Liver-related mortality in countries of the developed world: an ecological study approach to explain the variability.

Background: Liver-related mortality varies across developed nations.

Aim: To assess the relative role of various risk factors in relation to liver-related mortality in an ecological study approach.

Methods: Data for liver-related mortality, prevalence data for hepatitis B and C, human immunodeficiency virus (HIV), alcohol consumption per capita, Type 2 Diabetes mellitus (T2DM), overweight and obesity were extracted from peer-reviewed publications or WHO databases for different developed countries.

The role of knowledge in the contraceptive behaviour of sexually active young people in state care.

Aim: To analyse the role of sex-focused knowledge in the contraceptive behaviour of sexually active young people in state care.

Methods: The sample consisted of 19 care leavers (young people previously in state care) aged 18-22 years, 16 females and 3 males. In-depth interviewing was the method of data collection, and a qualitative strategy resembling modified analytical induction was used to analyse data.

Environmental health impacts of feeding crops to farmed fish.

Half of the seafood consumed globally now comes from aquaculture, or farmed seafood. Aquaculture therefore plays an increasingly important role in the global food system, the environment, and human health. Traditionally, aquaculture feed has contained high levels of wild fish, which is unsustainable for ocean ecosystems as demand grows.

Trastuzumab-deBouganin Conjugate Overcomes Multiple Mechanisms of T-DM1 Drug Resistance.

The development of antibody drug conjugates has provided enhanced potency to tumor-targeting antibodies by the addition of highly potent payloads. In the case of trastuzumab-DM1 (T-DM1), approved for the treatment of metastatic breast cancer, the addition of mertansine (DM1) to trastuzumab substantially increased progression-free survival. Despite these improvements, most patients eventually relapse due to complex mechanisms of resistance often associated with small molecule chemotherapeutics.

Value of the 8-oxodG/dG ratio in chronic liver inflammation of patients with hepatocellular carcinoma.

The aim of this study was to examine the role of oxidative DNA damage in chronic liver inflammation in the evolution of hepatocellular carcinoma. The accumulated data demonstrated that oxidative DNA damage and chronic liver inflammation are involved in the transformation of normal hepatocytes and their evolution towards hepatocellular carcinoma. However, the levels of 8-oxy-2'-deoxy-guanosine (8-oxodG), a biomarker of oxidative DNA damage, were overestimated and underestimated in previous reports due to various technical limitations.

Hofmeister Ion-Induced Changes in Water Structure Correlate with Changes in Solvation of an Aggregated Protein Complex.

RecA is a naturally aggregating Escherichia coli protein that catalyzes the strand exchange reaction utilized in DNA repair. Previous studies have shown that the presence of salts influence RecA activity, aggregation, and stability and that salts stabilize RecA in an inverse-anionic Hofmeister series. Here we utilized attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy and circular dichroism (CD) to investigate how various Hofmeister salts alter the water structure and RecA solvation and aggregation.

Human Leukocyte Antigen-Presented Macrophage Migration Inhibitory Factor Is a Surface Biomarker and Potential Therapeutic Target for Ovarian Cancer.

T cells recognize cancer cells via HLA/peptide complexes, and when disease overtakes these immune mechanisms, immunotherapy can exogenously target these same HLA/peptide surface markers. We previously identified an HLA-A2-presented peptide derived from macrophage migration inhibitory factor (MIF) and generated antibody RL21A against this HLA-A2/MIF complex. The objective of the current study was to assess the potential for targeting the HLA-A2/MIF complex in ovarian cancer.

Translational neurophysiological markers for activity of the metabotropic glutamate receptor (mGluR2) modulator JNJ-40411813: Sleep EEG correlates in rodents and healthy men.

Alterations in rapid eye movement sleep (REM) have been suggested as valid translational efficacy markers: activation of the metabotropic glutamate receptor 2 (mGluR2) was shown to increase REM latency and to decrease REM duration. The present paper addresses the effects on vigilance states of the mGluR2 positive allosteric modulator (PAM) JNJ-40411813 at different circadian times in rats and after afternoon dosing in humans. Due to its dual mGluR2 PAM/serotonin 2A (5-HT2A) receptor antagonism in rodents, mGlu2R specificity of effects was studied in wild-type (WT) and mGluR2 (-/-) mice.

Preliminary investigation of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one derivatives as a novel series of mGlu5 receptor positive allosteric modulators with efficacy in preclinical models of schizophrenia.

As part of our efforts to identify a suitable back-up compound to our recently disclosed mGlu5 positive allosteric modulator (PAM) clinical candidate VU0490551/JNJ-46778212, this letter details the investigation and challenges of a novel series of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one derivatives. From these efforts, compound 4k emerged as a potent and selective mGlu5 PAM displaying overall attractive in vitro (pharmacological and ADMET) and PK profiles combined with in vivo efficacy in preclinical models of schizophrenia. However, further advancement of the compound was precluded due to severely limiting CNS-related side-effects confirming the previously reported association between excessive mGlu5 activation and target-related toxicities.

Systematic Review of the Measurement Properties of Tools Used to Measure Behaviour Problems in Young Children with Autism.

Background: Behaviour problems are common in young children with autism spectrum disorder (ASD). There are many different tools used to measure behavior problems but little is known about their validity for the population.

Objectives: To evaluate the measurement properties of behaviour problems tools used in evaluation of intervention or observational research studies with children with ASD up to the age of six years.

Additive impact of pre-liver transplant metabolic factors on survival post-liver transplant.

Background And Aim: Diabetes at time of liver transplantation is associated with reduced post-transplant survival. We aimed to assess whether additional metabolic conditions such as obesity or hypertension had additive prognostic impact on post-transplantation survival.

Methods: A multi-center cohort study of 617 adult subjects undergoing liver transplantation between 2003 and 2009 has been used.

Domestic Violence and Private Family Court Proceedings: Promoting Child Welfare or Promoting Contact?

Despite improved understanding regarding domestic violence, child welfare and child contact, and related policy developments, problems persist regarding how the family courts deal with fathers' violence in contested contact/residence cases. In the study reported here, analysis was undertaken of welfare reports prepared for the courts in such cases to investigate how and to what extent issues of domestic violence and children's perspectives on these issues were taken into account when making recommendations to the courts. Analysis found that despite evidence of domestic violence and child welfare concerns, contact with fathers was viewed as desirable and inevitable in the vast majority of cases.

Pharmacological interventions for cognitive decline in people with Down syndrome.

Background: People with Down syndrome are vulnerable to developing dementia at an earlier age than the general population. Alzheimer's disease and cognitive decline in people with Down syndrome can place a significant burden on both the person with Down syndrome and their family and carers. Various pharmacological interventions, including donepezil, galantamine, memantine and rivastigmine, appear to have some effect in treating cognitive decline in people without Down syndrome, but their effectiveness for those with Down syndrome remains unclear.

Feeding the Corn Belt: Opportunities for phosphorus recycling in U.S. agriculture.

The supply of phosphorus (P) is a critical concern for food security. Concentrated mineral P deposits have been the source of almost all new P entering the biosphere. However, this resource is often used inefficiently, raising concerns about both nutrient pollution and future access to fertilizers.

1,4-Oxazine β-Secretase 1 (BACE1) Inhibitors: From Hit Generation to Orally Bioavailable Brain Penetrant Leads.

1,4-Oxazines are presented, which show good in vitro inhibition in enzymatic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine pKa while optimizing interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and especially P-glycoprotein efflux.

Longing for Ex-Partners out of Fear of Being Single.

This research investigated whether people who fear being single have a more difficult time letting go of ex-partners following a romantic breakup. Data were collected in a cross-sectional study (N = 209, 64% women, M  = 30 years old) as well as a 1-month daily experience study of individuals who just went through a romantic breakup (N = 117, 44% women, M  = 27 years old). Findings from both studies revealed that those with stronger fear of being single (Spielmann et al.

When "In Your Face" Is Not Out of Place: The Effect of Timing of Disclosure of a Same-Sex Dating Partner under Conditions of Contact.

In a series of experiments we examined heterosexuals' reactions to the timing of disclosure of a gender-matched confederate's same-sex dating partner. Disclosure occurred in a naturalistic context-that is, it occurred when meeting, or expecting to soon meet, a same-sex attracted individual, who voluntarily shared this information with the participant as a natural part of a broader topic of discussion. The confederate, when disclosing early rather than later, was approached more closely (Prestudy) and liked more (Studies 1-2).

Further optimization of the mGlu5 PAM clinical candidate VU0409551/JNJ-46778212: Progress and challenges towards a back-up compound.

This Letter describes the progress and challenges in the continued optimization of the mGlu5 positive allosteric modulator (PAM) clinical candidate VU0490551/JNJ-46778212. While many analogs addressed key areas for improvement, no one compound possessed the amalgamation of improvements needed within the (2(phenoxymethyl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-yl(aryl)methanone scaffold to advance as a back-up clinical candidate. However, many analogs displayed excellent solubility and physiochemical properties, and were active in the amphetamine-induced hyperlocomotion (AHL) model.

Discovery of VU0409551/JNJ-46778212: An mGlu5 Positive Allosteric Modulator Clinical Candidate Targeting Schizophrenia.

Herein, we report the structure-activity relationship of a novel series of (2(phenoxymethyl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-yl(aryl)methanones as potent, selective, and orally bioavailable metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulators (PAMs). On the basis of its robust in vitro potency and in vivo efficacy in multiple preclinical models of multiple domains of schizophrenia, coupled with a good DMPK profile and an acceptable therapeutic window, 17a (VU0409551/JNJ-46778212) was selected as a candidate for further development.

Symptoms of Obstructive Sleep Apnea, Gastroesophageal Reflux and the Risk of Barrett's Esophagus in a Population-Based Case-Control Study.

Background: Gastroesophageal reflux is overrepresented in people with obstructive sleep apnea (OSA) and it has been suggested that OSA worsens gastroesophageal reflux symptoms. Aggravated reflux might lead to an increased risk of Barrett's esophagus.

Aim: To assess the association between sleep apnea symptoms and Barrett's esophagus.

Systematic review of tools to measure outcomes for young children with autism spectrum disorder.

Background: The needs of children with autism spectrum disorder (ASD) are complex and this is reflected in the number and diversity of outcomes assessed and measurement tools used to collect evidence about children's progress. Relevant outcomes include improvement in core ASD impairments, such as communication, social awareness, sensory sensitivities and repetitiveness; skills such as social functioning and play; participation outcomes such as social inclusion; and parent and family impact.

Objectives: To examine the measurement properties of tools used to measure progress and outcomes in children with ASD up to the age of 6 years.