Adolescent Binge Drinking Is Associated With Accelerated Decline of Gray Matter Volume.

The age- and time-dependent effects of binge drinking on adolescent brain development have not been well characterized even though binge drinking is a health crisis among adolescents. The impact of binge drinking on gray matter volume (GMV) development was examined using 5 waves of longitudinal data from the National Consortium on Alcohol and NeuroDevelopment in Adolescence study. Binge drinkers (n = 166) were compared with non-binge drinkers (n = 82 after matching on potential confounders). Number of binge drinking episodes in the past year was linked to decreased GMVs in bilateral Desikan-Killiany cortical parcellations (26 of 34 with P < 0.05/34) with the strongest effects observed in frontal regions. Interactions of binge drinking episodes and baseline age demonstrated stronger effects in younger participants. Statistical models sensitive to number of binge episodes and their temporal proximity to brain volumes provided the best fits. Consistent with prior research, results of this study highlight the negative effects of binge drinking on the developing brain. Our results present novel findings that cortical GMV decreases were greater in closer proximity to binge drinking episodes in a dose-response manner. This relation suggests a causal effect and raises the possibility that normal growth trajectories may be reinstated with alcohol abstinence.

A randomized controlled trial of the impact of the Teen Council peer education program on youth development.

This paper presents results of an impact evaluation of Teen Council, a program that trains youth as peer educators. Teen Council is designed to help peer educators make healthy sexual and reproductive decisions, increase their confidence and abilities to educate their peers and inspire them to advocate for just sexual policies. The program's impact on these educators was evaluated using a randomized controlled trial. Over 5 years, interested high school students in seven states were randomly assigned to a study condition. An intent-to-treat framework using ordinary least square (OLS) regression was employed to measure program effects. Relative to control, Teen Council youth showed enhanced comfort with their own sexuality, greater comfort with and more frequent communication with parents about sexuality and more positive sexual health behaviors, including accessing reproductive health care and adopting more effective means of contraception. Teen Council youth also reported greater confidence in talking with peers about sexuality and more confidence in their civic engagement skills.

Removable capping layer for air-sensitive GdN.

The strongly correlated rare earth nitrides display unusual coupled magnetic, electronic and superconducting properties, with predicted topological states. However, their air-sensitiveness has prevented in-depth investigations of their properties. In this paper, we show that a 100 nm thick epitaxial samarium layer provides adequate passivation of 100 nm thick thin films of gadolinium nitride (GdN), the prototypical rare earth nitride, enabling ex-situ magnetic and structural characterizations. Using reflection high-energy electron diffraction, atomic force microscopy and energy dispersive x-ray spectroscopy, we investigate the thermal desorption of the samarium layer under vacuum. We finally demonstrate successful removal of the samarium capping layer in a separate vacuum chamber after exposure to air using a combination of argon ion sputtering and thermal desorption at 400 °C, recovering the GdN surface.

Beyond HbA1c : using continuous glucose monitoring metrics to enhance interpretation of treatment effect and improve clinical decision-making.

Assessment of glycaemic outcomes in the management of Type 1 and Type 2 diabetes has been revolutionized in the past decade with the increasing availability of accurate, user-friendly continuous glucose monitoring (CGM). This advancement has brought a need for new techniques to appropriately analyse and understand the voluminous and complex CGM data for application in research-related goals and clinical guidance for individuals. Traditionally, HbA1c was established using the Diabetes Control and Complications Trial (DCCT) and other trials as the ultimate measure of glycaemic control in terms of efficacy and, by default, risk of microvascular complications of diabetes. However, it is acknowledged that HbA1c alone is inadequate at describing an individual's daily glycaemic variation and risks for hypo- and hyperglycaemia, and it does not provide the guidance needed to decrease those risks. CGM data provide means by which to characterize an individual's daily glycaemic excursions on a different time scale measured in minutes rather than months. As a consequence, clinical reports, such as the ambulatory glucose profile, increasingly include summary statistics related to averages (mean glucose, time in range) as well as markers related to glycaemic variability (coefficient of variation, standard deviation). However, there is a need to translate those metrics into specific risks that can be addressed in an actionable plan by individuals with diabetes and providers. This review presents several clinical scenarios of glycaemic outcomes from CGM data that can be analysed to describe glycaemic variability and its attendant risks of hyperglycaemia and hypoglycaemia, moving towards relevant interpretation of the complex CGM data streams.

Synaptic dynamics in complex self-assembled nanoparticle networks.

We report a detailed study of neuromorphic switching behaviour in inherently complex percolating networks of self-assembled metal nanoparticles. We show that variation of the strength and duration of the electric field applied to this network of synapse-like atomic switches allows us to control the switching dynamics. Switching is observed for voltages above a well-defined threshold, with higher voltages leading to increased switching rates. We demonstrate two behavioral archetypes and show how the switching dynamics change as a function of duration and amplitude of the voltage stimulus. We show that the state of each synapse can influence the activity of the other synapses, leading to complex switching dynamics. We further demonstrate the influence of the morphology of the network on the measured device properties, and the constraints imposed by the overall network conductance. The correlated switching dynamics, device stability over long periods, and the simplicity of the device fabrication provide an attractive pathway to practical implementation of on-chip neuromorphic computing.

Topological phases in double layers of bismuthene and antimonene.

Two-dimensional topological insulators show great promise for spintronic applications. Much attention has been placed on single atomic or molecular layers, such as bismuthene. The selections of such materials are, however, limited. To broaden the base of candidate materials with desirable properties for applications, we report herein an exploration of the physics of double layers of bismuthene and antimonene. The electronic structure of a film depends on the number of layers, and it can be modified by epitaxial strain, by changing the effective spin-orbit coupling strength, and by the manner in which the layers are geometrically stacked. First-principles calculations for the double layers reveal a number of phases, including topological insulators, topological semimetals, Dirac semimetals, trivial semimetals, and trivial insulators. Their phase boundaries and the stability of the phases are investigated. The results illustrate a rich pattern of phases that can be realized by tuning lattice strain and effective spin-orbit coupling.

Assessment and validation of a defined fluid restriction protocol in the use of subcutaneous desmopressin for children with inherited bleeding disorders.

INTRODUCTION: Despite the availability of subcutaneous desmopressin (1-deamino-8-d-arginine vasopressin, SC-DDAVP) as a haemostatic agent for children with mild bleeding disorders, few publications specifically address the safety or efficacy of this mode of administration. AIM: Our aim was to assess whether a defined fluid restriction protocol was effective in preventing hyponatremia in children receiving perioperative SC-DDAVP, and to document adequate biological and clinical response in this setting. METHODS: We retrospectively analysed a cohort of children with mild bleeding disorders prescribed SC-DDAVP over a 5-year period following institution of a 'two-thirds maintenance' fluid restriction protocol. RESULTS: Sixty-nine patients received SC-DDAVP following this protocol, including 15 with mild haemophilia A, 49 with von Willebrand disease (VWD) and five with platelet storage pool disorder. In patients who underwent formal preoperative assessment a complete or partial response was observed in 28/29 with type 1 VWD and 14/15 with mild haemophilia A. Perioperative SC-DDAVP provided excellent haemostasis in all patients, with no requirement for factor concentrate or blood products. Mild asymptomatic hyponatremia was detected in seven children who received multiple doses of DDAVP (lowest sodium 129 mmol L(-1) ); however, adherence to the prescribed fluid restriction protocol was questionable in six of these cases. Symptomatic hyponatremia was not observed. CONCLUSION: Subcutaneous desmopressin was well-tolerated, with no serious side-effects observed, and good biological responses in preoperative trials. A two-thirds maintenance fluid regimen was effective at preventing symptomatic hyponatremia in our cohort, and is now the standard protocol for fluid restriction post-DDAVP administration in our centre.

Chronic Kidney Disease in Aged Cats: Clinical Features, Morphology, and Proposed Pathogeneses.

Chronic kidney disease (CKD) is the most common metabolic disease of domesticated cats, with most affected cats being geriatric (>12 years of age). The prevalence of CKD in cats exceeds that observed in dogs, and the frequency of the diagnosis of CKD in cats has increased in recent decades. Typical histologic features include interstitial inflammation, tubular atrophy, and fibrosis with secondary glomerulosclerosis. In contrast to people and dogs, primary glomerulopathies with marked proteinuria are remarkably rare findings in cats. Although a variety of primary renal diseases have been implicated, the disease is idiopathic in most cats. Tubulointerstitial changes, including fibrosis, are present in the early stages of feline CKD and become more severe in advanced disease. A variety of factors-including aging, ischemia, comorbid conditions, phosphorus overload, and routine vaccinations-have been implicated as factors that could contribute to the initiation of this disease in affected cats. Factors that are related to progression of established CKD, which occurs in some but not all cats, include dietary phosphorus intake, magnitude of proteinuria, and anemia. Renal fibrosis, a common histologic feature of aged feline kidneys, interferes with the normal relationship between peritubular capillaries and renal tubules. Experimentally, renal ischemia results in morphologic changes similar to those observed in spontaneous CKD. Renal hypoxia, perhaps episodic, may play a role in the initiation and progression of this disease.

Unilateral Renal Ischemia as a Model of Acute Kidney Injury and Renal Fibrosis in Cats.

The objectives of this study were to define the acute and chronic effects of 1-hour unilateral in vivo renal ischemia on renal function and histology in cats. Twenty-one adult purpose-bred research cats were anesthetized, and 1 kidney underwent renal artery and vein occlusion for 1 hour. Serum creatinine and urea concentrations, urine protein:creatinine ratio, urine-specific gravity, glomerular filtration rate, hematocrit, platelet concentration and function, and white blood cell count were measured at baseline and variable time points after ischemia. Renal histopathology was evaluated on days 3, 6, 12, 21, 42, and 70 postischemia; changes in smooth muscle actin and interstitial collagen were examined. Following ischemia, whole animal glomerular filtration rate was significantly reduced (57% of baseline on day 6; P < .05). At the early time points, the ischemic kidneys exhibited severe acute epithelial necrosis accompanied by evidence of regeneration of tubules predominantly within the corticomedullary junction. At later periods, postischemic kidneys had evidence of tubular atrophy and interstitial inflammation with significantly more smooth muscle actin and interstitial collagen staining and interstitial fibrosis when compared with the contralateral control kidneys. This study characterizes the course of ischemic acute kidney injury in cats and demonstrates that ischemic acute kidney injury triggers chronic fibrosis, interstitial inflammation, and tubular atrophy in feline kidneys. These late changes are typical of those observed in cats with naturally occurring chronic kidney disease.

When is enough enough? Developing consensus of definition of failure of immune tolerance induction in patients with haemophilia and inhibitors.

Immune tolerance induction (ITI) is the preferred management of haemophilia A patients who develop high titre inhibitors against factor VIII. However, the optimal ITI regimen, predictors of ITI outcome and definitions of successful and unsuccessful ITI remain unclear. The aim of this project was to develop a consensus on the definition of ITI treatment failure for Australian clinical practice using a modified Delphi approach. Three consecutive surveys were distributed to the directors of 17 haemophilia treatment centres in Australia. Participants were asked to rate their agreement with definitions of ITI treatment failure generated from a literature review. Thirty-five statements regarding ITI achieved consensus (majority agree or strongly agree) during the three survey rounds. After round 3, four statements achieved majority disagreement, and for two statements no consensus was reached. Our study demonstrates that clinicians in Australia necessitate an arbitrary time to assess ITI failure, but that clinical outcomes of ITI are important in assessing response. Assessment over any 3- to 6-month period without a 20% reduction in inhibitor titre is suggestive of failure, but a reduction in bleeding phenotype alone may be sufficient to continue ITI. Overall, a period of 3 or 5 years of ITI may be required to determine response to ITI. Documentation of improvement in clinical measures, supported by the laboratory features of factor VIII inhibitor levels and pharmacokinetics, is essential in assessing the success of failure of ITI in these patients.

von Willebrand disease and platelet disorders.

The diagnosis and management of bleeding disorders is made difficult by the complexity and variety of disorders, clinical symptoms and bleeding type and severity. von Willebrand disease (VWD) and platelet disorders are disorders of primary haemostasis and together represent the most common inherited bleeding disorders. In this article, we describe the diagnosis of VWD and platelet disorders and the treatment options for VWD.

Electronic size effects in three-dimensional nanostructures.

We show that bismuth nanostructures form three-dimensional patterns governed by two-dimensional electronic effects. Scanning tunneling microscopy reveals that both the vertical and the lateral dimensions of the structures strongly favor certain values and that the preferred widths are substantially different for each preferred height. First-principles calculations demonstrate that this vertical-lateral correlation is governed by the Fermi surface topology and that this is itself sensitively dependent on the dimensions of the structure.

Understanding the pharmacokinetics of tulathromycin: a pulmonary perspective.

Tulathromycin is approved in the United States for the treatment of respiratory disease in bovine and swine, infectious bovine keratoconjunctivitis associated with Moraxella bovis, and interdigital necrobacillosis in bovine. This macrolide highly concentrates in lung tissue and persists in the intra-airway compartment for a long time after a single administration. It also accumulates in inflammatory cells, including neutrophils and macrophages. This article reviews pharmacokinetic information about tulathromycin in different veterinary species with particular emphasis on the respiratory system.

An acute reversible experimental model of pneumonia in pigs: time-related histological and clinical signs changes.

The objective of this study was to evaluate the long-term survival rates, clinical response, and lung gross and microscopic changes in pigs treated intratracheally with lipopolysaccharide of Escherichia coli 0111:B4 (LPS-Ec). Healthy pigs were randomly allocated to three groups: (i) no-LPS-Ec (n=1), (ii) LPS-Ec-T1 (1 mg/mL, 10 mL/pig) (n=7), and (iii) LPS-Ec-T2 (0.5 mg/mL, 10 mL/pig) (n=6). Two pigs from each dose group were euthanized at 24 (n=3 for T1), 48 and 144 h post-LPS-Ec challenge. LPS-Ec-treated animals showed macroscopic lesions in middle lobes of the lung. A reversible recruitment of macrophages and neutrophils was observed at 24, 48, and 144 h post-LPS-Ec challenge. The highest cellular infiltration level was observed at 24 h after challenge. The highest clinical scores were evident in both experimental dose levels within 3 and 5 h after LPS-Ec administration. Administration of LPS-Ec, under the conditions evaluated, can be used to induce a reproducible model of acute pulmonary inflammation in pigs.

Pulmonary pharmacokinetics of tulathromycin in swine. Part I: Lung homogenate in healthy pigs and pigs challenged intratracheally with lipopolysaccharide of Escherichia coli.

The objective of the study was to assess the pharmacokinetics of tulathromycin in lung tissue homogenate (LT) and plasma from healthy and lipopolysaccharide (LPS)-challenged pigs. Clinically healthy pigs were allocated to two dosing groups of 36 animals each (group 1 and 2). All animals were treated with tulathromycin (2.5 mg/kg). Animals in group 2 were also challenged intratracheally with LPS from Escherichia coli (LPS-Ec) 3 h prior to tulathromycin administration. Blood and LT samples were collected from all animals during 17-day post-tulathromycin administration. For LT, one sample from the middle (ML) and caudal lobes (CL) was taken. The concentration of tulathromycin was significantly lower in the ML after the intratracheal administration of LPS-E. coli (P < 0.02). In healthy pigs and LPS-challenged animals, the distribution of the drug into the lungs was rapid and persisted at high levels for 17-day postadministration. The distribution of the drug within the lung seems to be homogenous, at least between the middle and caudal lobes within dosing groups. The concentration versus time profile of the drug and pharmacokinetic parameters in two different lung areas (middle and caudal lobe) were consistent within the groups. The clinical significance of these findings is unknown.

Pulmonary pharmacokinetics of tulathromycin in swine. Part 2: Intra-airways compartments.

The objective of this study was to assess the pharmacokinetics of tulathromycin in pulmonary and bronchial epithelial lining fluid (PELF and BELF) from pigs. Clinically healthy pigs were allocated to two groups of 36 animals each. All animals were treated with tulathromycin (2.5 mg/kg/i.m). Animals in group 2 were also challenged intratracheally with lipopolysaccharide from Escherichia coli 3 h prior to tulathromycin administration. Both PELF and BELF samples were harvested using bronchoalveolar lavage fluid and bronchial micro-sampling probes, respectively. Samples were taken for 17 days post-tulathromycin administration. No statistical differences in the concentration of tulathromycin were observed in PELF between groups. The concentration vs. time profile in BELF was evaluated only in Group 1. Tulathromycin distributed rapidly and extensively into the airway compartments. The time to maximal (Tmax ) concentration was 6 h postdrug administration in PELF but 72 h post-tulathromycin administration for BELF. In group 2, the Tmax was seen at 24 h post-tulathromycin administration. The area under the concentration time curve (h*ng/mL) was 522 000, 348 000 and 1 290 000 for PELFGroup-1 , PELFGroup-2 , and BELFGroup-1 , respectively. Tulathromycin not only distributed rapidly into intra-airway compartments at relatively high concentrations but also resided in the airway lining fluid for a long time (>4 days).

Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired.

Holoprosencephaly (HPE) is the most common structural anomaly of the human brain and is one of the anomalies seen in patients with deletions and duplications of chromosome 13. On the basis of molecular analysis of a series of patients with hemizygous deletions of the long arm of chromosome 13, we have defined a discrete region in band 13q32 where deletion leads to major developmental anomalies (the 13q32 deletion syndrome). This approximately 1-Mb region lies between markers D135136 and D13S147. Patients in which this region is deleted usually have major congenital malformations, including brain anomalies such as HPE or exencephaly, and digital anomalies such as absent thumbs. We now report that human ZIC2 maps to this critical deletion region and that heterozygous mutations in ZIC2 are associated with HPE. Haploinsufficiency for ZIC2 is likely to cause the brain malformations seen in 13q deletion patients.

Reservoir computing using networks of memristors: effects of topology and heterogeneity.

Reservoir computing (RC) has attracted significant interest as a framework for the implementation of novel neuromorphic computing architectures. Previously attention has been focussed on software-based reservoirs, where it has been demonstrated that reservoir topology plays a role in task performance, and functional advantage has been attributed to small-world and scale-free connectivity. However in hardware systems, such as electronic memristor networks, the mechanisms responsible for the reservoir dynamics are very different and the role of reservoir topology is largely unknown. Here we compare the performance of a range of memristive reservoirs in several RC tasks that are chosen to highlight different system requirements. We focus on percolating networks of nanoparticles (PNNs) which are novel self-assembled nanoscale systems that exhibit scale-free and small-world properties. We find that the performance of regular arrays of uniform memristive elements is limited by their symmetry but that this symmetry can be broken either by a heterogeneous distribution of memristor properties or a scale-free topology. The best perfomance across all tasks is observed for a scale-free network with uniform memistor properties. These results provide insight into the role of topology in neuromorphic reservoirs as well as an overview of the computational performance of scale-free networks of memristors in a range of benchmark tasks.

Pharmacokinetics of tulathromycin in healthy and neutropenic mice challenged intranasally with lipopolysaccharide from Escherichia coli.

Tulathromycin represents the first member of a novel subclass of macrolides, known as triamilides, approved to treat bovine and swine respiratory disease. The objectives of the present study were to assess the concentration-versus-time profile of tulathromycin in the plasma and lung tissue of healthy and neutropenic mice challenged intranasally with lipopolysaccharide (LPS) from Escherichia coli O111:B4. BALB/c mice were randomly allocated into four groups of 40 mice each: groups T-28 (tulathromycin at 28 mg/kg of body weight), T-7, T7-LPS, and T7-LPS-CP (cyclophosphamide). Mice in group T-28 were treated with tulathromycin at 28 mg/kg subcutaneously (s.c.) (time 0 h). The rest of the mice were treated with tulathromycin at 7 mg/kg s.c. (time 0 h). Animals in dose groups T-7-LPS and T7-LPS-CP received a single dose of E. coli LPS intranasally at -7 h. Mice in group T7-LPS-CP were also rendered neutropenic with cyclophosphamide (150 mg/kg intraperitoneally) prior to the administration of tulathromycin. Blood and lung tissue samples were obtained from 5 mice from each dose group at each sampling time over 144 h after the administration of tulathromycin. There were not statistical differences in lung tissue concentrations among groups T-7, T-7-LPS, and T7-LPS-CP. For all dose groups, the distribution of tulathromycin in the lungs was rapid and persisted at relatively high levels during 6 days postadministration. The concentration-versus-time profile of tulathromycin in lung tissue was not influenced by the intranasal administration of E. coli LPS. The results suggest that in mice, neutrophils may not have a positive influence on tulathromycin accumulation in lung tissue when the drug is administered during either a neutrophilic or a neutropenic state.

How we use recombinant activated Factor VII in patients with haemophilia A or B complicated by inhibitors. Working group of hematology experts from Australia and New Zealand, Melbourne, April 2011.

The management of bleeds in patients with haemophilia A or B complicated by inhibitors is complex. Recombinant activated Factor VII (rFVIIa; NovoSeven RT) is an established therapy in these patients. To develop a consensus-based guide on the practical usage of rFVIIa in haemophilia complicated by inhibitors, nine expert haemophilia specialists from Australia and New Zealand developed practice points on the usage of rFVIIa, based on their experience and supported by published data. Practice points were developed for 13 key topics: control of acute bleeding; prophylaxis; surgical prophylaxis; control of breakthrough bleeding during surgery or treatment of acute bleeds; paediatric use; use in elderly; intracranial haemorrhage; immune tolerance induction; difficult bleeds; clinical monitoring of therapy; laboratory monitoring of therapy; concomitant antifibrinolytic medication; practical dosing. Access to home therapy with rFVIIa is important in allowing patients to administer treatment early in bleed management. In adults, 90-120 µg/kg is the favoured starting dose in most settings. Initial dosing using 90-180 µg/kg is recommended for children due to the effect of age on the pharmacokinetics of rFVIIa. In the management of acute bleeds, 2-hourly dosing is appropriate until bleeding is controlled, with concomitant antifibrinolytic medication unless contraindicated. The practice points provide guidance on the usage of rFVIIa for all clinicians involved in the management of haemophilia complicated by inhibitors.