Coagulopathy in newborns with hypoxic ischemic encephalopathy (HIE) treated with therapeutic hypothermia: A retrospective case-control study

Background Newborns with hypoxic ischemic encephalopathy (HIE) are at risk for coagulopathy due to systemic oxygen deprivation. Additionally, therapeutic hypothermia (TH) slows enzymatic activity of the coagulation cascade, leading to constitutive prolongation of routinely assessed coagulation studies. The level of laboratory abnormality that predicts bleeding is unclear, leading to varying transfusion therapy practices. Methods HIE infants treated with TH between 2008–2012 were included in this retrospective study. Initial, minimum (min) and maximum (max) values of International Normalized Ratio (INR), activated partial thromboplastin time (aPTT), fibrinogen (Fib) and platelet (PLT) count (measured twice daily during TH) were collected. Bleeding was defined as clinically significant if associated with 1) decreased hemoglobin (Hb) by 2 g/dL in 24 hours, 2) transfusion of blood products for hemostasis, or 3) involvement of a critical organ system. Laboratory data between the bleeding group (BG) and non-bleeding group (NBG) were compared. Variables that differed significantly between groups were evaluated with Receiver Operating Characteristic Curve (ROC) analyses to determine cut-points to predict bleeding. Results Laboratory and bleeding data were collected from a total of 76 HIE infants with a mean (±SD) birthweight of 3.34 ± 0.67 kg and gestational age of 38.6 ± 1.9 wks. BG included 41 infants. Bleeding sites were intracranial (n = 13), gastrointestinal (n = 19), pulmonary (n = 18), hematuria (n = 11) or other (n = 1). There were no differences between BG and NBG in baseline characteristics (p \u3e 0.05). Both groups demonstrated INR and aPTT values beyond the acceptable reference ranges utilized for full tem newborns. BG had higher initial and max INR, initial aPTT, and lower min PLT and min Fib compared to NBG. ROC analyses revealed that platelet count \u3c130 \u3e× 109/L, fib level2 discriminated BG from NBG. Conclusions Laboratory evidence of coagulopathy is universal in HIE babies undergoing TH. Transfusion strategies to maintain PLT counts \u3e130 × 109/L, fib level \u3e1.5 g/L, and INRpopulation

Lactation and neonatal nutrition: defining and refining the critical questions.

This paper resulted from a conference entitled "Lactation and Milk: Defining and refining the critical questions" held at the University of Colorado School of Medicine from January 18-20, 2012. The mission of the conference was to identify unresolved questions and set future goals for research into human milk composition, mammary development and lactation. We first outline the unanswered questions regarding the composition of human milk (Section I) and the mechanisms by which milk components affect neonatal development, growth and health and recommend models for future research. Emerging questions about how milk components affect cognitive development and behavioral phenotype of the offspring are presented in Section II. In Section III we outline the important unanswered questions about regulation of mammary gland development, the heritability of defects, the effects of maternal nutrition, disease, metabolic status, and therapeutic drugs upon the subsequent lactation. Questions surrounding breastfeeding practice are also highlighted. In Section IV we describe the specific nutritional challenges faced by three different populations, namely preterm infants, infants born to obese mothers who may or may not have gestational diabetes, and infants born to undernourished mothers. The recognition that multidisciplinary training is critical to advancing the field led us to formulate specific training recommendations in Section V. Our recommendations for research emphasis are summarized in Section VI. In sum, we present a roadmap for multidisciplinary research into all aspects of human lactation, milk and its role in infant nutrition for the next decade and beyond

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Evidence synthesis to inform model-based cost-effectiveness evaluations of diagnostic tests: a methodological systematic review of health technology assessments

Background: Evaluations of diagnostic tests are challenging because of the indirect nature of their impact on patient outcomes. Model-based health economic evaluations of tests allow different types of evidence from various sources to be incorporated and enable cost-effectiveness estimates to be made beyond the duration of available study data. To parameterize a health-economic model fully, all the ways a test impacts on patient health must be quantified, including but not limited to diagnostic test accuracy. Methods: We assessed all UK NIHR HTA reports published May 2009-July 2015. Reports were included if they evaluated a diagnostic test, included a model-based health economic evaluation and included a systematic review and meta-analysis of test accuracy. From each eligible report we extracted information on the following topics: 1) what evidence aside from test accuracy was searched for and synthesised, 2) which methods were used to synthesise test accuracy evidence and how did the results inform the economic model, 3) how/whether threshold effects were explored, 4) how the potential dependency between multiple tests in a pathway was accounted for, and 5) for evaluations of tests targeted at the primary care setting, how evidence from differing healthcare settings was incorporated. Results: The bivariate or HSROC model was implemented in 20/22 reports that met all inclusion criteria. Test accuracy data for health economic modelling was obtained from meta-analyses completely in four reports, partially in fourteen reports and not at all in four reports. Only 2/7 reports that used a quantitative test gave clear threshold recommendations. All 22 reports explored the effect of uncertainty in accuracy parameters but most of those that used multiple tests did not allow for dependence between test results. 7/22 tests were potentially suitable for primary care but the majority found limited evidence on test accuracy in primary care settings. Conclusions: The uptake of appropriate meta-analysis methods for synthesising evidence on diagnostic test accuracy in UK NIHR HTAs has improved in recent years. Future research should focus on other evidence requirements for cost-effectiveness assessment, threshold effects for quantitative tests and the impact of multiple diagnostic tests

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Novel TTN Mutation Causing Severe Congenital Myopathy and Uncertain Association with Infantile Hydrocephalus

Arthrogryposis multiplex congenita (AMC) is characterized by nonprogressive symmetric contractures of multiple joints with normal intellect and normal systemic examination. AMC is often due to fetal akinesia, which has neurologic, muscular, and connective tissue etiologies. We present a case of AMC due to a variant in the titin (TTN) gene in a term neonate. The infant is homozygous for this variant, c.38442dup, which is predicted to result in a truncated protein (p.Pro12815Thr fs∗37, NM_001267550.2). A literature search (PubMed) failed to find reports of this TTN variant. The variant was classified as pathogenic and submitted to ClinVar. Titin is the body’s largest protein, expressed in skeletal and cardiac muscles and encoded by the TTN gene. Due to its large size (364 exons), the TTN gene has been difficult to sequence; the number of variants in the TTN gene and the spectrum of titinopathies are probably underestimated

The effects of serial stretch loading on stretch work and stretch- shorten cycle performance in the knee musculature

Training methods to optimize stretch-shorten cycle performance and an active muscle\u27s ability to resist a sudden stretch (stretch work) and the relationship between the two have not been fully explored. The purpose of this study was to examine the effects of an 8-week strengthening program of serial stretch loading on stretch work and stretch-shorten cycle performance in the quadriceps and hamstring muscles. Thirty-one asymptomatic subjects participated in pre- and post-tests of maximum voluntary isometric contractions, stretch work and stretch-shorten cycle trials, and single-leg vertical jumps. The training portion consisted of progressively resisted isotonic single-leg squats. One leg exercised against an isotonic load with serial stretch loading, while the other leg exercised against isotonic load alone. Training resulted in strength gains in both legs indicated by the increase in weight lifted during training, but not by maximum voluntary isometric contractions. Vertical jump height increased in both legs. In the hamstring, stretch work decreased and stretch-shorten cycle performance increased in both legs. In the quadriceps, serial stretch loading intervention resulted in increased stretch-shorten cycle performance and no significant change in stretch work. The correlation between stretch-shorten cycle and stretch work was weak but significant. These findings suggest that the use of serial stretch loading could improve muscular performance and enhance a muscle\u27s potential for dynamic stabilization

Effect of temperature on thromboelastography (TEG) and implications for clinical use in neonates undergoing therapeutic hypothermia

BACKGROUND: Encephalopathic neonates undergoing therapeutic hypothermia have increased risk for coagulopathy secondary to perinatal asphyxia and effects of cooling on the coagulation enzyme cascade. Thromboelastography (TEG) allows for a comprehensive assessment of coagulation that can be regulated for temperature. TEG has not been previously evaluated in newborns undergoing hypothermia treatment. METHODS: Encephalopathic neonates treated with systemic hypothermia were enrolled in this prospective observational study. Daily blood specimens were collected for standard coagulation tests and platelet counts during hypothermia and after rewarming. Concurrent TEG assays were performed at 33.5°C and 37.0°C for comparison. RESULTS: A total of 48 paired TEGs from 24 subjects were performed. Mean (± SD) birthweight was 3.2±0.7 Kg, gestational age 38.4±1.4 weeks, and 40% were male. TEG results differed significantly between assays performed at 37.0°C versus 33.5°C, indicating more impaired coagulation at 33.5°C. TEG parameters K, α, MA and CI were significantly associated with clinical bleeding (p<0.05). These remained significant (except for MA) after controlling for transfusion therapy. CONCLUSIONS: TEG results are affected by temperature, consistent with the known association of hypothermia with coagulopathy. Several TEG parameters are predictive of clinical bleeding in newborns undergoing hypothermia. Selected cutpoints to predict bleeding risk are temperature dependent