark K. Louder, Bob C. Lin, Chen-Hsiang Shen, Zizhang Sheng, Michelle X. Zheng, Nicole A. Doria-Rose, M. Gordon Joyce, Lawrence Shapiro, Ming Tian, Frederick W. Alt, Peter D. Kwong, John R. Mascola
Journal: Immunity (2021)
DRD1 downregulation contributes to mechanical stretch-induced lung endothelial barrier dysfunction
Authors: Yan Wang, Yu-Jian Liu, Dun-Feng Xu, Hui Zhang, Chu-Fan Xu, Yan-Fei Mao, Zhou Lv, Xiao-Yan Zhu, Lai Jiang
Journal: Theranostics (2021)

Rationale: The lung-protective effects of dopamine and its role in the pathology of ventilator-induced lung injury (VILI) are emerging. However, the underlying mechanisms are still largely unknown. Objective: To investigate the contribution of dopamine receptor dysregulation in the pathogenesis of VILI and therapeutic potential of dopamine D1 receptor (DRD1) agonist in VILI. Methods: The role of dopamine receptors in mechanical stretch-induced endothelial barrier dysfunction and lung injury was studied in DRD1 knockout mice, in isolated mouse lung vascular endothelial cells (MLVECs), and in lung samples from patients who underwent pulmonary lobectomy with mechanical ventilation for different time periods. Measurements and Main Results: DRD1 was downregulated in both surgical patients and mice exposed to mechanical ventilation. Prophylactic administration of dopamine or DRD1 agonist attenuated mechanical stretch-induced lung endothelial barrier dysfunction and lung injury. By contrast, pulmonary knockdown or global knockout of DRD1 exacerbated these effects. Prophylactic administration of dopamine attenuated mechanical stretch-induced α-tubulin deacetylation and subsequent endothelial hyperpermeability through DRD1 signaling. We identified that cyclic stretch-induced glycogen-synthase-kinase-3β activation led to phosphorylation and activation of histone deacetylase 6 (HDAC6), which resulted in deacetylation of α-tubulin. Upon activation, DRD1 signaling attenuated mechanical stretch-induced α-tubulin deacetylation and subsequent lung endothelial barrier dysfunction through cAMP/exchange protein activated by cAMP (EPAC)-mediated inactivation of HDAC6. Conclusions: This work identifies a novel protective role for DRD1 against mechanical stretch-induced lung endothelial barrier dysfunction and lung injury. Further study of the mechanisms involving DRD1 in the regulation of microtubule stability and interference with DRD1/cAMP/EPAC/HDAC6 signaling may provide insight into therapeutic approaches for VILI.
London trust given warning notice after death of mother during stillbirth
Authors: Clare Dyer
Journal: BMJ (2021)

Maternity services at the Royal Free Hospital in London have been rated inadequate and the hospital trust has been given a warning notice by the Care Quality Commission (CQC) after the death of a mother during a stillbirth.

The CQC made an unannounced visit last October and gave the warning notice in November after a coroner presiding over the inquest into Malyun Karama’s death concluded that her life would probably have been saved had a doctor responded to a midwife’s request to come to her aid.

In its inspection report,1 published on 6 January, the CQC said there was no robust process …
Gambling-related suicidality: stigma, shame, and neglect
Authors: Charles Livingstone, Angela Rintoul
Journal: The Lancet Public Health (2021)

The relationship between gambling and suicidality is now more apparent than ever. In The Lancet Public Health, Heather Wardle and Sally McManus1 provide an important addition to a growing body of literature on this important and greatly worrying issue. The factors that might lead many people to gamble are also likely to have been exacerbated this year by the COVID-19 pandemic and consequent economic recession, with further possible consequences for public health.
Abstract 16997: Polymorphic Ventricular Tachycardia: Torsade De Pointes or Purkinje Fiber Triggered Polymorphic Ventricular Tachycardia?
Authors: James Coromilas, Amardeep Saluja, William J Kostis, John Kassotis
Journal: Circulation (2018)

Introduction: Purkinje Fiber triggered polymorphic ventricular tachycardia (Purkinje VT) is often misidentified as torsade de pointes ventricular tachycardia (TdP), While TdP is almost always responsive to IV magnesium, correcting electrolytes and removing offending QT prolonging drugs, Purkinje VT is not amenable to this treatment, is usually refractory to anti-arrhythmic drug treatment and is best managed by ablation of Purkinje fiber triggers. Methods: We compared the clinical and electrocardiographic features of Purkinje VT to TdP to determine distinguishing features. Results: Since June 2015, we identified 11 patients (pts) with Purkinje VT and compared them to 11 patients with TdP. Ten of the 11 Purkinje VT pts were male vs 1 of 11 TdP pts (p &lt; 0.005). The LVEF was 22.4 ± 7.2 % in the Purkinje VT pts vs.39.8 ±10.4 % in the TdP pts (p &lt;0.005). Both the QTc (0.46 ± 0.05 vs. 0.62 ± 0.09 sec) and the coupling interval from the last normal complex to the first VT complex (0.35 ± 0.06 vs. 0.53 ± 0.08 sec) were shorter in the Purkinje VT pts than in the TdP pts (p &lt;0.0001 for both). Although the QTc was significantly longer in the TdP pts, 4 of the 11 Purkinje VT patients had QTc intervals ≥ 500 msec. All the Purkinje VT pts had frequent PVCs triggering the PMVT vs 5 of 11 pts with TdP who had PVC of the same morphology as the first complex of torsade preceding the TdP (p &lt;0.05). Patients with Purkinje VT were more likely to be in cardiogenic shock (6 of 11 vs 0 of 11) and to present with VT storm (7 of 11 vs 1 of 11) than pts with TdP (p &lt;0.05 for both). In addition, Pts with Purkinje VT were more likely to have associated episodes of rapid monomorphic VT (9 of 11 vs 2 of 11) than those with TdP (p &lt;0.01) Conclusions: Purkinje VT is distinguished from TdP by a short coupling interval, a relatively shorter QTc and the obligatory presence of triggering. PVCs. Pts with Purkinje VT are more likely to present with VT storm, cardiogenic shock and to have associated episodes of monomorphic VT/VFlutter than pts with TdP.
Neurotoxicity of Commonly Used Antineoplastic Agents
Authors: Howard D. Weiss, Michael D. Walker, Peter H. Wiernik
Journal: New England Journal of Medicine (1974)

Nitrogen Mustard (NSC-762)Nitrogen mustard (mechlorethamine) is the prototype of the "alkylating agent" class of Cytotoxic drugs. Favorable therapeutic effects from nitrogen mustard are common in Hodgkin's disease and other lymphomas and some solid tumors. The major toxicities of nitrogen mustard are bone-marrow suppression and gastrointestinal disturbances.There have been no reports of serious or life-threatening neurologic toxicity due to intravenous nitrogen mustard when conventional doses were used, except for a recent case presented by Bethlenfalvay and Bergin.85 They described a patient with Hodgkin's disease in whom chills, fever, hemiplegia, and coma developed within one week after each of two . . .
Hypertrophic Cardiomyopathy: Cardiac Magnetic Resonance Imaging Changes the Paradigm⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Nathaniel Reichek, Dipti Gupta
Journal: Journal of the American College of Cardiology (2008)
Abstract 12: Cerebrovascular Pressure Reactivity Predicts Outcome in Diffuse Hypoxic-Ischemic Brain Injury
Authors: Ramani Balu, Sanam Baghshomali, Benjamin S Abella, William A Kofke
Journal: Circulation (2018)

Introduction: Outcome prediction after diffuse hypoxic-ischemic brain injury (HIBI), which most commonly occurs after sudden cardiac arrest, remains fraught with uncertainty. Cerebral autoregulation (CA) normally limits fluctuations in cerebral blood flow through pressure induced changes in cerebral arteriolar diameter. CA is disrupted after brain injury, and the degree of autoregulatory failure correlates with the severity of brain injury. CA measurements may thus enable more accurate outcome prediction after HIBI. Hypothesis: We hypothesized that the degree of impairment in cerebrovascular pressure reactivity, one of the principle mechanisms of CA, correlates with the extent of HIBI and can predict outcome. Methods: Intracranial pressure (ICP) and mean arterial pressure (MAP) were continuously recorded for all subjects. The Pressure Reactivity Index (PRx) was calculated as a moving linear correlation coefficient between ICP and MAP for each 30 sec data epoch. PRx is positive when ICP increases in concert with MAP and implies impaired pressure reactivity. For each subject, both the mean PRx for the entire recording session as well as the proportion of PRx values &gt; 0.2 (previously found to predict poor outcome in TBI) were calculated. Results: We included 22 consecutive patients with HIBI who underwent invasive ICP monitoring in this single center observational study between 02/2016-02/2018. Median age was 41 (range 20-77), 36% (8/22) survived to hospital discharge, and 18% (4/22) had return of consciousness. The median time of ICP monitoring was 101 hr (range 8-381 hr). HIBI was due to cardiac arrest in 19/22 patients and prolonged hypoxia in 3/22. Mean PRx was significantly higher in patients without return of consciousness (0.49 ± 0.05 vs. 0.036 ± 0.032, p = 0.001), as was the proportion of PRx values &gt; 0.2 (0.73 ± 0.037 vs 0.34 ± 0.058, p &lt; 0.001). All patients with return of consciousness had mean PRx &lt; 0.2. Using this cutoff value, PRx had a 94% sensitivity and 100% specificity for predicting death or vegetative state. Conclusions: Continuous pressure reactivity measurements correlate with outcome after HIBI, and may be a useful adjunct for neuroprognostication. Future studies are needed to validate these findings in larger cohorts.
Archie Malcolm: distinguished bone pathologist
Authors: Alan Craft
Journal: BMJ (2021)

The correct diagnosis of a suspected bone tumour is a prerequisite for optimum management. Bone tumours are rare, so a pathologist cannot be expected to come to the right diagnosis immediately. In every generation one or two people emerge as national and international experts. When Archie Malcolm qualified in Glasgow he decided on a career in pathology and came under the tutelage and influence of Mary Catto, the outstanding bone pathologist of her generation. It did not take long for Malcolm to become fascinated by the complexities of the subject but also by its simplicity. Looking at a microscope slide is all about pattern recognition—birdwatchers call this the “jizz.” It is a combination of size, shape, colour, and—in the case of birds—posture, flight, sound, and habitat. Even after a brief glimpse it lets the observer recognise what it is, or what it can’t be. There are many additional tests that can be done, but almost invariably these would confirm what his first impression had been. Malcolm had a natural ability, which he rapidly honed to become the go-to UK expert for difficult cases. Within 10 years he was receiving a dozen or more specimens a week from all around the world.

He moved to Newcastle in 1981 and quietly set about developing a reputation for excellence and establishing the first regional …
Open Schools, Covid-19, and Child and Teacher Morbidity in Sweden
Authors: Jonas F. Ludvigsson, Lars Engerström, Charlotta Nordenhäll, Emma Larsson
Journal: New England Journal of Medicine (2021)

Open Schools, Covid-19, and Child and Teacher Morbidity This letter includes data on children and teachers in Sweden who were admitted to ICUs with Covid-19 between March 1 and June 30, 2020. There...
Consolidation Therapy for Acute Myeloid Leukemia: Defining a Benchmark
Authors: Selina M. Luger
Journal: Journal of Clinical Oncology (2021)

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in the Journal of Clinical Oncology, to patients seen in their own clinical practice.
Predictive Value of the Residual SYNTAX Score in Patients With Cardiogenic Shock
Authors: Olivier Barthélémy, Stéphanie Rouanet, Delphine Brugier, Nicolas Vignolles, Benjamin Bertin, Michel Zeitouni, Paul Guedeney, Marie Hauguel-Moreau, Georges Hage, Pavel Overtchouk, Ibrahim Akin, Steffen Desch, Eric Vicaut, Uwe Zeymer, Holger Thiele, Gilles Montalescot
Journal: Journal of the American College of Cardiology (2021)
Filaggrin Polymorphisms and the Uptake of Chemicals through the Skin—A Human Experimental Study
Authors: Emelie Rietz Liljedahl, Gunnar Johanson, Helena Korres de Paula, Moosa Faniband, Eva Assarsson, Margareta Littorin, Malin Engfeldt, Carola Lidén, Anneli Julander, Karin Wahlberg, Christian Lindh, Karin Broberg
Journal: Environmental Health Perspectives (2021)

The filaggrin protein is important for skin barrier structure and function. Loss-of-function (null) mutations in the filaggrin gene FLG may increase dermal absorption of chemicals.The objective of the study was to clarify if dermal absorption of chemicals differs depending on FLG genotype.We performed a quantitative real-time polymerase chain reaction (qPCR)-based genetic screen for loss-of-function mutations (FLG null) in 432 volunteers from the general population in southern Sweden and identified 28 FLG null carriers. In a dermal exposure experiment, we exposed 23 FLG null and 31 wild-type (wt) carriers to three organic compounds common in the environment: the polycyclic aromatic hydrocarbon pyrene, the pesticide pyrimethanil, and the ultraviolet-light absorber oxybenzone. We then used liquid-chromatography mass-spectrometry to measure the concentrations of these chemicals or their metabolites in the subjects' urine over 48 h following exposure. Furthermore, we used long-range PCR to measure FLG repeat copy number variants (CNV), and we performed population toxicokinetic analysis.Lag times for the uptake and dermal absorption rate of the chemicals differed significantly between FLG null and wt carriers with low (20-22 repeats) and high FLG CNV (23-24 repeats). We found a dose-dependent effect on chemical absorption with increasing lag times by increasing CNV for both pyrimethanil and pyrene, and decreasing area under the urinary excretion rate curve (AUC(0-40h)) with increasing CNV for pyrimethanil. FLG null carriers excreted 18% and 110% more metabolite (estimated by AUC(0-40h)) for pyrimethanil than wt carriers with low and high CNV, respectively.We conclude that FLG genotype influences the dermal absorption of some common chemicals. Overall, FLG null carriers were the most susceptible, with the shortest lag time and highest rate constants for skin absorption, and higher fractions of the applied dose excreted. Furthermore, our results indicate that low FLG CNV resulted in increased dermal absorption of chemicals. https://doi.org/10.1289/EHP7310.
Abstract 16026: Divergent Metabolic Programming in Pediatric and Adult Non-Ischemic Dilated Cardiomyopathy
Authors: Kathryn C Chatfield, Amrut V Ambardekar, Michael J Bennett, Michael R Bristow, Anastacia M Garcia, Anis Karimpour-Fard, Shelley D Miyamoto, Elisabeth K Phillips, genevieve Sparagna, Brian L Stauffer
Journal: Circulation (2019)

Introduction: Although abnormalities of mitochondrial function and beta-oxidation with depletion of tissue ATP stores are recognized features of end-stage heart failure (HF) in adults, cardiac meta...