tbuckley/cabot-search huggingface dataset:
Chronic Myeloid Leukemia in 2020
Authors: Rüdiger Hehlmann
Journal: HemaSphere (2020)

Abstract New insights have emerged from maturing long‐term academic and commercial clinical trials regarding optimum management of chronic myeloid leukemia (CML). Velocity of response has unexpectedly proved less important than hitherto thought, does not predict survival, and is of unclear relevance for treatment‐free remission (TFR). Serious and cumulative toxicity has been observed with tyrosine kinase inhibitors that had been expected to replace imatinib. Generic imatinib has become cost‐effective first‐line treatment in chronic phase despite chronic low‐grade side‐effects in many patients. Earlier recognition of end‐phase by genetic assessment might improve prospects for blast crisis (BC). TFR has become an important new treatment goal of CML. To reflect this new situation ELN has recently revised and updated its recommendations for treating CML. After a brief review of 175 years of CML history this review will focus on recent developments and on current evidence for treating CML in 2020.
Histamine H2 receptor negatively regulates oligodendrocyte differentiation in neonatal hypoxic-ischemic white matter injury
Authors: Lei Jiang, Li Cheng, Han Chen, Haibin Dai, Dadao An, Qianyi Ma, Yanrong Zheng, Xiangnan Zhang, Weiwei Hu, Zhong Chen
Journal: The Journal of Experimental Medicine (2020)

Neonatal hypoxic-ischemic encephalopathy (HIE) with the pathological characteristic of white matter injury often leads to lifelong cognitive and neurobehavioral dysfunction, but relevant therapies to promote remyelination are still unavailable. We found that histamine H2 receptor (H2R) negatively regulated the oligodendrocyte differentiation rate without affecting the oligodendrocytes at the oligodendrocyte precursor cell stage or mature stage following oxygen-glucose deprivation in vitro. Notably, selective deletion of the H2R gene (Hrh2) in differentiating oligodendrocytes (Hrh2fl/fl;CNPase-Cre) improved their differentiation, remyelination, and functional recovery following neonatal hypoxia-ischemia in mice. The regulation of oligodendrocyte differentiation by H2R is mediated by binding with Axin2, which leads to up-regulation of the Wnt/β-catenin signaling pathway. Furthermore, H2R antagonists also promoted oligodendrocyte differentiation and remyelination and the recovery of cognition and motor functions following neonatal hypoxia-ischemia. Thus, histamine H2R in oligodendrocytes could serve as a novel and effective therapeutic target for the retard of oligodendrocyte differentiation and remyelination following neonatal hypoxia-ischemia. The H2R antagonists may have potential therapeutic value for neonatal HIE.
Abstract IA01: Strategies for targeted and immune therapy in melanoma
Authors: Meenhard Herlyn
Journal: Cancer Research (2020)

Abstract Melanoma cells activate pathways that are also activated in proliferating fibroblasts, endothelial cells, or even inflammatory and immune cells. The tumor-secreted proteins and expressed cell surface receptors are associated with growth, migration, invasion, and antiapoptosis. Then there is a group of molecules that is not associated with the phenotype of differentiated cells in skin or tumor stroma but that represents re-expressed developmental genes. Several developmental pathway genes, such as those associated with noncanonical Wnt or Notch signaling, are commonly found on stem cells from the dermis that can give rise to melanocytes and on melanoma cells, but they are absent from or not activated in epidermal melanocytes. We have recently identified a G protein-coupled receptor, LPAR1, that is highly activated in neural crest-like stem cells and melanoma cells and absent from melanocytes. Expression is associated with resistance to BRAFV600E inhibition. When other subpopulations of melanoma cells were characterized that were associated with resistance to BRAF, MEK, or ERK small-molecule inhibitors, their major common property was very slow proliferation, which was in contrast to the bulk of the tumor cells. These “label-retaining cells,” characterized by expression of the H3K4 demethylase JARID1B and the protease SERPIN E2, and the EGF and NGF receptors, are not only drug resistant but also highly invasive in vitro and in experimental animal model. Nonproliferating, drug-resistant malignant cells may pre-exist in tumors. As the majority of melanoma cells are killed by kinase inhibitors, multikinase receptor-expressing cells begin proliferating to repopulate the tumor to its original heterogeneity. Thus, melanomas contain small subpopulations representing only 0.1-5% of all malignant cells that are critical for growth, invasion, and therapy resistance. To achieve total elimination of all malignant cells, we have to develop strategies to target not only the bulk of the tumor cells but also those with intrinsic resistance to common drugs. To closely mimic the conditions in patients’ tumors, we have developed &amp;gt;500 patient-derived xenografts. Together with the &amp;gt;300 permanent cell lines, they represent all clinical, genetic, and biologic groups of the disease. Since the human tumors only proliferate in immune-deficient mice, we have developed two humanized models that recapitulate the infiltration by human leukocytes into the human tumors. Inhibition of checkpoints with clinical-grade inhibitors stimulated the immune response, leading to focal or general tumor regression; thus, the models allow investigating the mechanisms of both stimulation and suppression of the immune system. Citation Format: Meenhard Herlyn. Strategies for targeted and immune therapy in melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA01.
Case Series of Multisystem Inflammatory Syndrome in Adults Associated with SARS-CoV-2 Infection — United Kingdom and United States, March–August 2020
Authors: Sapna Bamrah Morris, Noah G. Schwartz, Pragna Patel, Lilian Abbo, Laura Beauchamps, Shuba Balan, Ellen H. Lee, Rachel Paneth-Pollak, Anita Geevarughese, Maura K. Lash, Marie S. Dorsinville, Vennus Ballen, Daniel P. Eiras, Christopher Newton-Cheh, Emer Smith, Sara Robinson, Patricia Stogsdill, Sarah Lim, Sharon E. Fox, Gillian Richardson, Julie Hand, Nora T. Oliver, Aaron Kofman, Bobbi Bryant, Zachary Ende, Deblina Datta, Ermias Belay, Shana Godfred-Cato
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

During the course of the coronavirus disease 2019 (COVID-19) pandemic, reports of a new multisystem inflammatory syndrome in children (MIS-C) have been increasing in Europe and the United States (1-3). Clinical features in children have varied but predominantly include shock, cardiac dysfunction, abdominal pain, and elevated inflammatory markers, including C-reactive protein (CRP), ferritin, D-dimer, and interleukin-6 (1). Since June 2020, several case reports have described a similar syndrome in adults; this review describes in detail nine patients reported to CDC, seven from published case reports, and summarizes the findings in 11 patients described in three case series in peer-reviewed journals (4-6). These 27 patients had cardiovascular, gastrointestinal, dermatologic, and neurologic symptoms without severe respiratory illness and concurrently received positive test results for SARS-CoV-2, the virus that causes COVID-19, by polymerase chain reaction (PCR) or antibody assays indicating recent infection. Reports of these patients highlight the recognition of an illness referred to here as multisystem inflammatory syndrome in adults (MIS-A), the heterogeneity of clinical signs and symptoms, and the role for antibody testing in identifying similar cases among adults. Clinicians and health departments should consider MIS-A in adults with compatible signs and symptoms. These patients might not have positive SARS-CoV-2 PCR or antigen test results, and antibody testing might be needed to confirm previous SARS-CoV-2 infection. Because of the temporal association between MIS-A and SARS-CoV-2 infections, interventions that prevent COVID-19 might prevent MIS-A. Further research is needed to understand the pathogenesis and long-term effects of this newly described condition.
A Comparison of Late Mortality Among Survivors of Childhood Cancer in the United States and United Kingdom
Authors: Miranda M Fidler-Benaoudia, Kevin C Oeffinger, Yutaka Yasui, Leslie L Robison, David L Winter, Raoul C Reulen, Wendy M Leisenring, Yan Chen, Gregory T Armstrong, Michael M Hawkins
Journal: JNCI Journal of the National Cancer Institute (2020)

Abstract Background It is unclear whether late-effect risks among childhood cancer survivors vary internationally. We compared late mortality in the North American Childhood Cancer Survivor Study (CCSS) and British Childhood Cancer Survivor Study (BCCSS). Methods Late mortality was assessed among 49 822 5-year survivors of childhood cancer diagnosed before 15 years of age from 1970 to 1999 (CCSS, n = 31 596; BCCSS, n = 18 226) using cumulative mortality probabilities (CM%) and adjusted ratios of the standardized mortality ratio. Results The all-cause CM% at 10 years from diagnosis was statistically significantly lower in the CCSS (4.7%, 95% confidence interval [CI] = 4.5% to 5.0%) compared with the BCCSS (6.9%, 95% CI = 6.5% to 7.2%), attributable to a lower probability of death from recurrence or progression of the primary cancer, with statistically significant differences observed in survivors of leukemia, lymphoma, central nervous system tumors, and sarcoma. However, at 40 years from diagnosis, the CCSS had a greater CM% (22.3% vs 19.3%), attributable to a twofold higher risk of mortality from subsequent malignant neoplasms, cardiac and respiratory diseases, and other health-related causes. Differences increased when assessed by follow-up interval, with the CCSS faring worse as time-since-diagnosis increased. Finally, the gap in all-cause mortality widened more recently, with CCSS survivors diagnosed in 1990-1999 experiencing one-half the excess deaths observed in the BCCSS (ratios of the standardized mortality ratio = 0.5, 95% CI = 0.5 to 0.6). Conclusions Our findings suggest that US survivors may have received more intensive regimens to achieve sustainable remission and cure, but the cost of this approach was a higher risk of death from late effects. Although the clinical impact of these differences is unclear, our results provide important evidence to aid the discussion of late effects management.
<i>GGCX</i> mutations in a patient with overlapping pseudoxanthoma elasticum/cutis laxa‐like phenotype
Authors: D. Li, E. Ryu, A.H. Saeidian, L. Youssefian, E. Oliphant, S.F. Terry, P.L. Tong, J. Uitto, N.K. Haass, Q. Li
Journal: British Journal of Dermatology (2020)

Pseudoxanthoma elasticum (PXE) is a multisystem disorder characterized by ectopic mineralization of connective tissues with primary manifestations in the skin, eyes and the cardiovascular system. The classic forms of PXE are caused by mutations in the ABCC6 gene encoding the ABCC6 protein, expressed primarily in the liver. Cutis laxa (CL) manifests with loose and sagging skin with loss of recoil. In 2009 we investigated a 19-year-old patient with overlapping cutaneous features of PXE and CL, together with alpha thalassaemia. Genetic analysis failed to identify pathogenic mutations in ABCC6. More recently we developed a gene-targeted panel of next-generation sequencing technology. This panel has 29 genes, 22 of which, including ABCC6 and GGCX, are associated with ectopic mineralization phenotypes. Mutation analysis in the patient identified two heterozygous GGCX mutations: c.200_201delTT in exon 2 and c.763G>A, p.V255M in exon 7. The GGCX gene encodes a γ-glutamyl carboxylase necessary for activation of blood coagulation factors in the liver. The p.V255M mutation was previously reported to result in reduced γ-glutamyl carboxylase activity in vitro, while the c.200_201delTT mutation is novel. Previous studies reported that mutations in GGCX cause overlapping PXE/CL skin phenotypes in association with or without multiple vitamin K-dependent coagulation factor deficiency. Our patient had loose redundant skin, moderate-to-severe angioid streaks and characteristic calcification of elastic structures in the mid dermis, consistent with PXE/CL overlap, but no coagulation abnormalities. Our studies expand the GGCX mutation landscape in patients with PXE-like phenotypes.
Antibiotics for Appendicitis — Proceed with Caution
Authors: Danny Jacobs
Journal: New England Journal of Medicine (2020)

More than 30 years ago, while I was in training, the best diagnostician I have ever met said — much to my surprise — that some patients who had uncomplicated appendicitis could be successfully treated nonoperatively. He had drawn that conclusion from his practical experiences in the medical corps, well before the advent of modern diagnostic imaging and other technologies. His opinion clearly ran counter to standard teaching at that time in the United States. However, since then, the question of the relative efficacy of antibiotic therapy for the treatment of appendicitis has remained highly controversial. On the basis of . . .
Is extensive cardiopulmonary screening useful in athletes with previous asymptomatic or mild SARS-CoV-2 infection?
Authors: Salvatore Francesco Gervasi, Luca Pengue, Luca Damato, Riccardo Monti, Silvia Pradella, Tommaso Pirronti, Alessandro Bartoloni, Francesco Epifani, Alessio Saggese, Francesco Cuccaro, Massimiliano Bianco, Paolo Zeppilli, Vincenzo Palmieri
Journal: British Journal of Sports Medicine (2020)

Objective During the COVID-19 pandemic, it is essential to understand if and how to screen SARS-CoV-2-positive athletes to safely resume training and competitions. The aim of this study is to understand which investigations are useful in a screening protocol aimed at protecting health but also avoiding inappropriate examinations. Methods We conducted a cohort study of a professional soccer team that is based on an extensive screening protocol for resuming training during the COVID-19 pandemic. It included personal history, antigen swabs, blood tests, spirometry, resting/stress-test ECG with oxygen saturation monitoring, echocardiogram, Holter and chest CT. We also compared the findings with prior data from the same subjects before infection and with data from SARS-CoV-2-negative players. Results None of the players had positive swab and/or anti-SARS-CoV-2 IgM class antibodies. Out of 30 players, 18 (60%) had IgG class antibodies. None had suffered severe SARS-CoV-2-related disease, 12 (66.7%) had complained of mild COVID-19-related symptoms and 6 (33.3%) were asymptomatic. None of the players we examined revealed significant cardiovascular abnormalities after clinical recovery. A mild reduction in spirometry parameters versus pre-COVID-19 values was observed in all athletes, but it was statistically significant (p&lt;0.05) only in SARS-CoV-2-positive athletes. One SARS-CoV-2-positive player showed increased troponin I level, but extensive investigation did not show signs of myocardial damage. Conclusion In this small cohort of athletes with previous asymptomatic/mild SARS-CoV-2 infection, a comprehensive screening protocol including blood tests, spirometry, resting ECG, stress-test ECG with oxygen saturation monitoring and echocardiogram did not identify relevant anomalies. While larger studies are needed, extensive cardiorespiratory and haematological screening in athletes with asymptomatic/mild SARS-CoV-2 infection appears unnecessary.
Forty-Year Shifting Distribution of Systolic Blood Pressure With Population Hypertension Treatment and Control
Authors: Daniel T. Lackland, Virginia J. Howard, Mary Cushman, Suzanne Oparil, Brett Kissela, Monika M. Safford, Dawn O. Kleindorfer, Leslie A. McClure, George Howard
Journal: Circulation (2020)

Hypertension awareness, treatment, and control programs were initiated in the United States during the 1960s and 1970s. Whereas blood pressure (BP) control in the population and subsequent reduced hypertension-related disease risks have improved since the implementation of these interventions, it is unclear whether these BP changes can be generalized to diverse and high-risk populations. This report describes the 4-decade change in BP levels for the population in a high disease risk southeastern region of the United States. The objective is to determine the magnitude of the shift in systolic BP (SBP) among Blacks and Whites from the Southeast between 1960 and 2005 with the assessment of the unique population cohorts.A multicohort study design compared BPs from the CHS (Charleston Heart Study) and ECHS (Evans County Heart Study) in 1960 and the REGARDS study (Reasons for Geographic and Racial Differences in Stroke) 4 decades later. The analyses included participants ≥45 years of age from CHS (n=1323), ECHS (n=1842), and REGARDS (n=6294) with the main outcome of SBP distribution.Among Whites 45 to 54 years of age, the median SBP was 18 mm Hg (95% CI, 16-21 mm Hg) lower in 2005 than 1960. The median shift was a 45 mm Hg (95% CI, 37-51 mm Hg) decline for those ≥75 years of age. The shift was larger for Blacks, with median declines of 38 mm Hg (95% CI, 32-40 mm Hg) at 45 to 54 years of age and 50 mm Hg (95% CI, 33-60 mm Hg) for ages ≥75 years. The 95th percentile of SBP decreased 60 mm Hg for Whites and 70 mm Hg for Blacks.The results of the current analyses of the unique cohorts in the Southeast confirm the improvements in population SBP levels since 1960. This assessment provides new evidence of improvement in SBP, suggesting that strategies and programs implemented to improve hypertension treatment and control have been extraordinarily successful for both Blacks and Whites residing in a high-risk region of the United States. Severe BP elevations commonly observed in the 1960s have been nearly eliminated, with the current 75th percentile of BP generally less than the 25th percentile of BP in 1960.
Physical Therapy in Infantile Paralysis.
Authors: M CORDARO
Journal: JAMA (1933)

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Association of Medicaid Expansion Under the Patient Protection and Affordable Care Act With Use of Long-term Care
Authors: Courtney Harold Van Houtven, Brian E. McGarry, Eric Jutkowitz, David C. Grabowski
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Medicaid expansion is associated with increased access to health services, increased quality of medical care delivered, and reduced mortality, but little is known about its association with use of long-term care. <h3>Objective</h3> To examine the association of Medicaid expansion under the Patient Protection and Affordable Care Act (ACA) with long-term care use among newly eligible low-income adults and among older adults whose eligibility did not change. <h3>Design, Setting, and Participants</h3> This difference-in-difference cohort study used data from the Health and Retirement Study, a nationally representative longitudinal survey of persons 50 years or older. Long-term care use from 2008 to 2012 was compared with use from 2014 to 2016 among low-income adults aged 50 to 64 years without Medicare coverage residing in states in which Medicaid coverage expanded in 2014 and those living in states without expansion. Low-income adults who were covered by Medicare and were ineligible for expanded Medicaid were also included in the analysis. Data were analyzed from January 15, 2018, to December 31, 2019. <h3>Exposures</h3> Residence in a state with Medicaid expansion in 2014. <h3>Main Outcomes and Measures</h3> Any home health care use or any nursing home use in 2014 or 2016. All estimates are weighted to account for the Health and Retirement Study sampling design. <h3>Results</h3> Among the 891 individuals likely eligible for expanded Medicaid, the mean (SD) age was 55.2 (3.1) years; 534 (53.4%) were women, 482 (49.5%) were married, and 661 (45.9%) were White non-Hispanic. Before the ACA-funded Medicaid expansion, 0.4% (95% CI, −0.3% to 1.1%) in expansion states and 1.0% (95% CI, −0.1% to 2.2%) in nonexpansion states used nursing homes, and 1.9% (95% CI, 0.4%-3.4%) in expansion states and 7.1% (95% CI, 4.7%-9.5%) in nonexpansion states used any formal home care. The ACA-funded Medicaid expansion was associated with an increase of 4.4 percentage points (95% CI, 2.8-6.1 percentage points) in the probability of any long-term care use among low-income, middle-aged adults, with increases in home health use (3.8 percentage points; 95% CI, 2.0-5.6 percentage points) and in any nursing home use (2.1 percentage points; 95% CI, 0.9-3.3 percentage points). <h3>Conclusions and Relevance</h3> In this study, ACA-funded Medicaid expansion was associated with an increase in any long-term care use among newly eligible low-income, middle-aged adults, suggesting that the population covered by the Medicaid expansion may have had unmet long-term care needs before expansion.
Nebulised ALX-0171 for respiratory syncytial virus lower respiratory tract infection in hospitalised children: a double-blind, randomised, placebo-controlled, phase 2b trial
Authors: Steve Cunningham, Pedro A Piedra, Federico Martinon-Torres, Henryk Szymanski, Benedicte Brackeva, Evelyne Dombrecht, Laurent Detalle, Carmen Fleurinck, Steve Cunningham, Pedra A Piedra, Stijn Verhulst, Inge Matthijs, Marijke Proesmans, Tessa Goetghebuer, Miroslava Bosheva, Svilen Dosev, Olga Nikolova, Petranka Chakarova, Elba Wu Hupat, Juan Mesa Monsalve, Mirjana Turkalj, Natasa Mesaric Antoncic, Goran Tesovic, Mirna SIPL, Blazenka Kljaic Bukvic, Irena Ivkovic-Jurekovic, Biserka Cicak, Sylva Skalova, Gerd Horneff, Christian Vogelberg, Éva Gacs, Krisztina Kalocsai, Anna Madarasi, Lajos Kovacs, Zoltan Novak, Zsolt Bene, Shai Ashkenazi, Aviv Goldbart, Lea Bentur, Nadezda Kolosa, Dace Gardovska, Poh Guan Khaw, Teck Hock Toh, Jessie Anne De Bruyne, Kah Kee Tan, Edison Alberto, Benjamin, Junior Sablan, Anjanette de Leon, Henryk Szymanski, Miroslav Repko, Karol Kralinsky, Ignacio Salamanca de la Cueva, Carlos Rodrigo Gonzalo de Liria, Federico Martinón-Torres, María Pilar Cedena Romero, Emilio Monteagudo Montesinos, Jamaree Teeratakulpisarn, Thanyawee Puthanakit, Peninnah Oberdorfer, Boonyarat Warachit, Benedicte Brackeva, Evelyne Dombrecht, Laurent Detalle, Carmen Fleurinck
Journal: The Lancet Respiratory Medicine (2020)