bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations between clusters of early life risk factors and developmental vulnerability at age 5: a retrospective cohort study using population-wide linkage of administrative data in Tasmania, Australia
Authors: Taylor Catherine Louise , Christensen Daniel , Stafford Joel , Venn Alison , Preen David , Zubrick Stephen Rade 
Published: April 2020

ObjectiveEarly childhood is a critical time to address risk factors associated with developmental vulnerability. This study investigated the associations between clusters of early life risk factors and developmental vulnerability in children’s first year of full-time school at age 5.DesignA retrospective cohort study.SettingPopulation-wide linkage of administrative data records for children born in Tasmania, Australia in 2008–2010.ParticipantsThe cohort comprised 5440 children born in Tasmania in 2008–2010, with a Tasmanian 2015 Australian Early Development Census (AEDC) record and a Tasmanian Perinatal Collection record.Outcome measureThe AEDC is a national measure of child development across five domains: physical health and well-being, social competence, emotional maturity, language and cognitive skills (school-based), and communication skills and general knowledge. Children who scored below the 10th percentile on one or more AEDC domains were classified as developmentally vulnerable. Children with special needs are not included in the AEDC results.ResultsLatent class analysis identified five clusters of risk factors: low risks (65% of children), sociodemographic and health behaviour risks (24%), teenage mother and sociodemographic risks (6%), birth risks (3%), and birth, sociodemographic and health behaviour risks (2%). In this sample population, 20% of children were classified as developmentally vulnerable, but the proportion varied substantially by latent class. Logistic regression showed increased odds of developmental vulnerability associated with sociodemographic and health behaviour risks (OR 2.26, 95% CI 1.91 to 2.68, p<0.001), teenage mother and sociodemographic risks (OR 2.01, 95% CI 1.50 to 2.69, p<0.001), and birth, sociodemographic and health behaviour risks (OR 3.29, 95% CI 2.10 to 5.16. p<0.001), but not birth risks (OR 1.34, 95% CI 0.88 to 2.03, p=0.1649), relative to the reference group.ConclusionsThe patterning of risks across the five groups invites consideration of multisectoral policies and services to address complex clusters of risk factors associated with developmental vulnerability.
Multiple Interventions for Diabetic Foot Ulcer Treatment Trial (MIDFUT): study protocol for a randomised controlled trial
Authors: Brown Sarah , Nixon Jane , Ransom Myka , Gilberts Rachael , Dewhirst Nikki , McGinnis Elizabeth , Longo Roberta , Game Frances , Bojke Chris , Chadwick Paul , Chandrasekar Akila , Chetter Ian , Collier Howard , Fernandez Catherine , Homer-Vanniasinkam Shervanthi , Jude Edward , Leigh Richard , Lomas Richard , Vowden Peter , Wason James , Sharples Linda , Russell David 
Published: April 2020

IntroductionDiabetes affects more than 425 million people worldwide with a lifetime risk of diabetic foot ulcer (DFU) of up to 25%. Management includes wound debridement, wound dressings, offloading, treatment of infection and ischaemia, optimising glycaemic control; use of advanced adjuvant therapies is limited by high cost and lack of robust evidence.Methods and analysisA multicentre, seamless phase II/III, open, parallel group, multi-arm multi-stage randomised controlled trial in patients with a hard-to-heal DFU, with blinded outcome assessment. A maximum of 447 participants will be randomised (245 participants in phase II and 202 participants in phase III). The phase II primary objective will determine the efficacy of treatment strategies including hydrosurgical debridement ± decellularised dermal allograft, or the combination with negative pressure wound therapy, as an adjunct to treatment as usual (TAU), compared with TAU alone, with patients randomised in a 1:1:1:2 allocation. The outcome is achieving at least 50% reduction in index ulcer area at 4 weeks post randomisation.The phase III primary objective will determine whether one treatment strategy, continued from phase II, reduces time to healing of the index ulcer compared with TAU alone, with participants randomised in a 1:1 allocation. Secondary objectives will compare healing status of the index ulcer, infection rate, reulceration, quality of life, cost-effectiveness and incidence of adverse events over 52 weeks post randomisation. Phase II and phase III primary endpoint analysis will be conducted using a mixed-effects logistic regression model and Cox proportional hazards regression, respectively. A within-trial economic evaluation will be undertaken; the primary economic analysis will be a cost-utility analysis presenting ICERs for each treatment strategy in rank order of effectiveness, with effects expressed as quality-adjusted life years.The trial has predefined progression criteria for the selection of one treatment strategy into phase III based on efficacy, safety and costs at 4 weeks.Ethics and disseminationEthics approval has been granted by the National Research Ethics Service (NRES) Committee Yorkshire and The Humber - Bradford Leeds Research Ethics Committee; approved 26 April 2017; (REC reference: 17/YH/0055). There is planned publication of a monograph in National Institute for Health Research journals and main trial results and associated papers in high-impact peer-reviewed journals.Trial registration numberISRCTN64926597; registered on 6 June 2017
Serum Metabolomic Response to Low- and High-Dose Vitamin E Supplementation in Two Randomized Controlled Trials
Authors: Huang Jiaqi , Hodis Howard N. , Weinstein Stephanie J. , Mack Wendy J. , Sampson Joshua N. , Mondul Alison M. , Albanes Demetrius 
Published: April 2020

Abstract

Background:
Vitamin E is an essential micronutrient and critical human antioxidant previously tested for cancer preventative effects with conflicting clinical trial results that have yet to be explained biologically.

Methods:
We examined baseline and on-trial serum samples for 154 men randomly assigned to receive 400 IU vitamin E (as alpha-tocopheryl acetate; ATA) or placebo daily in the Vitamin E Atherosclerosis Prevention Study (VEAPS), and for 100 men administered 50 IU ATA or placebo daily in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC). Over 970 metabolites were identified using ultrahigh-performance LC/MS-MS. Linear regression models estimated the change in serum metabolites of men supplemented with vitamin E versus those receiving placebo in VEAPS as compared with ATBC.

Results:
Serum alpha-carboxyethyl hydrochroman (CEHC) sulfate, alpha-tocopherol, and beta/gamma-tocopherol were significantly altered by ATA supplementation in both trials (all P values ≤5.1 × 10−5, the Bonferroni multiple comparisons corrected statistical threshold). Serum C22 lactone sulfate was significantly decreased in response to the high-dose vitamin E in VEAPS (β = −0.70, P = 8.1 × 10−6), but not altered by the low dose in ATBC (β = −0.17, P = 0.4). In addition, changes in androgenic steroid metabolites were strongly correlated with the vitamin E supplement–associated change in C22 lactone sulfate only in the VEAPS trial.

Conclusions:
We found evidence of a dose-dependent vitamin E supplementation effect on a novel C22 lactone sulfate compound that was correlated with several androgenic steroids.

Impact:
Our data add information on a differential hormonal response based on vitamin E dose that could have direct relevance to opposing prostate cancer incidence results from previous large controlled trials.
Identification of a RAS-activating TMEM87A–RASGRF1 Fusion in an Exceptional Responder to Sunitinib with Non–Small Cell Lung Cancer
Authors: Cooper Alissa J. , Kobayashi Yoshihisa , Kim Dewey , Clifford Sarah E. , Kravets Sasha , Dahlberg Suzanne E. , Chambers Emily S. , Li Jiaqi , Rangachari Deepa , Nguyen Tom , Costa Daniel B. , Rabin Michael S. , Wagle Nikhil , Sholl Lynette M. , Jänne Pasi A , Oxnard Geoffrey R. 
Published: April 2020

Abstract

Purpose:
We pursued genomic analysis of an exceptional responder with non–small cell lung cancer (NSCLC) through a multi-platform effort to discover novel oncogenic targets.

Experimental Design:
In this open-label, single-arm phase II study (NCT01829217), an enriched cohort of patients with advanced NSCLC was treated with the multi-kinase inhibitor sunitinib. The primary endpoint was objective response rate. Tissue was collected for multi-platform genomic analysis of responders, and a candidate oncogene was validated using in vitro models edited by CRISPR-Cas9.

Results:
Of 13 patients enrolled, 1 patient (8%), a never smoker, had a partial response lasting 33 months. Genomic analysis of the responder identified no oncogenic variant using multi-platform DNA analysis including hotspot allelotyping, massively parallel hybrid-capture next-generation sequencing, and whole-exome sequencing. However, bulk RNA-sequencing (RNA-seq) revealed a novel fusion, TMEM87A–RASGRF1, with high overexpression of the fusion partners. RASGRF1 encodes a guanine exchange factor which activates RAS from GDP-RAS to GTP-RAS. Oncogenicity was demonstrated in NIH/3T3 models with intrinsic TMEM87A–RASGRF1 fusion. In addition, activation of MAPK was shown in PC9 models edited to express this fusion, although sensitivity to MAPK inhibition was seen without apparent sensitivity to sunitinib.

Conclusions:
Sunitinib exhibited limited activity in this enriched cohort of patients with advanced NSCLC. Nonetheless, we find that RNA-seq of exceptional responders represents a potentially underutilized opportunity to identify novel oncogenic targets including oncogenic activation of RASGRF1.
Pharmacodynamic Effects of Vorapaxar in Prior Myocardial Infarction Patients Treated With Potent Oral P2Y
12
Receptor Inhibitors With and Without Aspirin: Results of the VORA‐PRATIC Study
Authors: Franchi Francesco , Rollini Fabiana , Faz Gabriel , Rivas Jose Ramon , Rivas Andrea , Agarwal Malhar , Briceno Maryuri , Wali Mustafa , Nawaz Ahmed , Silva Gabriel , Shaikh Zubair , Maaliki Naji , Fahmi Kerolos , Been Latonya , Pineda Andres M. , Suryadevara Siva , Soffer Daniel , Zenni Martin M. , Baber Usman , Mehran Roxana , Jennings Lisa K. , Bass Theodore A. , Angiolillo Dominick J. 
Published: April 2020

Background

Vorapaxar as an adjunct to dual antiplatelet therapy (
DAPT
) reduces thrombotic events in patients with prior myocardial infarction at the expense of increased bleeding. Withdrawal of aspirin has emerged as a bleeding reduction strategy. The pharmacodynamic effects of vorapaxar with potent P2Y
12
inhibitors as well as the impact of dropping aspirin is unexplored and represented the aim of the VORA‐PRATIC (Vorapaxar Therapy in Patients With Prior Myocardial Infarction Treated With Newer Generation P2Y
12
Receptor Inhibitors Prasugrel and Ticagrelor) study.

Methods and Results

Post–myocardial infarction patients (n=130) on standard
DAPT
(aspirin+prasugrel or ticagrelor) were randomized to 1 of 3 arms: (1) triple therapy: aspirin+prasugrel/ticagrelor+vorapaxar; (2) dual therapy (drop aspirin): prasugrel/ticagrelor+vorapaxar; (3)
DAPT
: aspirin+prasugrel/ticagrelor. Pharmacodynamic assessments were performed at 3 time points (baseline and 7 and 30 days). Vorapaxar reduced CAT (collagen‐ADP‐TRAP)–induced platelet aggregation, a marker of platelet‐mediated global thrombogenicity (triple therapy versus
DAPT
at 30 days: mean difference=–27; 95%
CI
,–35 to –19;
P
<0.001; primary end point). This effect was attenuated but still significant in the absence of aspirin (dual therapy versus
DAPT
at 30 days: mean difference=–15; 95%
CI
,–23 to –7;
P
<0.001; between‐group comparisons,
P
<0.05). Vorapaxar abolished TRAP–induced aggregation (
P
<0.001), without affecting thrombin generation and clot strength. There were no differences in markers of P2Y
12
reactivity. Markers sensitive to aspirin‐induced effects increased (
P
<0.001) in the dual‐therapy arm.

Conclusions

In post–myocardial infarction patients treated with potent P2Y
12
inhibitors, vorapaxar reduces platelet‐driven global thrombogenicity, an effect that persisted, albeit attenuated, in the absence of aspirin and without affecting markers of P2Y
12
reactivity or clot kinetics. The clinical implications of these
PD
observations warrant future investigation.

Registration

URL
:
https://www.clini​caltr​ials.gov
. Unique identifier:
NCT
02545933.
Management of Masseter Muscle Hypertrophy and Role of Adjunctive Surgical Procedures
Authors: Anehosur Venkatesh , Mehra Anhad , Kumar Niranjan 
Published: April 2020

Aims and Objectives: The aim of this case series is to retrospectively analyze cases of masseter muscle hypertrophy and the surgical procedures carried out for their treatment in SDM craniofacial unit, Dharwad. The main objectives taken into account are the adjunctive procedures such as genioplasty and coronoidectomy, which help improve the esthetics and mouth opening of the patients postoperatively. Materials and Methods: This retrospective case series was conducted in the Department of Oral and Maxillofacial Surgery, SDM craniofacial unit, Dharwad, from 2010 to 2015. A total of 5 cases were operated on during this period. Orthopantomograms, computed tomography scans of the head and neck region, and lateral cephalograms of each patient were taken into account. Data were collected to study the treatment protocols and the adjunctive procedures, which helped improve the results of the surgery. Results: Of the 5 patients operated in the last 5 years, surgical debulking of the masseter muscle was the optimal treatment followed with genioplasty, which provided improved esthetics from the square-shaped jaw appearance. Coronoidectomy was helpful in increasing mouth opening in patients with trismus. Conclusion: The case series was not only carried out to enunciate causes of masseter muscle hypertrophy and its complications but also to discuss optimal treatment protocols along with adjunctive procedures to enhance the postoperative results and patient satisfaction.
Imatinib Mesylate (IM), Is an Alternative to Donor Lymphocyte Infusion (DLI) for Chronic Myelogenous Leukemia (CML) in Relapse after Allogeneic Stem Cell Transplantation: A 3-Year Follow-Up Report, on the Behalf of the Société Française de Greffe de Moëlle et de Thérapie Cellulaire (SFGM-TC) and the France Intergroupe de la Leucémie Myéloïde Chronique (Fi-LMC).
Authors: Pautas Cecile , Nicolini Frank , Cony-Makhoul Pascal , Giraudier Stephane , Bories Dominique , Buzyn Agnes , Dedhin Nathalie , Michallet Mauricette , Guilhot François , Jouet Jean-Pierre , Kuentz Mathieu 
Published: April 2020

Abstract
DLI are an efficient treatment for CML in relapse after allogeneic stem cell transplantation, with 60 to 70% of complete response. However, major side effects such has graft-versus-host disease (GVHD) or pancytopenia are frequently observed after this treatment. Imatinib mesylate has also been shown to be effective in a such situation (Blood 2002, 100 (5): 1590–95). In the present study, we report the French experience, with a 3 years median follow-up of 26 patients in relapse of CML after allograft (21 sibling, 4 unrelated, 1 cord blood transplantations). At time of treatment with IM, twenty patients were in chronic phase and 5 only were in molecular relapse, while 4 patients were in blastic phase. Median time from graft to relapse was 36 months (3–132 months) and the median time from relapse to Imatinib was 15 months ( 1–96 months). Ten patients had already received DLI, 14 patients Interferon. Only 6 patients had no treatment prior to IM. With a median follow-up of 32 months (16–44 months), 19 patients are alive and 5 died. The majority of patients in chronic (19/20) phase are alive. At time of last follow-up : Three (11%) patients fail to respond to IM, 2 (8%) have a partial response, 12 (46%) are in CCR with 9/12 in molecular remission, and 4 (15%) patients present relapse (1 blastic phase, 3 molecular relapse). Eleven patients are evaluable for VNTR chimerism, 8(72%) achieved full donor chimerism at last follow-up. IM was well tolerated, and 2 GVHD reactivations were observed but 8 (42%) patients experienced cytopenias requiring drug modulation or withdrawal, and two grade IV toxicities (muscle cramps, cardiomyopathy). Six patients stopped IM (2 toxicities, 4 long term molecular remissions). Four of these patients experienced molecular relapse (3 after 12 months, 1 at 3 months). One patient achieved molecular remission after a new challenge with IM. In conclusion, Imatinib mesylate is efficient and safe treatment for CML in relapse after allogeneic HSCT without reactivating GVHD, and is able to restore full donor chimerism in a majority of responsive patients. A complete and sustained molecular response is obtained in about one third of patients, however molecular relapse is frequent after IM withdrawal. The place of IM and/or DLI for CML in relapse after allogeneic HSCT needs to be addressed prospectively and requires a randomized trail.
Individual Replacement Therapy (IRT) with a Pasteurized C1-Inhibitor Concentrate Compared to Prophylaxis with Danazol in Patients with Hereditary Angioedema (HAE) - a Prospective Study.
Authors: Kreuz Wolfhart , Martinez-Saguer Inmarculada , Aygoeren-Puersuen Emel , Rusicke Eva , Klingebiel Thomas 
Published: April 2020

Abstract
Attenuated androgens like danazol are the current treatment of choice for long-term prophylaxis in patients with hereditary angioedema (HAE), who may experience life-threatening acute attacks. Unfortunately, this group of drugs bears the risk of severe side effects (e.g. depression, weight gain, hirsutism, transaminase elevations, liver adenoma and carcinoma, headaches, hypertension, menstrual abnormalities).
Objectives: We therefore explored the option to administer a pasteurized, plasma-derived C1-Inhibitor concentrate (C1-INH, Berinert®P) for individual replacement therapy (IRT) in patients with HAE in whom danazol induced severe side effects, was not effective or was contraindicated (e.g. children, pregnant women).
Methods: Prospective, observational, intra-individual cross over study, comparing efficacy, safety and quality of life of danazol (prophylaxis) vs. C1-INH (IRT) in 23 patients suffering from severe HAE.
Results: Mean annual attack frequency decreased from 48.8 ± 37.1 (danazol) to 8.1 ± 22.1 (C1-INH); p&lt;0.001. All patients who received pasteurized C1-INH were free of life threatening attacks (laryngeal edema) or adverse events, which did occur under long-term prophylaxis with danazol (Fig.). In addition, all quality of life parameters improved significantly; p&lt;0.001. During the entire 20-year observation period with C1-INH in all patients there was no transmission of HIV type 1/2, hepatitis A-, B-, C-, G-viruses, or parvovirus B19.
Conclusions: Compared to danazol, IRT with pasteurized C1-INH in patients with severe HAE significantly reduces the frequency of HAE attacks, especially of life-threatening attacks, and significantly improves the quality of life.
Identification of Ten Novel Mutations Associated with Inherited Coagulation Factor V Deficiency.
Authors: Patel Rinku , Cutler Jacky , Tait Campbell , Savidge Geoffrey 
Published: April 2020

Abstract
Factor V is a rare bleeding disorder characterized by low levels of plasma and/or platelet factor V, with an estimated prevalence of 1/1,000,000 and results from defects in the factor V gene. Human coagulation factor V (FV), a single chain glycoprotein, is synthesized in hepatocytes and megakaryocytes with 80% circulating free in plasma and the remainder being released upon platelet activation. The factor V gene comprises 25 exons ranging in size from 72bp to 2820bp coding for a protein which is oriented as A1-A2-B-A3-C1-C2 domains. FV is activated to its active form (FVa) by thrombin or activated factor X (FXa) which removes the B domain, generating a heavy chain and a light chain that are linked together in the presence of calcium ions. FVa binds to FXa and serves as its cofactor in the prothrombinase complex to convert prothrombin to thrombin. There is a high degree of homology between the A and C domains of FV and FVIII.
We have investigated 8 unrelated patients from two centres with phenotypic and clinical charisteristics of FV deficiency. Mutation screening was carried out in these patients using Denaturing high performance liquid chromatography (dHPLC) and sequencing. Probable causative mutations were identified in all patients.
A total of 10 novel mutations were identified in 8 patients and were located in the A1, A2, A3 and B domains. No mutations were identified in the C domain, and entries on the FV mutation database support our findings that mutations in this domain are less common than elsewhere in this gene. 5/8 patients were diagnosed with mild-moderate FV deficiency, and single heterozygous mutations were identified in each of these patients. 3 missense , 1 donor splicesite and 1 nonsense mutation were identified in the A1, A3 and B domains. The remaining 3/8 patients had severe FV deficiency (FV levels &lt;2u/dl). One was compound heterozygous for 2 missense mutations in the A3 domain; one had a missense mutation in the A2 domain and a frameshift mutation (insertion of a single base pair) in the A3 domain. We have as yet identified only a heterozygous missense mutation in the third patient with severe FV deficiency. Phenotypic data and family history are strongly suggestive of the presence of a second mutation. Quantitative DNA analysis has confirmed the presence of 2 FV alleles, and RNA analysis is in progress to identify the second mutation.
100 normal alleles were analysed by dHPLC analysis or allele specific amplification to exclude these changes from being polymorphisms. We also have examined the homology between factor V and factor VIII, and the degree of similarity, between native and mutant amino acids to support these mutations as being causative of FV deficiency.