tbuckley/cabot-search huggingface dataset:
T‐cell replete haploidentical stem cell transplantation attenuates the prognostic impact of <i>FLT3‐ITD</i> in acute myeloid leukemia: A report from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
Authors: Jonathan Canaani, Myriam Labopin, Xiao‐Jun Huang, William Arcese, Fabio Ciceri, Didier Blaise, Giuseppe Irrera, Lucia Lopez Corral, Benedetto Bruno, Stella Santarone, Maria Teresa Van Lint, Antonin Vitek, Jordi Esteve, Mohamad Mohty, Arnon Nagler
Journal: American Journal of Hematology (2018)

Acute myeloid leukemia (AML) patients harboring the FLT3-ITD mutation are considered a high risk patient subset preferentially allocated for allogeneic stem cell transplantation in first remission. Whether FLT3-ITD retains a prognostic role in haploidentical stem cell transplantation (haplo-SCT) is unknown. To analyze the prognostic impact of FLT3-ITD in haplo-SCT, we performed a retrospective analysis of the multicenter registry of the acute leukemia working party of the European Society for Blood and Marrow Transplantation. We included all adult AML patients with known FLT3 status who underwent a first T-cell replete related haplo-HCT in first complete remission from 2005 to 2016. We evaluated 293 patients of whom 202 were FLT3wt and 91 were FLT3-ITD mutated. FLT3-ITD patients were more likely to be NPM1 mutated as well as be in the intermediate risk cytogenetic risk category. In multivariate analysis, patients with FLT3-ITD had comparable rates of relapse incidence [Hazard ratio (HR) = 1.34, confidence interval (CI) 95%, 0.67-2.7; P = .9] and leukemia-free survival (HR = 0.99, CI 95%, 0.62-1.57; P = .9) to those of FLT3wt patients. Overall survival, the incidence of nonrelapse mortality, and graft versus host disease-free/relapse-free survival were not significantly impacted by FLT3-ITD status. Furthermore, relapse and overall survival were comparable between FLT3-ITD patients transplanted from various donor pools, namely matched siblings, unrelated donors, haplo-SCT). Finally, subset analysis of patients with intermediate risk cytogenetics confirmed the absence of a prognostic impact of FLT3-ITD also for this patient segment. In AML patients undergoing T-cell replete haplo-SCT, the FLT3-ITD mutation possibly does not retain its prognostic significance.
DEREGULATION OF RBM20 IN LAMIN A/C AND EMERIN RELATED CARDIOMYOPATHIES
Authors: Marwan Refaat, Dana Sedki, Hind C. Zahr, Dima Diab El Harakeh, Jan Lammerding, Georges Nemer, Diana E. Jaalouk
Journal: Journal of the American College of Cardiology (2018)
Abstract P346: Joint Associations of Obstructive Sleep Apnea and Excessive Daytime Sleepiness With Incident Cardiovascular Disease
Authors: Rachel P Ogilvie, Kamakshi Lakshminarayan, Sanjay R Patel, Pamela L Lutsey
Journal: Circulation (2018)

Background: Although excessive daytime sleepiness (EDS) is a common symptom of obstructive sleep apnea (OSA), and both EDS and OSA have separately been associated with increased risk of cardiovascular disease (CVD), their joint association with CVD risk is unknown. Examining the association of EDS and OSA with CVD risk may help refine the OSA phenotype. Methods: Among 3,874 Sleep Heart Health Study participants without prevalent CVD, moderate to severe OSA was defined by an apnea hypopnea index (AHI) ≥ 15 events per hour on in-home polysomnography. EDS was defined as an Epworth Sleepiness Scale score ≥ 11. Incident CVD events included adjudicated myocardial infarction, coronary revascularization and stroke. Cox proportional hazards models adjusted for age, sex, alcohol, smoking, and body mass index. Results: Mean age was 63.0 years with 55.4% female, mean AHI 9.3 events/hour, and 23.4% with EDS. Over a median of 10.4 years of follow-up, we identified 653 incident cases of CVD. In adjusted analyses, EDS (Hazard ratio: 1.22, 95% CI 1.01-1.47) but not moderate-severe OSA (HR: 0.98, 0.81-1.20) was associated with incident CVD. In stratified analyses, the CVD incidence rate varied from 15.6/1000 person-years in those with no OSA or EDS to 26.0/1000 person-years in those with OSA and EDS (figure). In multivariable analyses, the hazard ratio for moderate-severe OSA and EDS compared to no OSA and no EDS was 1.26 (0.91-1.73). Formal tests of statistical significance of the OSA and EDS interaction were not significant on either the additive or multiplicative scales. Conclusions: Having both EDS and moderate-severe OSA was not associated with an increased risk of CVD in our data.
Association Between Loss of Hospital-Based Obstetric Services and Birth Outcomes in Rural Counties in the United States
Authors: Katy B. Kozhimannil, Peiyin Hung, Carrie Henning-Smith, Michelle M. Casey, Shailendra Prasad
Journal: JAMA (2018)

Hospital-based obstetric services have decreased in rural US counties, but whether this has been associated with changes in birth location and outcomes is unknown.To examine the relationship between loss of hospital-based obstetric services and location of childbirth and birth outcomes in rural counties.A retrospective cohort study, using county-level regression models in an annual interrupted time series approach. Births occurring from 2004 to 2014 in rural US counties were identified using birth certificates linked to American Hospital Association Annual Surveys. Participants included 4 941 387 births in all 1086 rural counties with hospital-based obstetric services in 2004.Loss of hospital-based obstetric services in the county of maternal residence, stratified by adjacency to urban areas.Primary outcomes were county rates of (1) out-of-hospital births; (2) births in hospitals without obstetric units; and (3) preterm births (<37 weeks' gestation).Between 2004 and 2014, 179 rural counties lost hospital-based obstetric services. Of the 4 941 387 births studied, the mean (SD) maternal age was 26.2 (5.8) years. A mean (SD) of 75.9% (23.2%) of women who gave birth were non-Hispanic white, and 49.7% (15.6%) were college graduates. Rural counties not adjacent to urban areas that lost hospital-based obstetric services had significant increases in out-of-hospital births (0.70 percentage points [95% CI, 0.30 to 1.10]); births in a hospital without an obstetric unit (3.06 percentage points [95% CI, 2.66 to 3.46]); and preterm births (0.67 percentage points [95% CI, 0.02 to 1.33]), in the year after loss of services, compared with those with continual obstetric services. Rural counties adjacent to urban areas that lost hospital-based obstetric services also had significant increases in births in a hospital without obstetric services (1.80 percentage points [95% CI, 1.55 to 2.05]) in the year after loss of services, compared with those with continual obstetric services, and this was followed by a decreasing trend (-0.19 percentage points per year [95% CI, -0.25 to -0.14]).In rural US counties not adjacent to urban areas, loss of hospital-based obstetric services, compared with counties with continual services, was associated with increases in out-of-hospital and preterm births and births in hospitals without obstetric units in the following year; the latter also occurred in urban-adjacent counties. These findings may inform planning and policy regarding rural obstetric services.
Cbfβ2 controls differentiation of and confers homing capacity to prethymic progenitors
Authors: Mari Tenno, Satoshi Kojo, Divine-Fondzenyuy Lawir, Isabell Hess, Katsuyuki Shiroguchi, Takashi Ebihara, Takaho A. Endo, Sawako Muroi, Rumi Satoh, Hiroshi Kawamoto, Thomas Boehm, Ichiro Taniuchi
Journal: The Journal of Experimental Medicine (2018)

Multipotent hematopoietic progenitors must acquire thymus-homing capacity to initiate T lymphocyte development. Despite its importance, the transcriptional program underlying this process remains elusive. Cbfβ forms transcription factor complexes with Runx proteins, and here we show that Cbfβ2, encoded by an RNA splice variant of the Cbfb gene, is essential for extrathymic differentiation of T cell progenitors. Furthermore, Cbfβ2 endows extrathymic progenitors with thymus-homing capacity by inducing expression of the principal thymus-homing receptor, Ccr9. This occurs via direct binding of Cbfβ2 to cell type-specific enhancers, as is observed in Rorγt induction during differentiation of lymphoid tissue inducer cells by activation of an intronic enhancer. As in mice, an alternative splicing event in zebrafish generates a Cbfβ2-specific mRNA, important for ccr9 expression. Thus, despite phylogenetically and ontogenetically variable sites of origin of T cell progenitors, their robust thymus-homing capacity is ensured by an evolutionarily conserved mechanism emerging from functional diversification of Runx transcription factor complexes by acquisition of a novel splice variant.
Type 2 diabetes mellitus and heart failure: a position statement from the Heart Failure Association of the European Society of Cardiology
Authors: Petar M. Seferović, Mark C. Petrie, Gerasimos S. Filippatos, Stefan D. Anker, Giuseppe Rosano, Johann Bauersachs, Walter J. Paulus, Michel Komajda, Francesco Cosentino, Rudolf A. de Boer, Dimitrios Farmakis, Wolfram Doehner, Ekaterini Lambrinou, Yuri Lopatin, Massimo F. Piepoli, Michael J. Theodorakis, Henrik Wiggers, John Lekakis, Alexandre Mebazaa, Mamas A. Mamas, Carsten Tschöpe, Arno W. Hoes, Jelena P. Seferović, Jennifer Logue, Theresa McDonagh, Jillian P. Riley, Ivan Milinković, Marija Polovina, Dirk J. van Veldhuisen, Mitja Lainscak, Aldo P. Maggioni, Frank Ruschitzka, John J.V. McMurray
Journal: European Journal of Heart Failure (2018)
Children with sickle cell anemia with normal transcranial Doppler ultrasounds and without silent infarcts have a low incidence of new strokes
Authors: Lori C. Jordan, Dionna O. Roberts Williams, Mark J. Rodeghier, Brittany V. Covert Greene, Maria R. Ponisio, James F. Casella, Robert C. McKinstry, Michael J. Noetzel, Fenella J. Kirkham, Emily R. Meier, Beng Fuh, Melissa McNaull, Sharada Sarnaik, Suvankar Majumdar, Timothy L. McCavit, Michael R. DeBaun
Journal: American Journal of Hematology (2018)

Abstract In a prospective cohort study, we tested the hypothesis that children with sickle cell anemia (SCA) with normal transcranial Doppler ultrasound (TCD) velocities and without silent cerebral infarcts (SCIs) would have a lower incidence rate of new neurological events (strokes, seizures or transient ischemic attacks) compared to children with normal TCD measurements and SCIs, not receiving regular blood transfusions. Nonrandomized participants from the silent cerebral infarct transfusion (SIT) Trial who had screening magnetic resonance imaging (MRI) of the brain and normal TCD measurements were included. Follow‐up ended at the time of first neurological event (stroke, seizure or transient ischemic attack), start of regular blood transfusion, or loss to follow‐up, whichever came first. The primary endpoint was a new neurological event. Of 421 participants included, 68 had suspected SCIs. Mean follow‐up was 3.6 years. Incidence rates of new neurological events in nontransfused participants with normal TCD values with SCIs and without SCIs were 1.71 and 0.47 neurological events per 100 patient‐years, respectively, P = .065. The absence of SCI(s) at baseline was associated with a decreased risk of a new neurological event (hazard ratio 0.231, 95% CI 0.062‐0.858; P = .029). Local pediatric neurologists examined 67 of 68 participants with suspected SCIs and identified 2 with overt strokes classified as SCIs by local hematologists; subsequently one had a seizure and the other an ischemic stroke. Children with SCA, without SCIs, and normal TCD measurements have a significantly lower rate of new neurological events when compared to those with SCIs and normal TCD measurements. Pediatric neurology assessment may assist risk stratification.
Acupuncture: theatrical placebo or caring approach to pain?
Authors: Fiona Godlee
Journal: BMJ (2018)

How good is the evidence for acupuncture in managing pain?In our Head to Head this week (doi:10.1136/bmj.k970)the authors on both sides agree that studies show a small but statistically significant effect when it is compared with sham acupuncture.But there they part company.Asbjørn Hróbjartsson and Edzard Ernst say that there is no clinically relevant effect in the randomised trials and that what difference there is can't be distinguished from bias.The fact that studies don't blind the acupuncturists is a fatal flaw, they say.But, says Mike Cummings, sham acupuncture has higher response rates than oral placebo, so randomised controlled trials that use it as the comparator will tend to underestimate acupuncture's effects.He prefers studies that compare acupuncture with usual care.
Plinabulin, a novel small molecule clinical stage IO agent with anti-cancer activity, to prevent chemo-induced neutropenia and immune related AEs.
Authors: Ramon W. Mohanlal, Ken LLoyd, Lan Huang
Journal: Journal of Clinical Oncology (2018)

126 Background: Plinabulin (Plin) is a small molecule with tumor-inhibiting and immune-enhancing effects by targeting Dendritic Cells (DCs). In preclinical studies, Plin induces DC maturation and the production of MHCII, CD40, CD80 and CD86 and related antigen-specific T-cell activation. Plin had synergistic anticancer efficacy with PD1+CTLA4inhibitors in animal models. In addition, Plin increases expression of IL-1β, IL-6, IL-12 in DC cell, which cytokines protect neutrophils against apoptosis. In a Phase 2 (Ph2) trial, the addition of Plin to Docetaxel (Plin+Doc; n = 38) in NSCLC patients (pts) with a measurable lesion, improved mOS with 4.6 mo vs Doc alone (n = 38). DOR (a marker of immune effect) was ~1 yr longer (P &lt; 0.05) with Plin+Doc vs Doc alone. Plin exerted immune-enhancing effects (DOR), without increasing Immune-Related AEs (IR-AEs). This may suggest that Plin exerts immune-enhancing and anti-inflammatory effects. Methods: Prospective, randomized Ph2 clinical trial (NCT00630110) and non-clinical studies. Results: In-vitro screens showed that Plin is a PDE4-inhibitor, and clinical evidence (p &lt; 0.03; n = 90) of PDE4-inhibition with Plin was observed in Ph2. PDE4-inhibitors have steroid-like effects and are approved for the treatment of Inflammatory disorders, and thus have the potential to prevent IR-AEs. In addition, Plin prevented chemo-induced Neutropenia (CIN), through a mechanism, different from G-CSF, in non-clinical (with various chemotherapies) and Ph2. In Ph2, Gr 4 Neutropenia occurred in 5% with Plin+Doc vs 33 % off pts with Doc (p &lt; 0.0003) in Cycle 1, day 8. Plin is given 30 min after chemo (on the same day of chemo), and does not cause bone pain. G-CSF is given 24 hr after chemo, and causes bone pain in most pts. Conclusions: Plin exerts anticancer immune-enhancing effects, combined with anti-inflammatory effects, due to PDE4-inhibition. Plin holds the promise of an agent with anti-cancer efficacy, while also mitigating IR-AEs and CIN. Therefore, Plin is an attractive candidate for combination therapy with PD1-inhibitors (or PD-L1 inhibitors), PD1+CTLA-inhibitor, or PD1-inhibitor/chemotherapy.
Defining therapy goals for major molecular remission in chronic myeloid leukemia: results of the randomized CML Study IV
Authors: Susanne Saussele, Rüdiger Hehlmann, Alice Fabarius, Sabine Jeromin, Ulrike Proetel, Sebastien Rinaldetti, Katharina Kohlbrenner, Hermann Einsele, Christiane Falge, Lothar Kanz, Andreas Neubauer, Michael Kneba, Frank Stegelmann, Michael Pfreundschuh, Cornelius F. Waller, Elisabeth Oppliger Leibundgut, Dominik Heim, Stefan W. Krause, Wolf-Karsten Hofmann, Joerg Hasford, Markus Pfirrmann, Martin C. Müller, Andreas Hochhaus, Michael Lauseker
Journal: Leukemia (2018)

Major molecular remission (MMR) is an important therapy goal in chronic myeloid leukemia (CML). So far, MMR is not a failure criterion according to ELN management recommendation leading to uncertainties when to change therapy in CML patients not reaching MMR after 12 months. At monthly landmarks, for different molecular remission status Hazard ratios (HR) were estimated for patients registered to CML study IV who were divided in a learning and a validation sample. The minimum HR for MMR was found at 2.5 years with 0.28 (compared to patients without remission). In the validation sample, a significant advantage for progression-free survival (PFS) for patients in MMR could be detected (p-value 0.007). The optimal time to predict PFS in patients with MMR could be validated in an independent sample at 2.5 years. With our model we provide a suggestion when to define lack of MMR as therapy failure and thus treatment change should be considered. The optimal response time for 1% BCR-ABL at about 12-15 months was confirmed and for deep molecular remission no specific time point was detected. Nevertheless, it was demonstrated that the earlier the MMR is achieved the higher is the chance to attain deep molecular response later.
Progress Toward Poliomyelitis Eradication — Nigeria, January–December 2017
Authors: Omotayo Bolu, Chimeremma Nnadi, Eunice Damisa, Fiona Braka, Anisur Siddique, W. Roodly Archer, Philip Bammeke, Richard Banda, Jeffrey Higgins, Aboyowa Edukugo, Gatei wa Nganda, Joseph C. Forbi, Hongmei Liu, Saheed Gidado, Mohammed Soghaier, Richard Franka, Ndadilnasiya Waziri, Cara C. Burns, John Vertefeuille, Eric Wiesen, Usman Adamu
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Nearly three decades after the World Health Assembly launched the Global Polio Eradication Initiative in 1988, four of the six World Health Organization (WHO) regions have been certified polio-free (1). Nigeria is one of three countries, including Pakistan and Afghanistan, where wild poliovirus (WPV) transmission has never been interrupted. In September 2015, after >1 year without any reported WPV cases, Nigeria was removed from WHO's list of countries with endemic WPV transmission (2); however, during August and September 2016, four type 1 WPV (WPV1) cases were reported from Borno State, a state in northeastern Nigeria experiencing a violent insurgency (3). The Nigerian government, in collaboration with partners, launched a large-scale coordinated response to the outbreak (3). This report describes progress in polio eradication activities in Nigeria during January-December 2017 and updates previous reports (3-5). No WPV cases have been reported in Nigeria since September 2016; the latest case had onset of paralysis on August 21, 2016 (3). However, polio surveillance has not been feasible in insurgent-controlled areas of Borno State. Implementation of new strategies has helped mitigate the challenges of reaching and vaccinating children living in security-compromised areas, and other strategies are planned. Despite these initiatives, however, approximately 130,000-210,000 (28%-45%) of the estimated 469,000 eligible children living in inaccessible areas in 2016 have not been vaccinated. Sustained efforts to optimize surveillance and improve immunization coverage, especially among children in inaccessible areas, are needed.
National network of vascular surgery units will improve patient outcomes, says NHS Improvement
Authors: Ingrid Torjesen
Journal: BMJ (2018)

More patients will receive urgent surgery sooner by implementing a vascular networks model across the NHS in England, a report has said.1

The model would save lives by reducing the likelihood of patients having life threatening strokes, transient ischaemic attacks, aortic aneurysm ruptures, and arterial blockages, said the report from NHS Improvement’s Getting It Right First Time (GIRFT) programme.

Seventy NHS trusts in England conduct vascular surgery and many of these already collaborate within a local network. However, there is no standard …
The association between HSD3B1 genotype and steroid metabolism in normal and prostate cancer (PCa) tissue.
Authors: Hamid Emamekhoo, Pedro C. Barata, Cristina Magi-Galluzzi, Mike Berk, Jennifer Taylor, Allison Janine Tyler, Brian I. Rini, Petros Grivas, Timothy D. Gilligan, Moshe Chaim Ornstein, Andrew J. Stephenson, Eric A. Klein, Jihad Kaouk, Georges-Pascal Haber, Nima Sharifi, Jorge A. Garcia
Journal: Journal of Clinical Oncology (2018)

TPS155 Background: The common germline variant HSD3B1(1245C) encodes for a gain-of-function in 3βHSD1 which is associated with a shorter duration of response to androgen deprivation therapy (ADT) and more rapid disease progression to castration resistant PCa (CRPC) as shown previously in 5 independent cohorts. Therefore, evaluating the effect of such genotype variation on the level of steroid metabolites and the intratumoral dihydrotestosterone (DHT) concentration in benign and tumor tissue of men on ADT is of significant importance. We hypothesize that patients with homozygous HSD3B1 (1245C) genotype (HZ) will have a sustained androgen synthesis from extragonadal precursor steroids and higher concentrations of DHT compared to patients with wild-type HSD3B1 (1245A) (WT) inheritance in the context of testosterone suppression. In addition, it is expected that heterozygous HSD3B1 (1245C) patients (HTZ) will have intermediate levels of DHT. We also hypothesize that treatment with androgen receptor (AR) antagonist (apalutamide) will reverse the effects of elevated DHT on AR signaling in benign and malignant prostate tissue. Methods: In this Phase II trial (NCT02770391), men with newly diagnosed intermediate or high-risk PCa (GS ≥ 4+3, ≥cT2b, or PSA ≥ 10) who are scheduled to undergo radical prostatectomy (RP) will be enrolled into 3 groups based on their HSD3B1 genotype. All pts will receive one dose of 7.5 mg leuprolide injection and apalutamide 240 mg/day orally for 28 ± 3 days prior to RP. DHT and 7 other androgens (including testosterone, Dehydroepiandrosterone, Androstenedione) will be evaluated in the normal and malignant prostate tissue as well as serum samples obtained at the time of RP. AR regulated genes expression (including PSA, FKBP5, TMPRSS2) will be compared across 3 genotypes. A sample size of 57 pts (WT = 30, HTZ = 15, HZ = 12) will allow a statistical power of &gt; 80% (with two-sided α = 0.05) to detect a 4-fold trend in DHT concentrations in the resected prostate tissue (primary endpoint) as well as similar trend in other androgens (secondary endpoint). As of Oct 2017, 16 of planned 57 pts have been enrolled. Clinical trial information: NCT02770391.
Mepolizumab Treatment of Pediatric Eosinophilic Granulomatosis With Polyangiitis
Authors: Mathew X. Joseph, Lauren E. Jenkins, Michael E. Wechsler, Loretta S. Davis
Journal: JAMA Dermatology (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Initial Treatment of Hypertension
Authors: Sandra J. Taler
Journal: New England Journal of Medicine (2018)

The 2017 ACC–AHA Hypertension Guideline lowers the blood-pressure treatment target to less than 130/80 mm Hg. Management includes lifestyle modifications and pharmacotherapy, starting with an ACE inhibitor, angiotensin-receptor blocker, calcium-channel blocker, or thiazide diuretic.