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Introduction: Forensic mental health nurses working at the forefront of services can intermittently face enduring and somewhat harrowing or stressful situations. Enclosed is an example of the use of mechanical restraints (Soft Restraint Kit) for a two month period. Staff experience of working under such circumstances is an under reported area., Methods: The experience of nursing a patient under extreme conditions was captured through use of a qualitative study, using semi structured interviews with a purposive sample of (n = 10) staff nurses and nursing assistants in a high-security hospital., Results: Thematic analysis was undertaken generating four themes: sense of responsibility, aptitude, enablers/inhibitors, and consequence. Conclusions suggest that Soft Restraint Kits provide a useful method of containment, although prolonged use presents considerable challenges for staff. The importance of preparation and training cannot be underestimated and continued support and supervision are absolutely essential., (Copyright © 2020 Walker and Tulloch.)

The formation of interspecific hybrids results in the coexistence of two diverged genomes within the same nucleus. It has been hypothesized that negative epistatic interactions and regulatory interferences between the two sub-genomes may elicit a so-called genomic shock involving, among other alterations, broad transcriptional changes. To assess the magnitude of this shock in hybrid yeasts, we investigated the transcriptomic differences between a newly formed Saccharomyces cerevisiae × Saccharomyces uvarum diploid hybrid and its diploid parentals, which diverged ∼20 mya. RNA sequencing (RNA-Seq) based allele-specific expression (ASE) analysis indicated that gene expression changes in the hybrid genome are limited, with only ∼1-2% of genes significantly altering their expression with respect to a non-hybrid context. In comparison, a thermal shock altered six times more genes. Furthermore, differences in the expression between orthologous genes in the two parental species tended to be diminished for the corresponding homeologous genes in the hybrid. Finally, and consistent with the RNA-Seq results, we show a limited impact of hybridization on chromatin accessibility patterns, as assessed with assay for transposase-accessible chromatin using sequencing (ATAC-Seq). Overall, our results suggest a limited genomic shock in a newly formed yeast hybrid, which may explain the high frequency of successful hybridization in these organisms., (Copyright © 2020 Hovhannisyan, Saus, Ksiezopolska, Hinks Roberts, Louis and Gabaldón.)

Similarly to aged humans, senior horses (≥20 years) exhibit chronic low-grade inflammation systemically, known as inflamm-aging. Inflamm-aging in the senior horse has been characterized by increased circulating inflammatory cytokines as well as increased inflammatory cytokine production by lymphocytes and monocytes in response to a mitogen. Little is currently known regarding underlying causes of inflamm-aging. However, senior horses are also known to present with muscle wasting and often the endocrinopathy pituitary pars intermedia dysfunction (PPID). Despite the concurrence of these phenomena, the relationships inflamm-aging may have with measures of body composition and pituitary function in the horse remain unknown. Furthermore, nutrition has been a focus of research in an attempt to promote health span as well as life span in senior horses, with some nutrients, such as omega-3 fatty acids, having known anti-inflammatory effects. Thus, an exploratory study of a population of n = 42 similarly-managed senior horses was conducted to determine relationships between inflamm-aging and measures of circulating nutrients, body composition, age, and PPID. Serum was collected to determine vitamin, mineral, and fatty acid content. Peripheral blood mononuclear cells were also isolated to determine inflammatory cytokine production of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) following stimulation with a mitogen, as well as to determine gene expression of interleukin(IL)-1β, IL-6, IL-10, IFN-γ, and TNF-α. Serum IL-6 and C-reactive protein were determined by enzyme-linked immunosorbent assay. Whole blood was collected for hematological and biochemical analysis. Body composition was evaluated via ultrasound and muscle scoring for all 42 horses as well as by deuterium oxide dilution for a subset of n = 10 horses. Pituitary function was evaluated by measuring basal adrenocorticotropin hormone concentrations as well as by thyrotropin releasing hormone stimulation testing (to determine PPID status). Results showed various relationships between inflammatory markers and the other variables measured. Most notably, docosadienoic acid (C22:2n6c), docosapentaenoic acid (C22:5n3c), and folate were positively associated with numerous inflammatory parameters (P ≤ 0.05). Although no relationships were found between inflamm-aging and PPID, being positive for PPID was negatively associated with vitamin B12 (P ≤ 0.01). No relationships between inflammation and body composition were found. Even within this senior horse population, age was associated with multiple parameters, particularly with numerous inflammatory cytokines and fatty acids. In summary, inflamm-aging exhibited relationships with various other parameters examined, particularly with certain fatty acids. This exploratory study provides insights into physiological changes associated with inflamm-aging in the senior horse., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The development and succession of the microbiota in ileal mucus and lumen samples from three breeds of broiler chicken (Cobb 500, n = 36; Hubbard JA87, n = 38; and Ross 308, n = 36) was observed between 3 and 42 days post hatch (d.p.h). Chicks were housed in the same room of a climate-controlled, biosecure chicken housing unit. Between 0 and 14 d.p.h, chicks were kept in three circular brooder pens ensuring a mixture of breeds in each brooder. From 22 d.p.h, chicks were removed from the brooders and kept in the same room. DNA was extracted from a pooled sample of ileal mucus and luminal contents taken from five birds of each breed at 3, 7, 14, 21, 28, and 42 d.p.h. High-throughput Illumina sequencing was performed for the V4 hypervariable region of the 16S rRNA gene. The initial microbiota in the ileum varied between breeds. The common features were a low diversity and general dominance by one or two taxa such as Enterococcus or Escherichia with relatively low numbers of Lactobacillus . Escherichia became the most abundant genus in samples where Enterococcus was previously the dominant taxa. The next phase of development was marked by an increase in the abundance of Candidatus Arthromitus in the mucus and Lactobacillus in the lumen. The high abundance of Candidatus Arthromitus persisted between 7 and 14 d.p.h after which Lactobacillus became the most abundant genus in both the mucus and lumen. Dominance of the ileal microbiota by Lactobacillus was a transient feature. By 42 d.p.h, the relative abundance of Lactobacillus had fallen while a range of other taxa including Escherichia, Turicibacter , and members of Clostridiales increased. This general pattern was followed by all breeds, however, the rate at which succession occurred differed as Ross matured quicker than Cobb with Hubbard as an intermediate., (Copyright © 2020 Richards-Rios, Fothergill, Bernardeau and Wigley.)

Slow lorises are enigmatic animal that represent the only venomous primate lineage. Their defensive secretions have received little attention. In this study we determined the full length sequence of the protein secreted by their unique brachial glands. The full length sequences displayed homology to the main allergenic protein present in cat dander. We thus compared the molecular features of the slow loris brachial gland protein and the cat dander allergen protein, showing remarkable similarities between them. Thus we postulate that allergenic proteins play a role in the slow loris defensive arsenal. These results shed light on these neglected, novel animals., Competing Interests: The authors declare no conflict of interest.

Mephedrone (4-MMC, mephedrone) is a synthetic cathinone derivative included in the class of new psychoactive substances. It is commonly used simultaneously with alcohol (ethanol). The aim of the present study was to evaluate the interactions on subjective, cardiovascular and hormone effects and pharmacokinetics between mephedrone and alcohol in humans. Eleven male volunteers participated as outpatients in four experimental sessions in a double-blind, randomized, cross-over, and placebo-controlled clinical trial. Participants received a single oral dose of 200 mg of mephedrone plus 0.8 g/kg of alcohol (combination condition); 200 mg of mephedrone plus placebo alcohol (mephedrone condition); placebo mephedrone plus 0.8 g/kg of ethanol (alcohol condition); and placebo mephedrone plus placebo alcohol (placebo condition). Outcome variables included physiological (blood pressure, heart rate, temperature, and pupil diameter), psychomotor (Maddox wing), subjective (visual analogue scales, Addiction Research Center Inventory 49 item short form, and Valoración de los Efectos Subjetivos de Sustancias con Potencial de Abuso questionnaire), and pharmacokinetic parameters (mephedrone and ethanol concentrations). The study was registered in ClinicalTrials.gov, number NCT02294266. The mephedrone and alcohol combination produced an increase in the cardiovascular effects of mephedrone and induced a more intense feeling of euphoria and well-being in comparison to the two drugs alone. Mephedrone reduced the sedative effects produced by alcohol. These results are similar to those obtained when other psychostimulants such as amphetamines and 3,4-methylenedioxymethamphetamine are combined simultaneously with alcohol. The abuse liability of mephedrone combined with alcohol is greater than that induced by mephedrone alone., (Copyright © 2020 Papaseit, Pérez-Mañá, de Sousa Fernandes Perna, Olesti, Mateus, Kuypers, Theunissen, Fonseca, Torrens, Ramaekers, de la Torre and Farré.)

Background: Rapid evaluation was at the heart of National Health Service England's evaluation strategy of the new models of care vanguard programme. This was to facilitate the scale and spread of successful models of care throughout the health & social care system. The aim of this paper is to compare the findings of the two evaluations of the Enhanced health in Care Homes (EHCH) vanguard in Gateshead, one using a smaller data set for rapidity and one using a larger longitudinal data set and to investigate the implications of the use of rapid evaluations using interrupted time series (ITS) methods., Methods: A quasi-experimental design study in the form of an ITS was used to evaluate the impact of the vanguard on secondary care use. Two different models are presented differing by timeframes only. The short-term model consisted of data for 11 months data pre and 20 months post vanguard. The long-term model consisted of data for 23 months pre and 34 months post vanguard., Results: The cost consequences, including the cost of running the EHCH vanguard, were estimated using both a single tariff non-elective admissions methodology and a tariff per bed day methodology. The short-term model estimated a monthly cost increase of £73,408 using a single tariff methodology. When using a tariff per bed day, there was an estimated monthly cost increase of £14,315. The long-term model had, using a single tariff for non-elective admissions, an overall cost increase of £7576 per month. However, when using a tariff per bed-days, there was an estimated monthly cost reduction of £57,168., Conclusions: Although it is acknowledged that there is often a need for rapid evaluations in order to identify "quick wins" and to expedite learning within health and social care systems, we conclude that this may not be appropriate for quasi-experimental designs estimating effect using ITS for complex interventions. Our analyses suggests that care must be taken when conducting and interpreting the results of short-term evaluations using ITS methods, as they may produce misleading results and may lead to a misallocation of resources.

Background: The Critical Assessment of Functional Annotation (CAFA) is an ongoing, global, community-driven effort to evaluate and improve the computational annotation of protein function., Results: Here, we report on the results of the third CAFA challenge, CAFA3, that featured an expanded analysis over the previous CAFA rounds, both in terms of volume of data analyzed and the types of analysis performed. In a novel and major new development, computational predictions and assessment goals drove some of the experimental assays, resulting in new functional annotations for more than 1000 genes. Specifically, we performed experimental whole-genome mutation screening in Candida albicans and Pseudomonas aureginosa genomes, which provided us with genome-wide experimental data for genes associated with biofilm formation and motility. We further performed targeted assays on selected genes in Drosophila melanogaster, which we suspected of being involved in long-term memory., Conclusion: We conclude that while predictions of the molecular function and biological process annotations have slightly improved over time, those of the cellular component have not. Term-centric prediction of experimental annotations remains equally challenging; although the performance of the top methods is significantly better than the expectations set by baseline methods in C. albicans and D. melanogaster, it leaves considerable room and need for improvement. Finally, we report that the CAFA community now involves a broad range of participants with expertise in bioinformatics, biological experimentation, biocuration, and bio-ontologies, working together to improve functional annotation, computational function prediction, and our ability to manage big data in the era of large experimental screens.

The majority of cardiorespiratory arrests in children and infants are caused by respiratory insufficiency rather than cardiac problems; therefore, the order of delivering resuscitation is different to the delivery of basic life support to adults. The Nursing and Midwifery Council has stated that all nurses must be able to provide basic life support. This article will explain the process for recognising the need for, and delivering, basic life support to infants and children.

Background: Cyprus entered a prolonged financial recession, which escalated to a bailout agreement with a team of international lenders. This rendered as prerequisites structural reforms aiming to enhance efficiency of the system., Objectives: To report on the impact of the financial crisis and ensuing health sector reforms in Cyprus., Methods: A cross-sectional study with datasets from the 2010 and 2014 (11 088 individuals and 9983 individuals, respectively) Cyprus European Union Statistics on Income and Living Conditions. We analyzed data using a logistic regression model and also performed a documentary analysis., Results: Compared to 2010, in 2014 the percentage of Cypriots who self-reported their health state as very good was stable (1.03; confidence interval [CI] 95%, 0.98-1.09]), whereas the percentage of Cypriots who self-reported their health state as bad demonstrated a statistically significant reduction (0.75 [CI 95% 0.66-0.85]). The cumulative financial affordability impact the said measures had on the patients was negative: a significant increase was reported for patients reporting unmet medical needs ("cost" and "long waiting lists") (1.22 [CI 95% 1.03-1.35]), whereas inconclusive findings were reported apropos dental health needs (0.96 [CI 95% 0.88-1.04])., Conclusions: We demonstrate that crisis and health reforms did not exert any negative effects on Cypriots' health; nevertheless, a significant increase of patients who face difficulties in financing their health needs was reported. The mental health sector was, in particular, affected by the crisis, and consequently, health agencies must closely monitor this topic along with the aforementioned affordability issues., (Copyright © 2019 ISPOR–The professional society for health economics and outcomes research. Published by Elsevier Inc. All rights reserved.)

Background and Aim: Nitric oxide (NO) is the intracellular chemical responsible for initiating a penile erection. Despite conflicting clinical data, it continues to be publicized and promoted that orally administered l-arginine, the putative substrate for NO, enhances the erectile response presumably by stimulating NO production by the corporal tissues resulting in an increase in cGMP production. To shed light on this issue, an in vitro study was conducted to explore the effect of direct exogenous administration of l-arginine as well as its precursor and metabolite, l-citrulline, on the NO-cGMP pathway within the cavernosal smooth muscle (CSM) cell., Materials and Methods: CSM cells obtained from 8 to 10 week old Sprague-Dawley rats were grown in Dulbecco media with 20% fetal calf serum and then incubated with or without l-arginine (L-ARG) or l-citrulline (L-CIT) in a time course and dose-response manner. Sildenafil (0.4 mM), IBMX (1 mM), l-NAME (3 μM), ODQ (5 μM) and Deta Nonoate (10 μM) were used as either inhibitors or stimulators of the NO-cGMP pathway. mRNA and protein were extracted and used for the determination of the phosphodiesterase 5 (PDE5). PDE5 activity was determined by luminometry. cGMP content was determined by ELISA. Nitrite formation, an indicator of NO production, was measured in the cell culture media by a colorimetric assay. The cationic (CAT-1) and neutral (SNAT-1) amino acid transporters for L-ARG and L-CIT, respectively, were determined by Western blot., Results: When compared to untreated CSM cells, incubation with 0.25-4.0 mM of L-ARG or 0.3-4.8 mM of L-CIT anywhere between 3 and 24 h did not result in any additional nitrite or cGMP production. The addition of l-NAME, IBMX or ODQ to these L-ARG and L-CIT treated cells did not alter these results. L-CIT but not L-ARG increased PDE5 mRNA and protein content as well as the activity of the PDE5 enzyme. Both CAT-1 and SNAT-1 were expressed in the CSM cells., Conclusions: This in vitro study demonstrates that exogenous administration of L-ARG or L-CIT failed to stimulate production of either NO or cGMP by the corporal CSM cells. A re-evaluation of the presumptive role of the exogenous administration of L-ARG in improving the synthesis of NO at least at the level of the CSM cells appears warranted., (Copyright © 2019. Published by Elsevier Inc.)

Osteoporosis represents an imbalance between bone formation and bone resorption. As a result of low estrogen levels, it is markedly prevalent during menopause, thus making such patients susceptible to fractures. Both bone formation and resorption are modulated by nitric oxide (NO). Currently, there are no risk-free pharmaceutical prevention therapies for osteoporosis. COMB-4, a nutraceutical combination of Paullinia cupana, Muira puama, ginger, and L-citrulline, known to activate the NO-cGMP pathway, was reported to accelerate fracture healing in the rat. To determine whether COMB-4 could be effective in preventing menopausal osteoporosis, it was compared to estradiol (E2) in an ovariectomized (OVX) rat osteoporosis model. Nine-month-old female Sprague Dawley rats were divided into SHAM, OVX, OVX+E2, and OVX+COMB-4. After 100 days of treatment, bone mineral density (BMD) and bone mineral content (BMC) were measured by DXA scan. TRAP staining was performed in the femur and lumbar vertebrae. TRACP 5b and osteocalcin levels were assayed in the serum. MC3T3-E1 cells were differentiated into osteoblasts and treated with COMB-4 for one week in order to evaluate calcium deposition by Alizarin staining, cGMP production by ELISA, and upregulation of the nitric oxide synthase (NOS) enzymes by RT-PCR. OVX resulted in a decrease in BMD, BMC, and serum osteocalcin and an increase in serum TRACP 5b. Except for an increase in BMC with COMB-4, both E2 and COMB-4 reverted all bone and serum markers, as well as the number of osteoclasts in the vertebrae, to SHAM levels. Incubation of MC3T3-E1 cells with COMB-4 demonstrated an increase in the three NOS isoforms, cGMP, and calcium deposition. COMB-4 increased BMD in OVX rats by inhibiting bone resorption and increasing calcium deposition presumably via activation of the NO-cGMP pathway. It remains to be determined whether COMB-4 could be a potential nutraceutical therapy for the prevention of premenopausal bone loss.

Recreating the structure of human tissues in the laboratory is valuable for fundamental research, testing interventions, and reducing the use of animals. Critical to the use of such technology is the ability to produce tissue models that accurately reproduce the microanatomy of the native tissue. Current artificial cell-based skin systems lack thorough characterisation, are not representative of human skin, and can show variation. In this study, we have developed a novel full thickness model of human skin comprised of epidermal and dermal compartments. Using an inert porous scaffold, we created a dermal construct using human fibroblasts that secrete their own extracellular matrix proteins, which avoids the use of animal-derived materials. The dermal construct acts as a foundation upon which epidermal keratinocytes were seeded and differentiated into a stratified keratinised epithelium. In-depth morphological analyses of the model demonstrated very close similarities with native human skin. Extensive immunostaining and electron microscopy analysis revealed ultrastructural details such as keratohyalin granules and lamellar bodies within the stratum granulosum, specialised junctional complexes, and the presence of a basal lamina. These features reflect the functional characteristics and barrier properties of the skin equivalent. Robustness and reproducibility of in vitro models are important attributes in experimental practice, and we demonstrate the consistency of the skin construct between different users. In summary, a new model of full thickness human skin has been developed that possesses microanatomical features reminiscent of native tissue. This skin model platform will be of significant interest to scientists researching the structure and function of human skin., (© 2019 The Authors. Journal of Anatomy published by John Wiley & Sons Ltd on behalf of Anatomical Society.)

Background: Accumulating evidence suggests that breastfeeding benefits children's intelligence, possibly due to long-chain polyunsaturated fatty acids (LC-PUFAs) present in breast milk. Under a nutritional adequacy hypothesis, an interaction between breastfeeding and genetic variants associated with endogenous LC-PUFAs synthesis might be expected. However, the literature on this topic is controversial., Methods: We investigated this gene × environment interaction through a collaborative effort. The primary analysis involved >12 000 individuals and used ever breastfeeding, FADS2 polymorphisms rs174575 and rs1535 coded assuming a recessive effect of the G allele, and intelligence quotient (IQ) in Z scores., Results: There was no strong evidence of interaction, with pooled covariate-adjusted interaction coefficients (i.e. difference between genetic groups of the difference in IQ Z scores comparing ever with never breastfed individuals) of 0.12[(95% confidence interval (CI): -0.19; 0.43] and 0.06 (95% CI: -0.16; 0.27) for the rs174575 and rs1535 variants, respectively. Secondary analyses corroborated these results. In studies with ≥5.85 and <5.85 months of breastfeeding duration, pooled estimates for the rs174575 variant were 0.50 (95% CI: -0.06; 1.06) and 0.14 (95% CI: -0.10; 0.38), respectively, and 0.27 (95% CI: -0.28; 0.82) and -0.01 (95% CI: -0.19; 0.16) for the rs1535 variant., Conclusions: Our findings did not support an interaction between ever breastfeeding and FADS2 polymorphisms. However, subgroup analysis suggested that breastfeeding may supply LC-PUFAs requirements for cognitive development if breastfeeding lasts for some (currently unknown) time. Future studies in large individual-level datasets would allow properly powered subgroup analyses and further improve our understanding on the breastfeeding × FADS2 interaction., (© The Author(s) 2018. Published by Oxford University Press on behalf of the International Epidemiological Association.)

The growing trend in the use of the Internet and social media as a method of self-managing illness presents a critical opportunity to better understand the role of pro-anorexia (pro-ana) websites for eating disorders. Therefore, 155 pro-ana website messages regarding criticism that the site was responsible for developing anorexia were inductively thematically analysed. The analysis revealed five main themes: eating disorders are mental illnesses and websites do not cause mental illness, pro-ana websites and eating disorders are more than wanting to be thin (with sub-theme residents and visitors), eating disorders develop regardless of pro-ana websites, pro-ana sites do not cause eating disorders but they may trigger or encourage them (with sub-theme the problem is the user, not the site) and pro-ana sites provide support. Pro-ana websites and online communities present clinicians with complex treatment challenges. Collaborative, therapeutic consultations about pro-ana website use may help to establish how and when accessing them may hinder the treatment process.

Background: Inhaled furosemide offers a potentially novel treatment for dyspnoea, which may reflect modulation of pulmonary stretch receptor feedback to the brain. Specificity of relief is unclear because different neural pathways may account for different components of clinical dyspnoea. Our objective was to evaluate if inhaled furosemide relieves the air hunger component (uncomfortable urge to breathe) but not the sense of breathing work/effort of dyspnoea., Methods: A randomised, double blind, placebo-controlled crossover trial in 16 healthy volunteers studied in a university research laboratory. Each participant received 3 mist inhalations (either 40 mg furosemide or 4 ml saline) separated by 30-60 min on 2 test days. Each participant was randomised to mist order 'furosemide-saline-furosemide' (n- = 8) or 'saline-furosemide-saline' (n = 8) on both days. One day involved hypercapnic air hunger tests (mean ± SD PCO 2  = 50 ± 3.7 mmHg; constrained ventilation = 9 ± 1.5 L/min), the other involved work/effort tests with targeted ventilation (17 ± 3.1 L/min) and external resistive load (20cmH 2 O/L/s). Primary outcome was ratings of air hunger or work/effort every 15 s on a visual analogue scale. During saline inhalations, 1.5 mg furosemide was infused intravenously to match the expected systemic absorption from the lungs when furosemide is inhaled. Corresponding infusions of saline during furosemide inhalations maintained procedural blinding. Average visual analogue scale ratings (%full scale) during the last minute of air hunger or work/effort stimuli were analysed using Linear Mixed Methods., Results: Data from all 16 participants were analysed. Inhaled furosemide relative to inhaled saline significantly improved visual analogues scale ratings of air hunger (Least Squares Mean ± SE - 9.7 ± 2%; p = 0.0015) but not work/effort (+ 1.6 ± 2%; p = 0.903). There were no significant adverse events., Conclusions: Inhaled furosemide was effective at relieving laboratory induced air hunger but not work/effort in healthy adults; this is consistent with the notion that modulation of pulmonary stretch receptor feedback by inhaled furosemide leads to dyspnoea relief that is specific to air hunger, the most unpleasant quality of dyspnoea., Funding: Oxford Brookes University Central Research Fund., Trial Registration: ClinicalTrials.gov Identifier: NCT02881866 . Retrospectively registered on 29th August 2018.

In utero exposure to the ubiquitous plasticizer, bisphenol A (BPA) is associated with offspring obesity. As food intake/appetite is one of the critical elements contributing to obesity, we determined the effects of in vivo maternal BPA and in vitro BPA exposure on newborn hypothalamic stem cells which form the arcuate nucleus appetite center. For in vivo studies, female rats received BPA prior to and during pregnancy via drinking water, and newborn offspring primary hypothalamic neuroprogenitor (NPCs) were obtained and cultured. For in vitro BPA exposure, primary hypothalamic NPCs from healthy newborns were utilized. In both cases, we studied the effects of BPA on NPC proliferation and differentiation, including putative signal and appetite factors. Maternal BPA increased hypothalamic NPC proliferation and differentiation in newborns, in conjunction with increased neuroproliferative (Hes1) and proneurogenic (Ngn3) protein expression. With NPC differentiation, BPA exposure increased appetite peptide and reduced satiety peptide expression. In vitro BPA-treated control NPCs showed results that were consistent with in vivo data (increase appetite vs satiety peptide expression) and further showed a shift towards neuronal versus glial fate as well as an increase in the epigenetic regulator lysine-specific histone demethylase1 (LSD1). These findings emphasize the vulnerability of stem-cell populations that are involved in life-long regulation of metabolic homeostasis to epigenetically-mediated endocrine disruption by BPA during early life., (Copyright © 2018. Published by Elsevier Inc.)

Antimicrobial resistance (AMR) is a global challenge facing both human and animal healthcare professionals; an effective response to this threat requires a 'One-Health' approach to antimicrobial stewardship (AMS) to preserve important antibiotics for urgent clinical need. However, understanding of barriers and enablers to effective AMS behaviour in companion animal veterinary practice is currently limited. We conducted a Delphi study of 16 nationally recognised experts from UK-based veterinary policymakers, university academics and leaders of professional bodies. This Delphi study sought to identify veterinary behaviours which experts believe contribute to AMR and form vital aspects of AMS. Analysis of Delphi findings indicated a perceived hierarchy of behaviours, the most influential being antibiotic prescribing behaviours and interactions with clients. Other veterinary behaviours perceived as being important related to interactions with veterinary colleagues; infection control practices; and the use of diagnostic tests to confirm infection. Key barriers and enablers to AMS within each of these behavioural domains were identified. Specific interventions to address important barriers and enablers are recommended. To the authors' knowledge, this is the first study to establish expert consensus at a national level about which 'behaviours' (aspects of veterinarian practice) should be targeted in relation to AMR and AMS in companion animal veterinary practice., Competing Interests: Competing interests: None declared., (© British Veterinary Association (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background and Aims: There is evidence that endocrine disrupting chemicals (EDCs) have developmental effects at environmental concentrations. We investigated whether some EDCs are associated with the adverse birth outcome Small for Gestational Age (SGA)., Methods: We used PCB 153, p,p'-DDE, HCB, PFOS and PFOA measured in maternal, cord blood or breast milk samples of 5446 mother-child pairs (subset of 693 for the perfluorinated compounds) from seven European birth cohorts (1997-2012). SGA infants were those with birth weight below the 10th percentile for the norms defined by gestational age, country and infant's sex. We modelled the association between measured or estimated cord serum EDC concentrations and SGA using multiple logistic regression analyses. We explored effect modification by child's sex and maternal smoking during pregnancy., Results: Among the 5446 newborns, 570 (10.5%) were SGA. An interquartile range (IQR) increase in PCB 153 was associated with a modestly increased risk of SGA (odds ratio (OR) of 1.05 [95% CI: 1.04-1.07]) that was stronger in girls (OR of 1.09 [95% CI: 1.04-1.14]) than in boys (OR of 1.03 [95% CI: 1.03-1.04]) (p-interaction = 0.025). For HCB, we found a modestly increased odds of SGA in girls (OR of 1.04 [95% CI: 1.01-1.07] per IQR increase), and an inverse association in boys (OR of 0.90 [95% CI: 0.85-0.95]) (p-interaction = 0.0003). Assessment of the HCB-sex-smoking interaction suggested that the increased odds of SGA associated with HCB exposure was only in girls of smoking mothers (OR of 1.18 [95% CI: 1.11-1.25]) (p-interaction = 0.055). Higher concentrations of PFOA were associated with greater risk of SGA (OR of 1.64 [95% CI: 0.97-2.76]). Elevated PFOS levels were associated with increased odds of SGA in newborns of mothers who smoked during pregnancy (OR of 1.63 [95% CI: 1.02-2.59]), while an inverse association was found in those of non-smoking mothers (OR of 0.66 [95% CI: 0.61-0.72]) (p-interaction = 0.0004). No significant associations were found for p,p'-DDE., Conclusions: Prenatal environmental exposure to organochlorine and perfluorinated compounds with endocrine disrupting properties may contribute to the prevalence of SGA. We found indication of effect modification by child's sex and smoking during pregnancy. The direction of the associations differed by chemical and these effect modifiers, suggesting diverse mechanisms of action and biological pathways., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: COMP-4 is a natural compound-based dietary supplement consisting of the combination of ginger, Paullinia cupana, muira puama and l-citrulline, which when given long-term has been shown in the aged rat to a) upregulate iNOS in the penile smooth muscle cells (SMC), b) reverse the corporal SMC apoptosis and fibrosis associated with corporal veno-occlusive dysfunction (CVOD), and c) improve resulting erectile function. To elucidate the mechanism of how COMP-4 and its individual components modulate the iNOS-cGMP pathway, an in vitro study was conducted using a rat corporal primary SMC culture to determine its effect on NOS, soluble guanylate cyclase (sGC), cGMP and the phosphodiesterase 5 enzyme (PDE5)., Materials and Methods: Primary SMC cultures using the explant technique were initiated by cutting small pieces of corporal tissue from 8 week old Sprague-Dawley rats. The SMC were grown in Dulbecco media with 20% fetal calf serum. The SMC were then incubated with or without COMP-4 (0.69 mg/ml) or its ingredients alone (ginger: 0.225 mg/ml; muira puama, Paullinia cupana and l-citrulline each at 0.9 mg/ml) for up to 24 h mRNA and protein were extracted and used for the determination of NOS, sGC and PDE5 content. cGMP content was determined by ELISA. L-NIL (4 μM) was used as an inhibitor of iNOS activity., Results: Compared to the control values, COMP-4 upregulated expression of cGMP by 85%, induced a 42 fold increase in sGC as well as a 15 fold increase in both iNOS protein and mRNA content while it decreased both PDE5 mRNA and protein content each by about 50%. L-NIL completely inhibited the effect of COMP-4 on cGMP production. When compared with each of the individual four components of COMP-4, it appears that COMP-4 itself had the most profound effect in modulating each one the specific steps within the iNOS-cGMP pathway., Conclusions: This in vitro study demonstrates that COMP-4 is capable of activating the endogenous cellular iNOS-cGMP pathway within the CSM cells, which is theorized to be responsible for reducing the fibrosis and apoptosis as well as the CVOD observed in the aging rat penis. Further studies will be necessary in order to determine whether supplementation of COMP-4 on a daily basis may be beneficial in halting or reversing this aging related erectile dysfunction in the clinical setting., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aim: To explore the concept of home and its' expressed spatialities in current palliative care research., Background: Home is a central environment for living, caring, and dying. However, pure investigations of the sets of ideas linked to the concept seemed missing. Although identified as an important location, spatial perspectives expressed through the concept of home appeared unexplored., Design: Rodgers' evolutionary concept analysis., Data Sources: Scientific articles published between January 2009 and September 2015., Review Methods: Rodgers' evolutionary concept analysis. Resulting attributes were explored from two geographically informed spatial perspectives., Results: As main results, six attributes were identified and explored: Home as actor-capable of acting; emotional environment-something people have feelings for; place-a part of personal identity and a location; space-complex and relational spatial connections and a site for care; setting-passive background and absolute space; becoming-a fluid spatiality constantly folded. Examples of attributes and suggestions for further concept development were identified., Conclusions: The concept reflects various sets of ideas as well as expressing both relational and absolute perspectives of space. The most challenging for nursing research and practice seems to be investigation, operationalization, and testing the implementation of sets of ideas reflecting a relational thinking of space., (© 2018 Wiley Periodicals, Inc.)

Background: The earliest sign of an ongoing change in a man's erectile function (EF) is the increase in his refractory period. This is due to the onset of an aging related apoptosis of the corporal smooth muscle cells (CSMC) as a result of oxidative stress (ROS) within the CSMC itself. In response, the CSMC begin to upregulate the inducible nitric oxide synthase (iNOS) enzyme presumably to achieve high levels of nitric oxide (NO) used to combat ROS. Treatment of aged rats for 2 months with the nutraceutical Revactin ® , known to stimulate the iNOS-NO-cGMP pathway in CSMC, resulted in (I) an increase in CSMC content with a decrease in corporal fibrosis, (II) decrease in systemic ROS, and (III) improvement in EF. To determine whether Revactin ® could be used in the clinical setting, a pilot safety study was conducted., Methods: Fifty-four middle aged men (mean age 57.8±10.7; range, 33-77 years) were recruited for this safety study. Patients were given Revactin ® twice daily (total daily dose of 500 mg of ginger root, muira puama, and Paullinia cupana and 1,600 mg of L-citrulline) and were asked to complete the IIEF-15 questionnaire [domains: EF, orgasmic function (OF), sexual desire (SD), intercourse satisfaction (IS), overall satisfaction (OS)] at baseline (B), 1 month (M1), 2 months (M2) and 3 months (M3) and report any side effects. Those on erectogenic medications at B were requested to stop taking them during the trial. Data were analyzed using Wilcoxon paired test and Friedman rank test for trend., Results: Revactin ® was safe with only 5 patients reporting treatment side effects (e.g., dyspepsia, heartburn, migraine) and none considered severe. For those who stayed on the regimen (M1 =32; M2 =22; M3 =16), there was an increase in median domain scores for EF, OF, SD, IS, and OS over 3 months compared to baseline median scores but statistical significance was found only in the EF, IS, and OS median domain scores. Trend analysis indicated significant trend in EF, OS & IS (P<0.05). For the EF domain, the median scores were: M1 =21, M2 =22, M3 =19 relative to the B =16, 15.5, and 14.5, respectively (P<0.05). Overall, approximately 50% of the patients reported a significant improvement in EF (P<0.05). The major reason for trial discontinuation (M1 =22, M2 =9 and M3 =6) was non-compliance with pro-erectile medications., Conclusions: Revactin ® , a combination of 3 nutraceuticals packaged with L-citrulline, appears to have the same excellent safety profile known for each of its individual four components. The early improvement in EF seen in about 50% of these patients may be due to the elevated levels of cGMP produced via this iNOS-cGMP pathway. Further longitudinal studies with Revactin ® appear warranted., Competing Interests: Conflicts of Interest: J Rajfer is a stockholder in KLRM, LLC which supplied Revactin for the study and has a US patent pending on Revactin®. The other authors have no conflicts of interest to declare.

Background: Remote monitoring in obstetrics is relatively new; some studies have shown its effectiveness for both mother and child. However, few studies have evaluated the economic impact compared to conventional care, and no cost analysis of a remote monitoring prenatal follow-up program for women diagnosed with gestational hypertensive diseases (GHD) has been published., Objective: The aim of this study was to assess the costs of remote monitoring versus conventional care relative to reported benefits., Methods: Patient data from the Pregnancy Remote Monitoring (PREMOM) study were used. Health care costs were calculated from patient-specific hospital bills of Ziekenhuis Oost-Limburg (Genk, Belgium) in 2015. Cost comparison was made from three perspectives: the Belgian national health care system (HCS), the National Institution for Insurance of Disease and Disability (RIZIV), and costs for individual patients. The calculations were made for four major domains: prenatal follow-up, prenatal admission to the hospital, maternal and neonatal care at and after delivery, and total amount of costs. A simulation exercise was made in which it was calculated how much could be demanded of RIZIV for funding the remote monitoring service., Results: A total of 140 pregnancies were included, of which 43 received remote monitoring (30.7%) and 97 received conventional care (69.2%). From the three perspectives, there were no differences in costs for prenatal follow-up. Compared to conventional care, remote monitoring patients had 34.51% less HCS and 41.72% less RIZIV costs for laboratory test results (HCS: mean €0.00 [SD €55.34] vs mean €38.28 [SD € 44.08], P<.001; RIZIV: mean €21.09 [SD €27.94] vs mean €36.19 [SD €41.36], P<.001) and a reduction of 47.16% in HCS and 48.19% in RIZIV costs for neonatal care (HCS: mean €989.66 [SD €3020.22] vs mean €1872.92 [SD €5058.31], P<.001; RIZIV: mean €872.97 [SD €2761.64] vs mean €1684.86 [SD €4702.20], P<.001). HCS costs for medication were 1.92% lower in remote monitoring than conventional care (mean €209.22 [SD €213.32] vs mean €231.32 [SD 67.09], P=.02), but were 0.69% higher for RIZIV (mean €122.60 [SD €92.02] vs mean €121.78 [SD €20.77], P<.001). Overall HCS costs for remote monitoring were mean €4233.31 (SD €3463.31) per person and mean €4973.69 (SD €5219.00) per person for conventional care (P=.82), a reduction of €740.38 (14.89%) per person, with savings mainly for RIZIV of €848.97 per person (23.18%; mean €2797.42 [SD €2905.18] vs mean €3646.39 [SD €4878.47], P=.19). When an additional fee of €525.07 per month per pregnant woman for funding remote monitoring costs is demanded, remote monitoring is acceptable in their costs for HCS, RIZIV, and individual patients., Conclusions: In the current organization of Belgian health care, a remote monitoring prenatal follow-up of women with GHD is cost saving for the global health care system, mainly via savings for the insurance institution RIZIV., (©Dorien Lanssens, Thijs Vandenberk, Christophe JP Smeets, Hélène De Cannière, Sharona Vonck, Jade Claessens, Yenthel Heyrman, Dominique Vandijck, Valerie Storms, Inge M Thijs, Lars Grieten, Wilfried Gyselaers. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 26.03.2018.)

The authors hypothesized that the risk of cerebral palsy at 2 years in children born extremely preterm to overweight and obese women is increased relative to the risk among children born to neither overweight nor obese women. In a multicenter prospective cohort study, the authors created multinomial logistic regression models of the risk of diparetic, quadriparetic, and hemiparetic cerebral palsy that included the prepregnancy body mass index of mothers of 1014 children born extremely preterm, cerebral palsy diagnoses of children at 2 years, as well as information about potential confounders. Overweight and obese women were not at increased risk of giving birth to a child who had cerebral palsy. The risk ratios associated with overweight varied between 1.1 for quadriparesis (95% CI = 0.5, 2.1) to 2.0 for hemiparesis (95% CI = 0.4, 9.8). The risk ratios associated with obesity varied between 0.7 for diparesis (95% CI = 0.2, 2.5) to 2.5 for hemiparesis (95% CI = 0.4, 13).

Background: Maternal pre-pregnancy obesity, in term-born children, is associated with an increased risk of attention problems, however this relationship has not been explored among children born extremely preterm., Aim: To estimate the risk of attention problems at age 10years in children born very preterm to overweight (i.e., body mass index (BMI) 25-29kg/m 2 ) and obese (i.e., BMI≥30kg/m 2 ) women relative to the risk among children born to women who were neither overweight nor obese (i.e. BMI<25kg/m 2 )., Study Design: Multi-center prospective cohort study., Methods: A total of 764 children born before the 28th week of gestation and whose mother's pre-pregnancy height and pre-pregnancy weight were obtained at birth had an IQ≥70 at age 10years when parents and teachers completed Child Symptom Inventory-4 questionnaires that included items about the presence of ADHD., Results: Compared to children whose mother's pre-pregnancy weight was in the normal range (BMI<25kg/m 2 ), children were at increased risk of parent-identified ADHD behaviors if their mother was overweight (odds ratio (OR)=1.9; 95% confidence interval (CI): 1.1, 3.3), or obese (OR=2.3; 95% CI: 1.4, 3.9). They were not at increased risk of teacher-identified ADHD characteristics if their mother was overweight before her pregnancy (OR=1.0; 95% CI: 0.6, 1.8), or obese (OR=1.0; 95% CI: 0.6, 1.6)., Conclusion: Maternal overweight and obesity are associated with increased risk of parent-identified ADHD characteristics at 10years of age in children born extremely preterm., (Copyright © 2017. Published by Elsevier B.V.)

Background: The World Health Organization recommends benzylpenicillin and gentamicin as antimicrobial treatment for infants with sepsis in low-income settings, and ceftriaxone or cefotaxime as an alternative. In a meta-analysis from 13 low-income settings, Staphylococcus aureus, Klebsiella spp. and Escherichia coli accounted for 55% of infants with sepsis. In a review of bacterial meningitis, resistance to third generation cephalosporins was >50% of all isolates, and 44% of Gram-negative isolates were gentamicin resistant. However, ceftriaxone may cause neonatal jaundice, and gentamicin may cause deafness. Therefore, we compared parenteral benzylpenicillin plus gentamicin with ceftriaxone as first-line treatment, assessing outcome and adverse events., Methods: This was an open randomized trial carried out in the Queen Elizabeth Central Hospital, Blantyre, Malawi, from 2010 to 2013. Infants <60 days of age with possible severe sepsis received either benzylpenicillin and gentamicin or ceftriaxone. Adverse events and outcomes were recorded until 6 months post discharge., Results: Three-hundred forty-eight infants were included in analyses. Outcome in the benzylpenicillin and gentamicin and ceftriaxone groups was similar; deaths were 13.7% and 16.5% and sequelae were 14.5% and 11.2%, respectively. More infants in the penicillin/gentamicin group required phototherapy: 15% versus 5%, P = 0.03. Thirteen (6%) survivors had bilateral hearing loss. There was no difference between the treatment groups. By 6 months post discharge, 11 more infants had died, and 17 more children were found to have sequelae., Conclusions: Ceftriaxone and gentamicin are safe for infants in our setting. Infants should receive long-term follow-up as many poor outcomes occurred after hospital discharge.

Adverse outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory purposes. AOP links a molecular initiating event (MIE) to the adverse outcome (AO) via key events (KE), in a way specified by key event relationships (KER). Although this approach to formalize mechanistic toxicological information only started in 2010, over 200 AOPs have already been established. At this stage, new requirements arise, such as the need for harmonization and re-assessment, for continuous updating, as well as for alerting about pitfalls, misuses and limits of applicability. In this review, the history of the AOP concept and its most prominent strengths are discussed, including the advantages of a formalized approach, the systematic collection of weight of evidence, the linkage of mechanisms to apical end points, the examination of the plausibility of epidemiological data, the identification of critical knowledge gaps and the design of mechanistic test methods. To prepare the ground for a broadened and appropriate use of AOPs, some widespread misconceptions are explained. Moreover, potential weaknesses and shortcomings of the current AOP rule set are addressed (1) to facilitate the discussion on its further evolution and (2) to better define appropriate vs. less suitable application areas. Exemplary toxicological studies are presented to discuss the linearity assumptions of AOP, the management of event modifiers and compensatory mechanisms, and whether a separation of toxicodynamics from toxicokinetics including metabolism is possible in the framework of pathway plasticity. Suggestions on how to compromise between different needs of AOP stakeholders have been added. A clear definition of open questions and limitations is provided to encourage further progress in the field.

Background: DNA-PK and PARP inhibitors sensitize cancer cells to chemo- and radiotherapy. ETS transcription factors (EWS-FLI1) have been described as biomarkers for PARP-inhibitor sensitivity. Sensitivity to single agent PARP inhibitors has so far been limited to homologous recombination repair (HRR) deficient tumors, exploiting synthetic lethality., Results: In clonogenic assays, single agent rucaparib LD 50 values for continuously exposed cells were similar to those observed in HRR-defective cells (CAPAN-1 cell line, BRCA2 defective); however, both ES cell lines (TC-71, CADO-ES1) had functional HRR. In vivo rucaparib administration (10 mg/kg daily) showed no responses. In clonogenic assays, rucaparib enhanced temozolomide, camptothecin and radiation cytotoxicity, which was most profound for temozolomide (15-29 fold enhancement). NU7441 increased the cytotoxicity of etoposide, doxorubicin and radiation., Materials and Methods: We assessed PARP1/2 (rucaparib) and DNA-PK (NU7441) inhibitors in Ewing sarcoma (ES) cell lines by performing growth inhibition and clonogenic assays. HRR was measured by RAD51 focus formation. Single agent rucaparib was assessed in an in vivo orthotopic model., Conclusions: Single agent rucaparib ES sensitivity in vitro was not replicated in vivo . DNA-PK and PARP inhibitors are good chemo-/radiosensitizers in ES. The future of these inhibitors lies in their combination with chemo-/radiotherapy, which needs to be evaluated in clinical trials., Competing Interests: CONFLICTS OF INTEREST The authors BV, YTS, HB, AS and SW have no conflict of interest to declare. The senior author (NC) declares that she has received research funding from Pfizer in connection with rucaparib in the past, and DRN has received (AstraZeneca) or is currently in receipt (Astex Pharmaceuticals) of funding to develop DNA PK inhibitors. DRN and NC are named as inventors on the patent describing the discovery of rucaparib and receive remuneration in line with Institutional policy covering Rewards to Inventors.

Background: fetal Alcohol Spectrum Disorders is a term used to describe a range of physical, cognitive and behavioural deficits in the offspring of women who drank alcohol during pregnancy. A growing body of evidence suggests alcohol consumption in the presence of poor maternal nutrition may increase the risk of harm to the developing fetus., Objective: to investigate relationships between maternal dietary patterns and alcohol consumption, and explore which factors influence women's decisions about what to eat and drink during pregnancy., Design: a mixed methods study comprising a questionnaire (paper-based and online) and semi-structured, in-depth interviews with a sub-sample of women who completed the questionnaire., Participants: women were eligible for inclusion if they were ≥16 years of age, pregnant and living in the UK and were recruited through antenatal clinics, specialist substance misuse antenatal clinics or via social media platforms; 350 women completed a questionnaire and a sub-sample of 6 women participated in an interview., Methods: the questionnaire comprised the Alcohol Use Disorders Identification Test Consumption to measure alcohol consumption patterns and a Food Frequency Questionnaire to measure dietary intake. Dietary pattern analysis was conducted using Principle Components Analysis and linear regression models were used to explore relationships between dietary pattern scores and alcohol consumption. Analyses were adjusted for socio-demographic and lifestyle characteristics. Semi-structured, in-depth interviews were conducted face-to-face and analysed thematically., Findings: two key dietary patterns were derived. Women who reported frequent alcohol consumption before and during pregnancy were more likely to adhere to the 'Prudent' dietary pattern compared to those who abstained. No relationships were observed between alcohol consumption and adherence to the 'Cafeteria' dietary pattern. Six key themes were identified through the qualitative analysis: (1) pregnancy as a time to review behaviour; (2) listen to your body - it will tell you what you need; (3) treats are still important - on special occasions; (4) social and cultural expectations constrain behaviour; (5) inconsistent or ambiguous information creates uncertainty; and 6) confidence increases following a successful pregnancy., Conclusions: those who drink low levels of alcohol during pregnancy may have better quality diets compared to women who report no alcohol consumption. The reasons for this are complex and influenced by social context and previous pregnancy experience, which should be considered when healthcare professionals provide advice during this period., (Copyright © 2017. Published by Elsevier Ltd.)

Objective: To assess the association between maternal prepregnancy body mass index and adequacy of pregnancy weight gain in relation to neurocognitive function in school-aged children born extremely preterm., Study Design: Study participants were 535 ten-year-old children enrolled previously in the prospective multicenter Extremely Low Gestational Age Newborns cohort study who were products of singleton pregnancies. Soon after delivery, mothers provided information about prepregnancy weight. Prepregnancy body mass index and adequacy of weight gain were characterized based on this information. Children underwent a neurocognitive evaluation at 10 years of age., Results: Maternal prepregnancy obesity was associated with increased odds of a lower score for Differential Ability Scales-II Verbal IQ, for Developmental Neuropsychological Assessment-II measures of processing speed and visual fine motor control, and for Wechsler Individual Achievement Test-III Spelling. Children born to mothers who gained an excessive amount of weight were at increased odds of a low score on the Oral and Written Language Scales Oral Expression assessment. Conversely, children whose mother did not gain an adequate amount of weight were at increased odds of a lower score on the Oral and Written Language Scales Oral Expression and Wechsler Individual Achievement Test-III Word Reading assessments., Conclusion: In this cohort of infants born extremely preterm, maternal obesity was associated with poorer performance on some assessments of neurocognitive function. Our findings are consistent with the observational and experimental literature and suggest that opportunities may exist to mitigate risk through education and behavioral intervention before pregnancy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

RI is an emergent trilingual boy, literate in Greek and English, with difficulties in reading and spelling in both languages. Assessment with non-literacy tests revealed a deficit in phonological ability and in visual memory for sequentially presented characters. RI took part in a training programme that targeted sublexical spelling processes. Post-intervention assessment revealed improvement in reading and spelling in Greek but not in English. Assessments of lexical and sublexical skills showed improvement in nonword spelling and nonword reading for Greek. For English, there was some indication of improvement in nonword reading at delayed post-intervention testing, but no evidence of improvement in nonword spelling. Possible reasons for the difference in outcome for the two languages are considered, including the level of transparency of written Greek and English.

Background: Large general population surveys show that heavy regular and episodic alcohol consumption are associated with lower intakes of fruits and vegetables, and higher intakes of processed and fried meat. This is of particular concern regarding pregnant women, as both alcohol intake and inadequate maternal nutrition are independently associated with adverse fetal outcomes. The current study aimed to determine associations between maternal dietary patterns and alcohol consumption during pregnancy., Methods: Women were participating in the Avon Longitudinal Study of Parents and Children, and provided details of alcohol consumption at 18 weeks' gestation and diet at 32 weeks' gestation (n = 9,839). Dietary patterns were derived from the food frequency questionnaire data using principal components analysis. Associations between alcohol consumption and dietary patterns were determined using multiple linear regression, adjusted for various sociodemographic and lifestyle factors., Results: After adjustment, drinking ≥1 unit/d during the first trimester (β = 0.23 [95% CI: 0.08, 0.38]; p = 0.002) and binge drinking (≥4 units in 1 day) during the first half of pregnancy (β = 0.14 [95% CI: 0.07, 0.21]; p < 0.0001) were associated with greater adherence to the "Processed" dietary pattern (high intakes of processed meat and low intakes of fruit and vegetables). Light-to-moderate alcohol consumption (≤1 drink/d) during the first trimester was associated with greater adherence to the "Health conscious" dietary pattern (high intakes of fruit, vegetables, whole grains, and fish) (β = 0.09 [95% CI: 0.04, 0.14]; p < 0.0001)., Conclusions: Two important components of health behavior during pregnancy appear to be related: greater consumption of processed foods associated with heavier alcohol consumption, and healthier dietary choices associated with light-to-moderate alcohol intake. Potential synergistic effects of these behaviors may have implications for maternal and fetal health and warrant further investigation. A more holistic approach to addressing health behaviors in women of reproductive age is required., (Copyright © 2017 by the Research Society on Alcoholism.)

There has been limited research studying neighbourhood support for caregivers. Therefore, the aim of the present study was to investigate the support from neighbourhoods between both caregivers and non-caregivers in a country-wide and population-based setting. Data were retrieved from England Community Life Survey, 2012-2014, a new annual household survey conducted by face-to-face interview since 2012, with a representative sample size of 5-6000 adult (aged 16 years and over) resident per year in England. Chi-square test and logistic regression modelling were performed to examine the variance in support from and perception toward neighbourhoods between caregivers and non-caregivers. Of 15,320 study participants, 2315 (16.0%) had a caring responsibility. There was not much variance in feeling belonging, comfortably asking neighbours to keep keys, comfortably asking neighbours to mind children, believing neighbours pulling together and trusting people in the neighbourhood between caregivers and non-caregivers. However, caregivers seemed to be more likely to chat to neighbours (OR 0.77, 95% CI 0.69-0.87, P < 0.001) and comfortably ask neighbours to help collect grocery (OR 0.89, 95% CI 0.81-0.98, P = 0.023). In addition, caregivers tended to perceive their neighbourhoods unsatisfactory (OR 1.17, 95% CI 1.05-1.32, P = 0.007) and worsened in the last 2 years (OR 1.36, 95% CI 1.22-1.51, P < 0.001). For future research, a longitudinal neighbourhood monitoring surveillance for all people would be suggested. For practice and policy, environmental health and nursing programs might need to extend education trainings and interventions to cover all neighbourhoods at different time points that can lessen both disease and caregiving burden and therefore optimize health and quality of life.

Erectile dysfunction (ED) will visit every man at some time in his life. The age at when that knock on the door is heard is totally dependent on one's genetics as well as other extrinsic factors. Unlike guests who come for a visit and then leave, once ED shows up it tends to hang around forever. To add insult to injury, the longer ED hangs around, the worse it will get. It is estimated that by the time a man is in his 40's, he has about a 40% chance of having some form of ED and this prevalence increases about 10% per decade thereafter. This suggests that the aging related process that leads to ED begins early in life. It turns out that the most common cause of ED, regardless of the patient's age, is due to a problem with the vascular system of the penis. However, this specific aging related vascular problem is not caused by arterial disease but due to a dysfunction and/or loss of the corporal smooth muscle cells (SMC), the main constituent of the corporal sinusoids. As one gets older, these SMC continue to degrade and disappear. When approximately 15% of these cells have been impacted, it results in an inability of the corporal tissue to retain and/or prevent the blood from "leaking" out of the corporal sinusoids into the systemic veins. However, the corporal SMC themselves begin to combat this aging process by expressing the inducible nitric oxide synthase (iNOS) enzyme to make nitric oxide (NO) in an attempt to quench the high intracellular oxidative stress responsible for the SMC apoptosis. When this iNOS pathway is then pharmacologically upregulated, reversal of these aging related changes in the corpora with correction of the venous leakage is observed. Since we believe that aging related ED is pathologically the same disorder as essential hypertension, the development of a therapeutic regimen that can halt, delay or possibly reverse the cellular processes that lead to aging related ED should also be applicable to those patients diagnosed with essential hypertension., Competing Interests: Conflicts of Interest: JR is one of the founders of KLRM, LLC, Long Beach, CA, USA. The other authors have no conflicts of interest to declare.

Objectives: We investigated the effects on fracture healing of two up-regulators of inducible nitric oxide synthase (iNOS) in a rat model of an open femoral osteotomy: tadalafil, a phosphodiesterase inhibitor, and the recently reported nutraceutical, COMB-4 (consisting of L-citrulline, Paullinia cupana, ginger and muira puama), given orally for either 14 or 42 days., Materials and Methods: Unilateral femoral osteotomies were created in 58 male rats and fixed with an intramedullary compression nail. Rats were treated daily either with vehicle, tadalafil or COMB-4. Biomechanical testing of the healed fracture was performed on day 42. The volume, mineral content and bone density of the callus were measured by quantitative CT on days 14 and 42. Expression of iNOS was measured by immunohistochemistry., Results: When compared with the control group, the COMB-4 group exhibited 46% higher maximum strength ( t -test, p = 0.029) and 92% higher stiffness ( t -test, p = 0.023), but no significant changes were observed in the tadalafil group. At days 14 and 42, there was no significant difference between the three groups with respect to callus volume, mineral content and bone density. Expression of iNOS at day 14 was significantly higher in the COMB-4 group which, as expected, had returned to baseline levels at day 42., Conclusion: This study demonstrates an enhancement in fracture healing by an oral natural product known to augment iNOS expression. Cite this article: R. A. Rajfer, A. Kilic, A. S. Neviaser, L. M. Schulte, S. M. Hlaing, J. Landeros, M. G. Ferrini, E. Ebramzadeh, S-H. Park. Enhancement of fracture healing in the rat, modulated by compounds that stimulate inducible nitric oxide synthase: Acceleration of fracture healing via inducible nitric oxide synthase. Bone Joint Res 2017:6:-97. DOI: 10.1302/2046-3758.62.BJR-2016-0164.R2., (© 2017 Park et al.)

Background: ECCO essential requirements for quality cancer care (ERQCC) are checklists and explanations of organisation and actions that are necessary to give high-quality care to patients who have a specific tumour type. They are written by European experts representing all disciplines involved in cancer care. ERQCC papers give oncology teams, patients, policymakers and managers an overview of the elements needed in any healthcare system to provide high quality of care throughout the patient journey. References are made to clinical guidelines and other resources where appropriate, and the focus is on care in Europe. Sarcoma: essential requirements for quality care • Sarcomas - which can be classified into soft tissue and bone sarcomas - are rare, but all rare cancers make up more than 20% of cancers in Europe, and there are substantial inequalities in access to high-quality care. Sarcomas, of which there are many subtypes, comprise a particularly complex and demanding challenge for healthcare systems and providers. This paper presents essential requirements for quality cancer care of soft tissue sarcomas in adults and bone sarcomas. • High-quality care must only be carried out in specialised sarcoma centres (including paediatric cancer centres) which have both a core multidisciplinary team and an extended team of allied professionals, and which are subject to quality and audit procedures. Access to such units is far from universal in all European countries. • It is essential that, to meet European aspirations for high-quality comprehensive cancer control, healthcare organisations implement the requirements in this paper, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis and follow-up, to treatment, to improve survival and quality of life for patients., Conclusion: Taken together, the information presented in this paper provides a comprehensive description of the essential requirements for establishing a high-quality service for soft tissue sarcomas in adults and bone sarcomas. The ECCO expert group is aware that it is not possible to propose a 'one size fits all' system for all countries, but urges that access to multidisciplinary teams is guaranteed to all patients with sarcoma., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

The increasing number of children suffering from developmental disorders has raised questions regarding their association with the presence of environmental contaminants in mothers and children. We therefore developed a new method for the determination of 78 proven and potential developmental neurotoxicants, including polychlorinated biphenyls, legacy pesticides, pyrethroids, and old and new halogenated flame retardants in breast milk. The essential part of sample preparation was dialysis as a non-destructive clean-up step which was newly used at 10 °C and showed more efficient lipid removal (up to 96%) than the conventional methods such as gel permeation chromatography or freezing-lipid filtration and thus ensured low limits of detection (LOD) by reducing the sample volume prior to injection. Next advantages were significant solvent reduction and no risk of sample cross-contamination. Gas chromatography coupled with high resolution mass spectrometry (GC-HRMS) was subsequently used for the separation and compound quantification. The method was validated using breast milk samples fortified with the analyzed compounds. Recoveries for most of the compounds ranged from 63 to 121% with a relative standard deviation of 2-25%, and LODs ranged between 0.001 and 0.87 ng g -1 lipid weight. The method was applied to breast milk samples from a Dutch birth cohort where 35 out of the 78 compounds were quantified in more than 60% of the samples. For novel flame retardants, the method provides unique results regarding their occurrence in human matrices in Europe. Overall, the analysis of a complex mixture of developmental neurotoxicants could be useful for the assessment of the influence of the studied compounds to child health and development. Graphical abstract Flow diagram of the method and levels of the developmental neurotoxicants in Dutch human milk samples.

Background: People with severe mental illness (PWSMI) die 15-20 years earlier than people in the general population and this is often due to preventable smoking-related health conditions. Studies that identify barriers and facilitators to smoking cessation are crucial for policy makers and health care professionals., Aims: This appraisal aims to identify and critically appraise qualitative studies which explore smoking experiences and barriers to smoking cessation among PWSMI., Method: Articles were retrieved from electronic health related databases including Web of Science, Scopus, PubMed, Sage, Biomed, Medline, Embase, and electronic hand searches of bibliographies from key articles., Results: Eleven papers were identified. Although the overall quality of studies were sufficient, most had limited information relating to trustworthiness and sociodemographic details. Cost savings and health benefits were frequently cited as facilitators to quitting, however may be of limited impact as smoking for existential purposes, social inclusion, and mental health management appear to be considered highly important among PWSMI., Conclusions: Findings were restricted to predominantly individual barriers to smoking cessation which may be more resistant to change as service users rely on smoking to manage their mental health and smoking is embedded in the culture of mental health settings., Implications: This critical appraisal identifies qualitative evidence regarding which factors facilitate or prevent individuals with severe mental illness from engaging with smoking cessation. Healthcare professionals and policy makers should address external barriers to quitting smoking as this may increase participation in intervention studies, inform policy and assist in the development of a feasible and acceptable smoking cessation intervention among PWSMI. Methodological considerations highlight that future research should include sociodemographic and contextual factors to improve utility and applicability of findings., (© The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Risk prediction models for cardiovascular death are important for providing advice on lifestyle and in decision-making regarding primary preventive drug treatment. The latest Swedish version of the Systematic COronary Risk Evaluation (SCORE 2015) has yet not been tested in the population., Objective: The objective of this study was to estimate the prevalence of high and very high risk of fatal cardiovascular disease (CVD) of the current population according to 2015 SCORE Sweden and to evaluate the predictive accuracy of the 2003 Swedish version of SCORE (2003 SCORE Sweden) and 2015 SCORE Sweden in a population with declining CVD mortality., Methods: We estimated the high and very high risk group for cardiovascular death for individuals 40-65 years of age in the 2014 Northern Sweden MONICA population survey excluding subjects with known diabetes or previous CVD (n = 813). Using the 1999 MONICA survey (n = 3347) followed up for 10 years for CVD mortality, we assessed the calibration of both 2003 and 2015 SCORE Sweden., Results: In 2014 2.6% of the population was considered at high or very high risk for fatal CVD, 95% were men and 76% were in the age group 60-65 years. Including subjects with a single markedly elevated risk factor, known diabetes or CVD, 12% of the population was at high or very high risk. During 10 years of follow-up of the 1999 cohort, 34 CVD deaths (24 men and 10 women) occurred. The 2003 SCORE overestimated the risk of death from CVD (ratio predicted/observed 2.3, P < 0.001) whereas the 2015 SCORE slightly overestimated the number of deaths (predicted/observed 1.3, P = 0.12). The 2015 SCORE predicted more accurately than the 2003 SCORE the number of deaths in the different risk and age categories., Conclusion: The 2015 SCORE Sweden more adequately than 2003 SCORE Sweden predicts the number of deaths. In 2014, the proportion of high-risk individuals is small in northern Sweden. The main use of 2015 SCORE Sweden would therefore be as an educational tool between the physician and people without diabetes or CVD in a consultation regarding cardiovascular risk., (© The European Society of Cardiology 2016.)

Hefzibah Eyal-Giladi was a creative and innovative pioneering scientist in the creation of the field of early chick embryo development. She had a sharp thinking and enthusiastic attitude, which enabled her to make a deep impression that was highly valued by the general scientific community. Notably, she was a highly successful female researcher in an era which was dominated by male scientists. Her unique personality and keen intellect enabled her to break these borders in a most successful manner. The experiments conducted by her personally, her students and her collaborators served to provide the basic knowledge and paradigms for future scientists in the field, also paving the way for discoveries in other vertebrate model systems. The experimental embryology assays she performed were "old school", examining embryos and explants at a precise morphological level of tissue interactions. In recent years, most of the experimentation in embryology has shifted to molecular and genetic levels. However, the results obtained with these technologically advanced research tools still re-confirm the fundamental findings obtained by Eyal-Giladi using "classic" experimental embryology techniques. Finally, Hefzibah Eyal-Giladi was an outstanding teacher and lecturer. For five decades, she trained and taught generations of undergraduate and graduate students in Israel, exposing them to the field of embryology and developmental biology in the most exciting and enthusiastic way.

Background: In recent years, prevalence rates of behavioral disorders in children have increased. One factor possibly implied in the etiology of behavioral disorders is exposure to perfluoroalkyl substances (PFASs). The use of PFASs is highly integrated into everyday life, and exposure is ubiquitous. Exposure to PFASs during early life may be particularly harmful, as it represents a critical time window for brain development. However, research in the area is limited, especially among preschool children. The objective of the current study was to explore the relationship between prenatal exposure to several PFASs and behavioral development at the age of 18 months., Methods: Data from the Dutch cohort LINC (Linking Maternal Nutrition to Child Health) were used. Perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) were measured in cord plasma. The total exposure of PFASs was also calculated (ΣPFASs). Behavioral development was assessed with the Child Behavior Checklist 1.5-5 (CBCL 1.5-5). The CBCL scales "Attention Deficit Hyperactivity Disorder" (ADHD) and "Externalizing problems" were used for further analysis. Separate regression models were composed for each combination, in which exposure levels were classified in tertiles. Both whole population and sex-stratified analyses were performed. A family history of ADHD, the educational level, smoking or using alcohol or illicit drugs during pregnancy were considered as confounders. In total, data from 76 mother-child pairs was included., Results: No significant associations were found between prenatal PFAS exposure and ADHD scores in the whole population and in the sex-stratified analyses. With regard to externalizing behavior, a significant negative association was found between the highest levels of ΣPFAS exposure and externalizing problem behavior in the whole population, but only in the crude model. After stratifying for sex, boys in the second and third tertile of exposure to PFOA presented significantly lower scores on the Externalizing Problem Scale than boys with the lowest exposure levels in the adjusted model. Girls exposed to higher levels of ΣPFAS exposure (T2) showed significantly lower scores on the Externalizing Problem Scale, in both crude and adjusted models. No significant associations with PFOS were found., Conclusions: RESULTS from the current study show that prenatal exposure to PFOA was negatively related to externalizing behavior in boys. RESULTS were different for boys and girls, emphasizing that mechanisms at work might be sex-dependent. However, results should be interpreted with caution as the sample size was small.

Children of obese mothers are at increased risk of developmental adversities. Maternal obesity is linked to an inflammatory in utero environment, which, in turn, is associated with neurodevelopmental impairments in the offspring. This is an integrated mechanism review of animal and human literature related to the hypothesis that maternal obesity causes maternal and fetal inflammation, and that this inflammation adversely affects the neurodevelopment of children. We propose integrative models in which several aspects of inflammation are considered along the causative pathway linking maternal obesity with neurodevelopmental limitations.