bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimising electronic prescribing in hospitals: a scoping review protocol
Authors: Williams Jac , Bates David W , Sheikh Aziz
Published: April 2020

Introduction

Electronic prescribing (ePrescribing) systems can improve the quality of prescribing decisions and substantially reduce the risk of serious medication errors in hospitals. However, realising these benefits depends on ensuring that relevant sociotechnical considerations are addressed. Optimising ePrescribing systems is essential to maximise the associated benefits and minimise the accompanying risks of these large-scale and expensive health informatics infrastructures.

Methods

We will undertake a systematic scoping review of the literature to identify strategies to achieve optimisation of ePrescribing systems. We will search Medline, Embase and CINAHL for the period 1 January 2010 to 1 June 2019 and the grey literature by using Google Scholar. Independent reviewers will screen the results using predefined inclusion and exclusion criteria and will extract data for narrative and thematic synthesis.

Discussion

This work will be published in a peer-reviewed journal and we will ensure that the findings are both accessible and interpretable to the public, academics, policymakers and National Health Service leaders.
Sex-specific and age-specific characteristics of body composition and its effect on bone mineral density in adults in southern China: a cross-sectional study
Authors: Xiao Zeyu , Tan Zhiqiang , Shang Jingjie , Cheng Yong , Tang Yongjin , Guo Bin , Gong Jian , Xu Hao
Published: April 2020

Objectives

This study was an attempt to investigate the variation trend of body composition with ageing and explore the association between regional body composition and bone mineral density (BMD).

Design

Cross-sectional study.

Setting and participants

A total of 5749 healthy adults aged 20–95 years was recruited from 2004 to 2017.

Primary outcome measures

Whole-body lean mass (LM), fat mass (FM), android FM, gynoid FM, appendicular lean mass (ALM) and BMD in the lumbar spine, femoral neck and total hip were obtained by dual-energy X-ray absorptiometry (DXA). The android/gynoid fat mass ratio (A/G FMR) based on DXA scan was calculated as an indicator of adipose distribution. Pearson correlation and multiple linear regression analyses were used to determine the associations between body composition, adipose distribution, and BMD of each skeletal site.

Results

Whole-body FM, percentage of whole-body FM, Android FM and A/G FMR consistently increased with age in both genders, especially in women, and ALM began to decrease in the fifth decade for both men and women. In multivariable linear regression models with age, body mass index, A/G FMR and ALM as predictor variables, ALM was associated with the most BMD variance of all skeletal sites in men (standard β ranged from 0.207 to 0.405, p<0.001), although not the largest but still a positive predictor of BMD in women (standard β ranged from 0.074 to 0.186, p<0.05). A/G FMR was an inverse predictor of BMD at all skeletal sites for women (standard β ranged from −249 to −0.052, p<0.01) but not in men.

Conclusions

In this large cohort of Chinese adults, ALM had a strong positive association with BMD in both genders. A/G FMR as an indicator of central adipose accumulation was inversely associated with BMD in women but not in men.
Prevalence and incidence of type 1 diabetes in Ireland: a retrospective cross-sectional study using a national pharmacy claims data from 2016
Authors: Gajewska Katarzyna Anna , Biesma Regien , Sreenan Seamus , Bennett Kathleen
Published: April 2020

Objectives

The aim of this study is to estimate the prevalence and incidence of type 1 diabetes in the Irish population using a national pharmacy claims database in the absence of a national diabetes register.

Design

National, population-based, retrospective, cross-sectional study.

Setting

Community care with data available through the Health Service Executive Pharmacy Claims Reimbursement Scheme from 2011 to 2016.

Participants

Individuals with type 1 diabetes were identified by coprescription of insulin and glucometer test strips without any prolonged course (>12 months) of oral hypoglycaemic agents prior to commencing insulin. Those claiming prescriptions for long-acting insulin only, without any prandial insulin, were excluded from the analysis. Incidence was estimated based on the first claim for insulin in 2016, with no insulin use in the preceding 12 months.

Main outcome measures

Prevalence of type 1 diabetes in children (<18 years) and adults (≥18 years); incidence of type 1 diabetes in children (≤14 years) and adolescents and adults (>14 years).

Results

There were 20 081 prevalent cases of type 1 diabetes in 2016. The crude prevalence was 0.42% (95% CI 0.42% to 0.43%). Most prevalent cases (n=17 053, 85%) were in adults with a prevalence of 0.48% (95% CI 0.47% to 0.48%). There were 1527 new cases of type 1 diabetes in 2016, giving an incidence rate of 32 per 100 000 population/year (95% CI 30.5 to 33.7). There was a significant positive linear trend for age, for prevalence (p<0.0001) and incidence (p=0.014). The prevalence and incidence were 1.2-fold and 1.3-fold higher in men than women, respectively. Significant variations in prevalence (p<0.0001) and incidence (p<0.001) between the different geographical regions were observed.

Conclusions

This study provides epidemiological estimates of type 1 diabetes across age groups in Ireland, with the majority of prevalent cases in adults. Establishing a national diabetes register is essential to enable updated epidemiological estimates of diabetes and for planning of services in Ireland.
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

Objective

Early 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.

Design

A retrospective cohort study.

Setting

Population-wide linkage of administrative data records for children born in Tasmania, Australia in 2008–2010.

Participants

The 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 measure

The 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.

Results

Latent 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.

Conclusions

The 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

Introduction

Diabetes 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 analysis

A 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 dissemination

Ethics 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 number

ISRCTN64926597; registered on 6 June 2017
Synthesis of fluorocyclopropanes via the enantioselective cyclopropanation of fluoro-substituted allylic alcohols using zinc carbenoids
Authors: Delion Laëtitia , Poisson Thomas , Jubault Philippe , Pannecoucke Xavier , Charette André B.
Published: April 2020

Cyclopropanation reactions using zinc carbenoids are a powerful means to access cyclopropanes. Described herein is an enantioselective version of the reaction using zinc reagents and a chiral dioxaborolane ligand in the generation of fluorocyclopropanes. Readily available 2- and 3-fluoroallylic alcohols were efficiently cyclopropanated in high yields and excellent enantioselectivities. This method provides access to a variety of structurally diverse chiral fluorocyclopropanes that can be used as useful chiral building blocks.
A combined solid-state 17O NMR, crystallographic, and computational study of oxiranes
Authors: Rinald Andrew , Terskikh Victor , Schatte Gabriele , Wu Gang
Published: April 2020

We report the synthesis and solid-state 17O NMR characterization of three 17O-labeled oxiranes: (2S*,3S*)-2,3-bis(4-nitrophenyl)-[17O]oxirane, (2S*,3R*)-2,3-bis(4-nitrophenyl)-[17O]oxirane, and 2,2,3-triphenyl-[17O]oxirane. In addition, we have determined the crystal structure of (2S*,3R*)-2,3-bis(4-nitrophenyl)oxirane by X-ray crystallography. When the experimentally determined 17O NMR tensors for oxiranes (where the C–O–C bond angle is about 60°) are compared with those for dimethyl ether (where the C–O–C bond angle is 113°) and other R–O–R′ functional groups, we found that the highly constrained geometry of oxiranes results in distinct tensor orientations in the molecular frame of reference. The experimental results are complemented by quantum chemical computations. This study represents the first time that 17O chemical shift and quadrupole coupling tensors are simultaneously determined for oxirane compounds.
Galectin-3 mediates high-glucose-induced cardiomyocyte injury by the NADPH oxidase/reactive oxygen species pathway
Authors: Sun Jingang , Zhang Lijuan , Fang Jianhai , Yang Shuguo , Chen Lianghua
Published: April 2020

Galectin-3 is a member of the β-galactoside-binding lectin family taking part in the regulation of inflammation, angiogenesis, and fibrosis. This study was designed to study the improved effect of galectin-3 inhibition on diabetic cardiomyopathy (DCM). Sprague–Dawley rats were randomized into the control, DCM, and DCM + modified citrus pectin (MCP) (a galectin–3 pharmacological inhibitor) groups. After 8 weeks, streptozotocin-induced DCM led to high blood glucose level, oxidative stress, cardiac injury, and dysfunction accompanied by suppressed body mass. On the contrary, MCP (100 mg·kg−1·day−1) administration improved body mass and blood glucose level and attenuated cardiac injury and dysfunction in DCM rats. Additionally, MCP attenuated pathological changes in plasma and myocardial tissue markers of oxidative stress, such as hydrogen peroxide and malonyldialdehyde, although it did not change superoxide dismutase activities, which were decreased in the DCM group. The levels of oxidative stress associated proteins evaluated by Western blot, such as p67phox and NADPH oxidase 4, were obviously increased in the DCM group, while they were reversed by MCP treatment. Therefore, galectin-3-mediated high-glucose-induced cardiomyocyte injury and galectin-3 inhibition attenuated DCM by suppressing NADPH oxidase. These findings suggested that galectin-3 could be a potential target for treatment of patients with DCM.
Ocular Findings in the 16p11.2 Microdeletion Syndrome: A Case Report and Literature Review
Authors: Stingl Cybil S. , Jackson-Cook Colleen , Couser Natario L.
Published: April 2020

The recurrent 16p11.2 microdeletion is characterized by developmental delays and a wide spectrum of congenital anomalies. It has been well reported that individuals with this ∼593-kb interstitial deletion have an increased susceptibility toward the autism spectrum disorder (ASD). Abnormalities of the eye and ocular adnexa are also commonly associated findings seen in individuals with the 16p11.2 microdeletion syndrome, although these ophthalmic manifestations have not been well characterized. We conducted an extensive literature review to highlight the eye features in patients with the 16p11.2 microdeletion syndrome and describe a 5-year-old boy with the syndrome. The boy initially presented with intellectual disability, speech delay, and defiant behavior; diagnoses of attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) were established. He had a Chiari malformation type 1. His ophthalmic features included strabismus, hyperopia, and ptosis, and a posterior embryotoxon was present bilaterally. From a systematic review of prior reported cases, the most common eye and ocular adnexa findings observed were downslanting palpebral fissures, deep-set eyes, ptosis, and hypertelorism.
Renoprotective Effects of a New Free Radical Scavenger, XH-003, against Cisplatin-Induced Nephrotoxicity
Authors: Liu Ya-Hong , Li Kui , Tian Hong-Qi
Published: April 2020

Acute renal injury has an incidence of 25%–30% in patients with tumors who are treated with cisplatin and in patients for whom no specific drugs are available for treatment. Amifostine is the only FDA-approved chemoprotective drug; however, its clinical application is limited because of side effects. The small-molecule antioxidant XH-003, an acute radiation syndrome- (ARS-) protective drug independently developed in our laboratory, with 100% intellectual property rights, overcomes the side effects of amifostine but retains its high efficacy. In this study, XH-003 showed a chemoprotective effect similar to that of amifostine. A mechanistic study showed that XH-003 could significantly reduce cisplatin-induced increases in serum creatinine and urea nitrogen, increase the activity of antioxidant enzymes (SOD, CAT, and GSH-Px), reduce oxidative stress and tissue inflammation, and alleviate renal tissue damage by blocking the activity of the mitochondrial apoptosis pathway. Most importantly, XH-003 could reduce the accumulation of cisplatin in renal tissue by regulating the expression of proteins involved in cisplatin uptake and excretion, such as organic cation transporter 2 and MRP2. Moreover, in an in vivo xenotransplantation model, XH-003 did not interfere with the antitumor effect of cisplatin. These data provide strong evidence that the ARS-protective agent has a great potential for protecting against chemotherapy-induced toxicity. Thus, XH-003 can be considered in antitumor therapy.
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

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

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.
A new species of Capparidastrum (Capparaceae Juss.) from the Cauca inter Andean valley of Colombia

Authors: MERCADO-GÓMEZ JORGE D. , MORALES-PUENTES MARÍA EUGENIA
Published: April 2020

We describe and illustrate a new species of Capparidastrum subgen. Pulviniglans (Capparaceae). Capparidastrum dugandii occurs in tropical dry forest fragments of the Colombian inter-Andean valley of the Dagua River, near the municipality of Santa Fe de Antioquia. Capparidastrum dugandii is distinguished from other species of subgen. Pulviniglans molecularly and by the lowest number of stamens (18–20). In addition, the species is endemic to the Cauca biogeographic province.
Examining the Association Between Chaplain Care and Patient Experience
Authors: Damen Annelieke , Murphy Patricia , Fullam Francis , Mylod Deirdre , Shah Raj C , Fitchett George
Published: April 2020

A developing body of evidence indicates that chaplain care is associated with higher levels of patient/family satisfaction with their hospital care. We examined the association between chaplain care and patient experience among patients at Rush University Medical Center in Chicago who responded to Hospital Consumer Assessment of Healthcare Providers and Systems and Press Ganey survey items between 2011 and 2017. Information about chaplain care was taken from the inpatients’ electronic medical record. Our analyses included 11 741 patients, 26.5% of whom had received any chaplain care. Patients with lower self-rated health were more likely to have received chaplain care ( P < .001). In bivariate analyses, chaplain care was associated with lower likelihood of reporting the highest score for 4 patient experience items ( P < .001). In multi-variable models that adjusted for patient self-rated health and other factors, the association between chaplain care and the 4 patient experience items was nonsignificant. There was no effect modification for patient religious affiliation, self-rated health, or other demographic factors. The chaplain care-patient experience association may be more complex than has initially appeared, and further research is needed to help us better understand it.
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

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

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<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<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

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 <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.
Preoperative Fibrin Monomer Allows Prediction on Excessive Intraoperative Blood Loss - Finally a Preoperative Coagulation Screening That Works?.
Authors: Korte Wolfgang C. , Wettstein Patrick , Gabi Konrad , Rohner Mirjam , Corbetta Cinzia , Schnider Thomas
Published: April 2020

We recently demonstrated that patients with intraoperative coagulopathy and increased blood loss show a persistent pre-, intra- and postoperative increase in fibrin monomer concentration as well as an excessive intraoperative consumption of fibrinogen and F. XIII. We therefore wanted to test the hypothesis that preoperative fibrin monomer concentrations can be used as a risk indicator for intraoperative blood loss.

In 168 patients admitted to the surgical service of our hospital, median intraoperative blood loss increased significantly with preoperative fibrin monomer (FM) quartiles (50, 100, 200 and 400 ml in preoperative FM quartiles 1 to 4; p<0.001, ANOVA on ranks and p<0.05 for group wise comparison, Rank Sum test). Stratification in FM quartile groups was unrelated to diagnoses with the exception of laparoscopic cholecystectomy (found significantly less frequent in quartile 4 than 1). Most importantly, accuracy evaluation showed that preoperative fibrin monomer concentration < 3 μg/l excluded intraoperative blood loss > 500 ml with 92% sensitivity, 95% negative predictive value and 41% exclusion rate. This compares well to other exclusion strategies such as the exclusion of deep venous thrombosis with the help of D-dimer and probability scores. In contrast, blood loss was unrelated to preoperative values of prothrombin time, platelet count and actived partial thromboplastin time. The FM ROC curve compared to the PT ROC curve is shown in the figure; the area under the curve for the FM ROC curve was significantly greater than the one for the PT ROC curve (0.743, 95% CI 0.655 – 0.811 vs. 0.555, 95% CI 0.473 – 0.635).

These results - obtained in a second, independent and prospective study - confirm the hypothesis generated from our first study that preoperative fibrin monomer concentrations allow prediction on excessive intraoperative blood loss. We suggest that preoperative fibrin monomer concentrations be further studied for identification of patients that might benefit from intensified intraoperative monitoring.

Figure Figure
Coagulation Abnormalities in Patients with Noonan Syndrome - a Single Centre Case Series.
Authors: Stoffman Jayson M. , Chodirker Bernard N. , Israels Sara J.
Published: April 2020

Noonan syndrome (NS) is an autosomal dominant disorder that includes short stature, characteristic facies, congenital heart defect, webbed neck, and developmental delay. A mutation in the PTPN11 gene can be identified in 50% of patients. A bleeding tendency is included in the phenotypic spectrum, with factor XI deficiency and platelet abnormalities described most frequently. At Winnipeg’s Health Sciences Centre, 24 patients with features typical of NS have been studied by the Special Haemostasis Laboratory. Four patients in whom the diagnosis was suspected but not considered definite are also included in this analysis. Clinical complaints included easy bruising (9), epistaxis (2), menorrhagia (1), and a family history of bleeding problems (3). Sixteen patients were referred for investigation following the diagnosis of NS. All 28 patients had coagulation screening tests: 16 patients had an abnormal PT and 12 had an abnormal aPTT. Thrombin time was slightly prolonged in 6 of 23 patients. Reptilase time was normal in 8 patients, and fibrinogen concentration was normal in 20 patients.

Factor XI levels were measured in 14 patients, with a mean value of 62% (range 32–99%). Only 2 patients had levels below the normal range. One of 13 patients evaluated for FXII levels was deficient (FXII 25%), and 2 of 19 patients evaluated for FIX levels had mild FIX deficiency (FIX 40 and 49%) without symptomatic bleeding. No other factor deficiencies were identified. Twenty-four patients had determinations of von Willebrand Factor antigen and activity; 2 had results consistent with mild Type 1 von Willebrand Disease.

Platelet aggregation studies were done in 22 patients. A variety of abnormalities were noted, with the most frequent being abnormal aggregation with epinephrine (7/22). Dense granule number was decreased in 2 of 7 samples studied by electron microscopy. Lupus anticoagulants were detected in 3 of 13 patients screened. Thrombophilia investigations in 4 patients detected decreased protein S in one patient who had been diagnosed previously with protein S deficiency.

This unselected case series, the largest reported to date in the literature, illustrates the heterogeneity of coagulation abnormalities that may occur in NS. Symptoms, when present, were mild, and often did not correlate with laboratory abnormalities. Non-specific platelet aggregation defects were the most commonly identified abnormalities. In contrast to the literature, factor XI deficiency was not prevalent. A specific etiology for the variable bleeding tendency has not yet been identified in NS.
Activation of the Coagulation System Should Be Considered in the Initial Phase of Chemotherapy in Acute Myeloid Leukemia.
Authors: Astermark Jan , Strandberg Karin , Sallerfors Bengt , Stenflo Johan , Berntorp Erik
Published: April 2020

Malignant hematologic disorders may be associated with coagulopathy causing bleeding or thromboembolic complications. Severe infections as well as chemotherapy may augment this risk by the action of inflammatory mediators and the release of proteases. We evaluated the hemostatic process in 10 patients with acute myeloid leukemia (no acute promyelocytic leukemia) before the start of induction therapy with IDA-C and daily during the following two weeks of treatment. Various hemostatic parameters were studied, including the complex between activated protein C and the protein C inhibitor (APC-PCI) with a newly developed method, thrombin generation, protein C, prothrombin fragment 1+2 (F1+2), antithrombin and factor VIII. The APC-PCI concentration was relatively high in all patients at start of treatment (mean 0.81 ± SEM 0.27 μg/L; normal range 0.07–0.26 μg/L) reflecting an activation of the coagulation system, and further increased during the initial phase of chemotherapy reaching the highest level on Day 3 to 5 of 1.67±0.53 μg/L (p=0.0047). The concentration of the complex then declined during the following 10 days to 0.10±0.03 μg/L on Day 14, i.e. to a concentration significantly lower than that at start of treatment (p=0.005). The concentration of F1+2 varied in a similar way with a concentration of 2.17±0.51 nM at start of treatment and an increase on Day 3–5 to 4.17±0.93 nM (p=0.005) followed by a decline to 1.09±0.22 nM on Day 14. Thrombin generation was relatively high in the initial phase of chemotherapy (319.0±44.5 nM) and then declined to 154.6±17.2 nM on Day 14 (p=0.008). The protein C activity was relatively low at start (0.70±0.05 IU/mL) indicating a state of consumption, but showed a trend towards normalization during treatment reaching an average level of 0.78±0.05 IU/mL for all patients on Day 14 (p=0.103). The factor VIII level was high and relatively stable during the two weeks of treatment with a range of 1.73±0.16 to 1.89±0.17 IU/mL, indicating a reactive state. The level of antithrombin was normal at start of treatment (1.00±0.05 IU/mL) and throughout the study period. Our data show that acute myeloid leukemia may be associated with a significant coagulopathy and that the activity in the coagulation process is increased during the initial phase of chemotherapy. This should be considered in patients at start of treatment, in particular, in patients with septicemia and/or signs of disseminated intravascular coagulation.
Elevated Prothrombin Fragment F1+2 Levels during Pregnancy in Women with Previous Venous Thromboembolism.
Authors: Zotz Rainer B. , Gerhardt Andrea , Marzotko Steffi , Wagner Karl J. , Bender Hans G. , Scharf Rudiger E.
Published: April 2020

Changes in blood coagulation and fibrinolysis during pregnancy create a state of hypercoagulability. This phenomenon predisposes to venous thromboembolism. Indicators of hypercoagulation in normal pregnancy are circulating thrombin-antithrombin complexes and increased levels of prothrombin fragment 1+2. A significant positive correlation between gestational age and elevated prothrombin fragment 1+2 has been shown. We hypothesized that women with previous venous thromboembolism are at a higher hypercoagulable state during subsequent pregnancies than women without prior thrombotic complications.

In a prospective study, we determined prothrombin fragment F1+2 over pregnancy among 109 women (175 measurements) with previous venous thromboembolism, and among 75 pregnant women (75 measurements) without previous venous thromboembolism. The prothrombin fragment F1+2 levels were statistically analyzed over time using a Mixed Model. This model allows a longitudinal analysis of the influence of a between-subjects factor (e.g. history of thrombosis) on prothrombin fragment F1+2 levels, the influence of a within-subjects factor (weeks of gestation) on prothrombin fragment F1+2 levels, and the interaction of the history of thrombosis and weeks of gestation representing a change of risk factor-dependent differences over time (weeks of gestation).

Among women with a previous history of venous thrombosis, prothrombin fragment F1+2 values were significantly higher during the course of pregnancy than among pregnant women without venous thromboembolism (p=0.0014). The results were adjusted for the physiological increase of prothrombin fragment F1+2 over pregnancy and were independent of heparin prophylaxis. Thus, determination of indicators of hypercoagulation like prothrombin fragment F1+2 represent an additional approach independent of known and unknown risk determinants of thrombosis to identify women at risk for venous thromboembolism during pregnancy.