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Antagonists of retinol-binding protein 4 (RBP4) impede ocular uptake of serum all-trans retinol (1) and have been shown to reduce cytotoxic bisretinoid formation in the retinal pigment epithelium (RPE), which is associated with the pathogenesis of both dry age-related macular degeneration (AMD) and Stargardt disease. Thus, these agents show promise as a potential pharmacotherapy by which to stem further neurodegeneration and concomitant vision loss associated with geographic atrophy of the macula. We previously disclosed the discovery of a novel series of nonretinoid RBP4 antagonists, represented by bicyclic [3.3.0]-octahydrocyclopenta[c]pyrrolo analogue 4. We describe herein the utilization of a pyrimidine-4-carboxylic acid fragment as a suitable isostere for the anthranilic acid appendage of 4, which led to the discovery of standout antagonist 33. Analogue 33 possesses exquisite in vitro RBP4 binding affinity and favorable drug-like characteristics and was found to reduce circulating plasma RBP4 levels in vivo in a robust manner (>90%).

Through medicinal chemistry lead optimization studies focused on calculated properties and guided by X-ray crystallography and computational modeling, potent pan-JNK inhibitors were identified that showed submicromolar activity in a cellular assay. Using in vitro ADME profiling data, 9t was identified as possessing favorable permeability and a low potential for efflux, but it was rapidly cleared in liver microsomal incubations. In a mouse pharmacokinetics study, compound 9t was brain-penetrant after oral dosing, but exposure was limited by high plasma clearance. Brain exposure at a level expected to support modulation of a pharmacodynamic marker in mouse was achieved when the compound was coadministered with the pan-cytochrome P450 inhibitor 1-aminobenzotriazole.

Taiwan has one of the lowest fertility rates in Asia. High direct and indirect costs of childbearing have been identified as key drivers behind this at the macro-level, but little is known about the mechanism of these influences at the individual-level. In 32 qualitative interviews with parents in Taipei, we sought to explore the salient factors for couples in their decisions about having further children. We identified a tension between gendered expectations of childcare responsibilities and women's desire to ‘build a life of one's own’ – a life with options and the freedom to pursue career and social aspirations. Based on our grounded analysis, we reflect on the high relevance of individualisation, risk society and incomplete gender revolution theories for understanding why many couples – and women in particular – choose to cease childbearing at parity one.

Unintentional injury is an important cause of infant and child hospitalisation and parents play a key role in reducing children's risk-taking behaviour. Studies show that maternal and paternal parenting and supervision of children differ, but there is little research showing how fathers’ parenting may influence children's tendency to engage in risk-taking behaviour. Recent theoretical developments suggest that father's parenting may be particularly effective in encouraging safe risk taking. In this study, we examine how well parenting practices typically undertaken by fathers predict rates of children's injury risk at three years. Questionnaire data were collected from 46 fathers. Results show that both duration of rough-and-tumble play and fathers’ encouragement of perseverance predicted lower rates of injury behaviours, while their stimulation of risk taking predicted higher rates of injury behaviours. The results are discussed in the light of developmentally appropriate risk taking and fathering.

Although there is increasing evidence of paternal influence on child outcomes such as language and cognition, researchers are not yet clear on the features of father-child play that are most valuable in terms of child development. Physical play such as rough and tumble play (RTP) is a favored type of father-child play in Western societies that has been linked to children's socioemotional competence. It is important, therefore, to determine the implications of this play for child development. In this review and meta-analysis, associations between father-child physical play and child behavior were examined. The review also focused on study methods. Sixteen studies are reviewed, N = 1,521 father-child dyads, 35% boys. Study characteristics such as definitions of physical play, play settings, play measures, and coding were examined. The meta-analysis found weak to moderate population effects for links between father-child physical play and child aggression, social competence, emotional skills, and self-regulation. Research investigating the effect of father-child physical play on children's development will be improved when definitions clearly identify the nature of play, settings facilitate boisterous play, and measures include frequency and quality of play interactions. This play shows promise as an enhancer of positive father-child relationships and a catalyst for child development.

We present a new conceptual framework for studying trajectories to obtaining abortion-related care. It assembles for the first time all of the known factors influencing a trajectory and encourages readers to consider the ways these macro- and micro-level factors operate in multiple and sometimes conflicting ways. Based on presentation to and feedback from abortion experts (researchers, providers, funders, policymakers and advisors, advocates) (n = 325) between 03/06/2014 and 22/08/2015, and a systematic mapping of peer-reviewed literature (n = 424) published between 01/01/2011 and 30/10/2017, our framework synthesises the factors shaping abortion trajectories, grouped into three domains: abortion-specific experiences, individual contexts, and (inter)national and sub-national contexts. Our framework includes time-dependent processes involved in an individual trajectory, starting with timing of pregnancy awareness. This framework can be used to guide testable hypotheses about enabling and inhibiting influences on care-seeking behaviour and consideration about how abortion trajectories might be influenced by policy or practice. Research based on understanding of trajectories has the potential to improve women's experiences and outcomes of abortion-related care.

Political and academic concern that care for older adults in Sub-Saharan Africa is insufficient and under strain in light of changing demography and society is long standing (UN, 1982), but poorly set out. Questions remain unanswered: What is meant by ‘care’ and what is the care that older adults need? Do (all) older adults want this (undefined) care? If they do, when do they want it and from whom? Much of the established discourse implies incapacity in older age, a burden of care to be shouldered by family, and homogenised ‘elderly people’ who want, and sometimes successfully motivate, care. This chapter considers the way older men and women in rural southern Malawi talk about care. It argues that research conversations about care became a discursive space in which participants explored what the giving, receiving and needing of care meant for their sense of selves as they aged. All participants presented their experiences of care in ways which they understood would demonstrate positive self-identities. They talked much less about availability of care, and much more about what the giving and receiving of care ‘said’ about them. Drawing on sociological theories of identity, the chapter considers the implications of the meanings associated with different types of care for older adults’ age-related identity scripts.

Objective Nonalcoholic steatohepatitis (NASH) is a form of chronic liver disease (CLD): patients have an increased risk of developing cirrhosis, liver failure, and complications (e.g. hepatocellular carcinoma). NASH has a high clinical burden, and likely impairs patients’ health-related quality of life (HRQoL), but there are currently no licensed therapies. The objective of this robust pragmatic literature review was to identify and describe recent studies on the HRQoL burden of NASH from the patient perspective. Methods English-language primary research studies were identified that measured HRQoL in adults with NASH (population-based studies or clinical trials of pharmacological therapy). Searches were conducted in the following bibliographical databases: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), and Health Technology Assessment Database (HTA). Abstracts from selected congresses (2015/2016) were hand searched. Articles were assessed for relevance by two independent reviewers, and HRQoL data were extracted. Results A total of 567 de-duplicated abstracts were identified, and 20 full-text articles were reviewed. Eight studies were included: five quantitative, two interventional, and one qualitative. The quantitative and interventional studies measured HRQoL using the Short-Form 36 (SF-36) and the Chronic Liver Disease Questionnaire (CLDQ), and the qualitative study involved focus groups and individual interviews. Overall, the studies showed that NASH affects HRQoL, especially physical functioning, with many patients reporting being fatigued. In quantitative studies, overall, patients with NASH had a reduced HRQoL versus normative populations and nonalcoholic fatty liver disease (NAFLD) patients, but not versus chronic liver diseases. A longitudinal study showed that when weight loss was achieved, HRQoL improvement over 6 months was greater in patients with NASH versus NAFLD. Qualitative research suggested that, in addition to fatigue, other symptoms are also burdensome, having a broad negative impact on patients’ lives. The impact of pharmacological treatment on HRQoL was explored in only two included studies. Conclusions HRQoL is impaired in patients with NASH. Patients experience a range of symptoms, especially fatigue, and the impact on their lives is broad. Further research is needed to understand the HRQoL burden of NASH (e.g. assessing NASH-specific impacts not captured by SF-36 and CLDQ) and the impact of future NASH therapies on HRQoL.

We sought to create a new research and clinical instrument -the Influence and Motivation for Patient ACTivation in Diabetes care (IMPACT-D™) - to measure the degree to which patients with type 2 diabetes (T2DM) value health and believe they can influence it.Candidate items were generated via a literature review, expert opinion, and qualitative interviews and focus groups with T2DM patients in Chicago, IL and Chapel Hill, NC. Psychometric testing guided by item response theory was conducted among an online panel of 500 English-speaking adults with T2DM. Differential item functioning analyses evaluated item performance across key participant characteristics. To determine construct validity, IMPACT-D™ scores were compared to other general measures of personality and patient activation. A second study among 300 patients recruited from two internal medicine clinics further assessed associations between the IMPACT-D™ and health outcomes. Cognitive interviews confirmed patient understanding of IMPACT-D™ items and instructions.Exploratory factor analyses revealed a single-factor solution that included 6 items. The IMPACT-D™ demonstrated adequate reliability (α = 0.72) and moderate construct validity with patient activation (r = 0.51, p 0.001) and personality-conscientiousness subscales (r = 0.29, p 0.001). Higher scores on the IMPACT-D™ were associated with better physical health (r = 0.17, p = 0.003) and lower severity of depressive (r = -0.35, p 0.001) and anxiety (r = -0.28, p 0.001) symptoms. There were no significant differences by blood pressure (r = -0.0021, p = 0.9) or haemoglobin A1c (r = -0.069p = 0.2).The IMPACT-D holds potential for use in both clinical care and research applications. Future studies should evaluate how to best operationalize its use for both settings.

Policies to enhance bicycling are correlated with health outcomes. Research has yet to provide an adequate, empirically derived explanation for this finding.To examine a comprehensive model of a pathway potentially linking bicycle policies to overweight/obesity.Data representing multiple years between 2006 and 2012 from CDC, U.S. Census Bureau, U.S. Department of Transportation, and the Alliance for Biking and Walking were subjected to bivariate and multivariate analyses in 2013. A path model was created to explain the relationship between bicycle policies and overweight/obesity in the 48 largest U.S. cities.Zero-order correlations were significant between the number of bicycle policies and the percentage of workers bicycling to work and rates of overweight/obesity. These relationships did not remain statistically significant in the multivariate analysis. However, more bicycle policies were associated with a greater number of bicycle infrastructure components (p0.005). In turn, bicycling infrastructure components were positively related to the percentage of workers bicycling to work (p0.001), which was inversely associated with overweight/obesity rates (p0.05).The results of this study suggest that large cities with more policies aimed at promoting bicycling have fewer overweight/obese residents, partially because the policies are related to supportive bicycling infrastructures that promote bicycling to work.

Accumulation of lipofuscin in the retina is associated with pathogenesis of atrophic age-related macular degeneration and Stargardt disease. Lipofuscin bisretinoids (exemplified by N-retinylidene-N-retinylethanolamine) seem to mediate lipofuscin toxicity. Synthesis of lipofuscin bisretinoids depends on the influx of retinol from serum to the retina. Compounds antagonizing the retinol-dependent interaction of retinol-binding protein 4 (RBP4) with transthyretin in the serum would reduce serum RBP4 and retinol and inhibit bisretinoid formation. We recently showed that A1120 (3), a potent carboxylic acid based RBP4 antagonist, can significantly reduce lipofuscin bisretinoid formation in the retinas of Abca4(-/-) mice. As part of the NIH Blueprint Neurotherapeutics Network project we undertook the in vitro exploration to identify novel conformationally flexible and constrained RBP4 antagonists with improved potency and metabolic stability. We also demonstrate that upon acute and chronic dosing in rats, 43, a potent cyclopentyl fused pyrrolidine antagonist, reduced circulating plasma RBP4 protein levels by approximately 60%.

Energetic, competitive, body-contact play (rough and tumble play (RTP)) is commonly observed among young children and is reported as an important feature of father–child relationships. Animal studies have demonstrated positive developmental effects of peer–peer play-wrestling, influencing cognitive and social outcomes. The purpose of this paper is to discuss the nature of RTP between father and child and its relationship to child development and to describe a theoretically informed measure of the quality of father–child RTP.

This paper examines how older adults living in rural Malawi explain and understand their sex lives. We present sex in this setting as a field in which broader understandings of ageing, aged identities, and conceptions of person- or adulthood in older age are played out and constructed. Qualitative data were collected from men (N=20) and women (N=23) aged 50 to around 90 using in-depth multiple dependent interviews (N=135) between 2008 and 2010. The giving and receipt of sexual pleasure was considered natural and God-given. Primarily understood as a matter of ‘power’, sex was on the one hand, beneficial to older bodies, but on the other, not accessible to such bodies. Declining sexual frequency was associated with declining desire for sex, or frustration stemming from continued desire for sex. These discourses emerged from the way the ageing body was constructed as a weakened body, incompatible with understandings of adulthood based on physical productivity. Older men and women used sex to discursively respond to these challenges to their adulthood in two ways. Firstly, sex was used to confirm strength, physical productivity, and therefore, identity as an ‘adult’. Secondly, adulthood itself was redefined as being based on moral, rather than physical productivity, and refraining from sex was used to demonstrate wisdom, self-control and therefore their ‘adult’ identity. Our results provide in-depth understanding of the ways constructions of ageing and sex can influence complex experiences of marital and non-marital sex in older age. We contribute to debates on sexuality in the gerontological literature by moving discussion beyond the presentation of continued sexuality as somehow exceptional or an indicator of successful ageing. Finally, in a setting of considerable HIV prevalence at older ages, our results challenge a preoccupation with fertility and chronological age in the collection of sexual health data in Africa.

Long-term care is provided for individuals – particularly older people – who have lost self-care capacity because of chronic illness or disability, to improve personal functioning and quality of life. Most long-term care today is provided by unpaid family caregivers, but state-provided and other services are growing in importance. There is increasing emphasis on providing care in community settings in preference to formal residential care settings. Financing of long-term care relies heavily on collective prepayment and out-of-pocket arrangements, with funding shifting increasingly onto service users and families. Self-directed support systems are being introduced in some countries. The future affordability of long-term care is a major challenge across the world.

Background: Although psychosocial care has been regarded as central to palliative and supportive care, there have been few empirically tested approaches to individual intervention. Aim: The subjective experience of advanced cancer patients receiving a new manualized brief individual psychotherapy, referred to as Managing Cancer and Living Meaningfully (CALM), was examined prior to the initiation of a randomized controlled trial testing the effectiveness of this intervention. Design: Semi-structured interviews were conducted with patients who had a diagnosis of advanced cancer, and who underwent the intervention. Setting/Participants: Patients were recruited from a large urban regional cancer center in Toronto, Canada. The 10 interviewees included seven women and three men. All had completed between three to six CALM sessions prior to the interview. Results: The CALM intervention was associated with profound and unique patient-identified benefits and no patient-identified risks or concerns. Five interrelated benefits of the intervention were identified: (1) a safe place to process the experience of advanced cancer; (2) permission to talk about death and dying; (3) assistance in managing the illness and navigating the healthcare system; (4) resolution of relational strain; and (5) an opportunity to ‘be seen as a whole person’ within the healthcare system. These benefits were regarded by participants as unique in their cancer journey. Conclusions: Findings from a qualitative study suggest that the CALM intervention provides substantial benefits for patients with advanced cancer prior to the end of life. Findings informed the development of a randomized controlled trial to evaluate the effectiveness of this intervention.

To examine the long-term effects of having one overweight or obese parent on child weight status and determine whether these effects vary according to parent sex. Prospective study: Longitudinal Study of Australian Children (LSAC). Two-parent families (N=3285) from the LSAC were included if height and weight data were available for both parents and their child at the 2004 and 2008 time points. Child weight status category (healthy, overweight, obese) in 2008 when the child was aged 8–9 years. Regression modelling was used to investigate how self-reported parent weight status in 2004 influenced measured child weight status 4 years later. Parent body mass index (BMI) was significantly correlated with child BMI, but there was no evidence of sex-specific associations between parent and child BMI correlations. The results from the regression analysis showed that having an overweight or obese father, but a healthy weight mother, significantly increased the odds of child obesity (odds ratio: 4.18, 95% confidence interval (CI): 1.01–17.33 and odds ratio: 14.88, 95% CI: 2.61–84.77, respectively), but the reverse scenario (overweight or obese mother with a healthy weight father) was not a significant predictor of child overweight or obesity (odds ratio: 2.52, 95% CI: 0.38–16.71 and odds ratio: 2.56, 95% CI: 0.31–21.26, respectively). Children with overweight or obese fathers are at a higher risk of becoming obese. This suggests that interventions are urgently required to test the efficacy of treating overweight fathers as a key strategy for childhood obesity prevention and/or treatment.

A new series of 5-(pyridinon-1-yl)indazoles with MCH-1 antagonist activity were synthesized. Potential cardiovascular risk for these compounds was assessed based upon their interaction with the hERG potassium channel in a mini-patch clamp assay. Selected compounds were studied in a 5-day diet-induced obese mouse model to evaluate their potential use as weight loss agents. Structural modification of the 5-(pyridinon-1-yl)indazoles to give 5-(furopyridinon-5-yl)indazoles provided compounds with enhanced pharmacokinetic properties and improved efficacy.

Rationale Evidence-based medicine (EBM) is commonly advocated as a ‘gold standard’ of clinical practice. A prominent definition of EBM is: the integration of best research evidence with clinical expertise and patient values. Over time, various versions of a conceptual model or framework for implementing EBM (i.e. how to practice EBM) have been developed. Aims and objectives This paper (i) traces the evolution of the different versions of the conceptual model; (ii) tries to make explicit the underlying goals, assumptions and logic of the various versions by exploring the definitions and meaning of the components identified in each model, and the methods suggested for integrating these into clinical practice; and (iii) offers an analytic critique of the various model iterations. Methods A literature review was undertaken to identify, summarize, and compare the content of articles and books discussing EBM as a conceptual model to guide physicians in clinical practice. Results Our findings suggest that the EBM model of clinical practice, as it has evolved over time, is largely belief-based, because it is lacking in empirical evidence and theoretical support. The model is not well developed and articulated in terms of defining model components, justifying their inclusion and suggesting ways to integrate these in clinical practice. Conclusion These findings are significant because without a model that clearly defines what constitutes an EBM approach to clinical practice we cannot (i) consistently teach clinicians how to do it and (ii) evaluate whether it is being done.

5-HT(1A) receptor knockout (1AKO) mice have a robust anxiety phenotype. Tissue-specific "rescue" strategies and electrophysiology have implicated a critical role for postsynaptic 5-HT(1A) receptors, particularly in the CA1 region of the hippocampus.In this study, we evaluated differences in membrane properties and synaptic activity in CA1 hippocampal pyramidal cells between 1AKOs and wild-type (WT) controls to better understand the cellular correlates of anxiety in this mouse model.Whole-cell patch-clamp recordings were conducted in CA1 pyramidal cells in hippocampal brain slices from 1AKOs and WTs that had previously been screened for anxiety with the elevated-plus maze. Spontaneous miniature inhibitory and excitatory postsynaptic currents (IPSCs and EPSCs) and stimulus-evoked eIPSCs and eEPSCs were recorded in addition to the effect of the benzodiazepine agonist diazepam or the inverse agonist FG 7142 on γ-aminobutyric acid (GABA)ergic eIPSCs.Evoked EPSC amplitude was greater in 1AKOs than WTs. When subjects were pooled across genotypes, anxiety measures correlated with eEPSC amplitude, indicating enhanced postsynaptic glutamate synaptic activity under conditions of synaptic activation in anxious subjects. While GABA synaptic activity and sensitivity to diazepam were not affected by genotype or correlated with anxiety, sensitivity to the anxiogenic FG 7142 was smaller in anxious subjects.These data indicate enhanced postsynaptic glutamate receptor sensitivity and decreased GABAergic inhibition by a benzodiazepine inverse agonist in CA1 hippocampal neurons of anxious mice are produced by deletion of the 5-HT(1A) receptor. These data provide new information about interactions between 5-HT, GABA, and glutamate systems during the expression of chronic anxiety.

We used quantitative modeling of remember–know responses (Tulving, 1985) to investigate the processes underlying recognition memory for faces in the choice-similarity paradigm (Tulving, 1981). Similarity between recognition test choices produces opposite effects on confidence and accuracy in this paradigm. We extended existing models of this double dissociation to account for remember–know responses, by adding a variable recollection criterion to Clark’s (1997) single-process model and by adding graded recollection strength to Dobbins, Kroll, and Liu’s (1998) dual-process model. Both models provided an accurate and comprehensive account of objective and subjective judgments in an experiment we conducted on memory for faces, and of data from Dobbins et al. on memory for natural scenes. Model selection techniques were used to refine these accounts, providing insight into the psychological processes proposed by each approach and into their implications for the relationship between recollection and confidence in two-alternative forced choice recognition.

We investigate the effects of word characteristics on episodic recognition memory using analyses that avoid Clark’s (1973) “language-as-a-fixed-effect” fallacy. Our results demonstrate the importance of modeling word variability and show that episodic memory for words is strongly affected by item noise ( Criss & Shiffrin, 2004 ), as measured by the orthographic similarity between experimental items. We found that the word frequency effect was not related to the item noise effects, whereas the effect of neighborhood density, which measures the similarity of a word to all other words in the lexicon, was greatly attenuated when item noise was controlled. Our results are also consistent with a likelihood based recognition decision mechanism that produces a mirror effect by taking into account item and subject characteristics.

University of Newcastle, Callaghan, New South Wales, Australia Memory similarity, the similarity between a test lure and memory traces, reduces confidence and accuracy in all forms of recognition memory. In contrast, Tulving (1981) showed that, in recognition memory for scenic pictures, choice similarity, the similarity between forced choice test alternatives, increased accuracy but decreased confidence. In the present study, we replicated both memory and choice similarity effects and the dissociation between accuracy and confidence with pictures of faces. State-trace analysis confirmed the dissociation and identified two dimensions underlying these effects, one associated with choice similarity and another associated with memory similarity. Further analysis showed that the effect of study—test lag was associated with the memory-similarity dimension.

Stress-related psychiatric disorders such as anxiety and depression involve dysfunction of the serotonin [5-hydroxytryptamine (5-HT)] system. Previous studies have found that the stress neurohormone corticotropin-releasing factor (CRF) inhibits 5-HT neurons in the dorsal raphe nucleus (DRN)in vivo. The goals of the present study were to characterize the CRF receptor subtypes (CRF-R1 and -R2) and cellular mechanisms underlying CRF–5-HT interactions. Visualized whole-cell patch-clamp recording techniques in brain slices were used to measure spontaneous or evoked GABA synaptic activity in DRN neurons of rats and CRF effects on these measures. CRF-R1 and -R2-selective agonists were bath applied alone or in combination with receptor-selective antagonists. CRF increased presynaptic GABA release selectively onto 5-HT neurons, an effect mediated by the CRF-R1 receptor. CRF increased postsynaptic GABA receptor sensitivity selectively in 5-HT neurons, an effect to which both receptor subtypes contributed. CRF also had direct effects on DRN neurons, eliciting an inward current in 5-HT neurons mediated by the CRF-R2 receptor and in non-5-HT neurons mediated by the CRF-R1 receptor. These results indicate that CRF has direct membrane effects on 5-HT DRN neurons as well as indirect effects on GABAergic synaptic transmission that are mediated by distinct receptor subtypes. The inhibition of 5-HT DRN neurons by CRFin vivomay therefore be primarily an indirect effect via stimulation of inhibitory GABA synaptic transmission. These results regarding the cellular mechanisms underlying the complex interaction between CRF, 5-HT, and GABA systems could contribute to the development of novel treatments for stress-related psychiatric disorders.

North Carolina is one of 32 states that requires undocumented college students to pay out-of-state tuition, no matter how long they have lived in the state. In the struggle for tuition equity, youth across the country have turned to grassroots organizing and lobbying.

Summary Swim stress regulates forebrain 5-hydroxytryptamine (5-HT) release in a complex manner and its effects are initiated in the serotonergic dorsal raphe nucleus (DRN). The purpose of this study was to examine the effects of swim stress on the physiology of DRN neurons in conjunction with 5-HT immunohistochemistry. Basic membrane properties, 5-HT 1A and 5-HT 1B receptor-mediated responses and glutamatergic excitatory postsynaptic currents (EPSCs) were measured using whole-cell patch clamp techniques. Rats were forced to swim for 15 min and 24 h later DRN brain slices were prepared for electrophysiology. Swim stress altered the resting membrane potential, input resistance and action potential duration of DRN neurons in a neurochemical-specific manner. Swim stress selectively elevated glutamate EPSC frequency in 5-HT DRN neurons. Swim stress non-selectively reduced EPSC amplitude in all DRN cells. Swim stress elevated the 5-HT 1B receptor-mediated inhibition of glutamatergic synaptic activity that selectively targeted 5-HT cells. Non-5-HT DRN neurons appeared to be particularly responsive to the effects of a milder handling stress. Handling elevated EPSC frequency, reduced EPSC decay time and enhanced a 5-HT 1B receptor-mediated inhibition of mEPSC frequency selectively in non-5-HT DRN cells. These results indicate that swim stress has both direct, i.e., changes in membrane characteristics, and indirect effects, i.e., via glutamatergic afferents, on DRN neurons. These results also indicate that there are distinct local glutamatergic afferents to neurochemically specific populations of DRN neurons, and furthermore that these distinct afferents are differentially regulated by swim stress. These cellular changes may contribute to the complex effects of swim stress on 5-HT neurotransmission and/or the behavioral changes underlying the forced swimming test model of depression.

OBJECTIVE:The American Academy of Pediatrics recommends intramuscular (IM) vitamin K prophylaxis for all newborns to prevent vitamin K deficiency bleeding. Given the serious implications of late-onset vitamin K deficiency bleeding, our objective was to examine factors influencing parents’ decisions to refuse IM vitamin K prophylaxis.METHODS:Parents intending to refuse IM vitamin K prophylaxis at delivery were recruited from 5 community hospitals, 1 academic medical center, and 2 birthing centers in a single Southeastern state. Participants completed a written survey including demographics, birth and parenting decisions (eg, breastfeeding), and open-ended questions about their vitamin K information sources, concerns, and knowledge of risks.RESULTS:The incidence of refusal was highest at the birthing centers. Fifty-four parents intending to refuse IM vitamin K completed the survey. Most were white (78%), over age 30 (57%), and college graduates (65%). All reported intention to exclusively breastfeed. Most refused hepatitis B vaccine (90%) and erythromycin eye ointment (77%). The most common source of information was the Internet (70%). Concerns included synthetic or toxic ingredients (37%), excessive dose (28%), and side effects (24%). Eighty-three percent of parents reported awareness of risks associated with vitamin K refusal. However, only 6 parents (11%) decided to accept IM prophylaxis.CONCLUSIONS:This study provides an understanding of the concerns, mindset, and information sources used by parents refusing IM vitamin K. Educating parents about the importance of IM prophylaxis should begin in the prenatal period and must address concerns parents identify on the Internet.

Multi-family therapy (MFT) has yet to be evaluated in families of adults with anorexia nervosa (AN). The study aims were: (i) assess the feasibility of MFT for AN; and, (ii) assess whether MFT is associated with improved outcomes for families compared with single-family therapy (SFT). Adult patients with AN consecutively referred to an eating disorder treatment program were assigned (non-randomly) to receive eight sessions of SFT or MFT. Assessment occurred pre-therapy, immediately post-therapy, and at 3-month follow-up. A total of 37 female patients (13 SFT, 24 MFT) and 45 family members (16 SFT, 29 MFT) completed treatment. There were significant time effects for patients' BMI, eating disorder-related psychopathology and multiple family outcome measures. There were no differences between MFT and SFT on family outcome measures at end of treatment and 3 months post treatment. MFT is a feasible intervention that can be used in adult intensive treatment for those with AN.

This paper presents a conceptual framework which captures the macro-environmental and micro-level contexts and processes of a woman's pathway to terminating her pregnancy or seeking abortion-related care. The framework has global applicability, across legal contexts and safety spectra. It can be applied at all points in the reproductive lifespan and all marital statuses. The purpose of this framework is to identify and specify the most salient aspects of abortion decision-making across populations. Social scientists as well as policy and programme planners can use the framework to highlight aspects of the macro/micro environment that facilitate or hinder women's abilities to terminate unwanted pregnancies safely and in a timely manner.

Given that maternal morbidity and mortality from unsafe abortion persist, especially in Africa, there is a pressing need to understand the abortion decision-making process. However, little is known about men's influence on and involvement in women's abortion decision making and care seeking.A qualitative study was conducted at the largest public provider of abortion-related care in Zambia. Thematic framework analysis was used to categorize and synthesize data from in-depth interviews conducted in 2013 with 71 women who received a safe abortion and 41 who received care following an incomplete (unsafe) abortion.Men influenced whether women sought a safe or unsafe abortion; their actions, lack of action and anticipated actions-negative and positive-reflected broader gender inequities. Abandonment by men, and the desire to avoid disclosing pregnancy to men because of fear of their reactions or interference, were important influences on some women's decision to seek abortion, on the secrecy and urgency with which abortion was pursued and on the level of risk assumed. However, other women discussed men's positive influences on their abortion care seeking. In this setting of low awareness of the legality and availability of abortion, some men used their greater social and economic resources to facilitate safe abortion by providing information and paying for care.Increasing knowledge about the legality and availability of safe abortion is vital not only among sexually active women, but also among those they confide in, including men.Contexto: Dado que, especialmente en África, persiste la morbilidad y mortalidad materna derivada del aborto inseguro, hay una necesidad apremiante de comprender el proceso de toma de decisiones asociado con el aborto. Sin embargo, es poco lo que se sabe sobre la influencia e involucramiento de los hombres en la toma de decisiones de las mujeres y en la búsqueda de atención médica relativa al aborto. Métodos: Se condujo un estudio cualitativo en la institución pública proveedora de servicios relacionados con el aborto más grande de Zambia. Se usó análisis de marco temático para categorizar y sintetizar datos de entrevistas en profundidad realizadas en 2013 con 71 mujeres que recibieron servicios de aborto seguro y 41 que recibieron atención posterior a un aborto incompleto (inseguro). Resultados: Los hombres ejercieron influencia sobre las mujeres en cuanto a la búsqueda de un aborto seguro o inseguro; sus acciones, la falta de acción y las acciones anticipadas —negativas y positivas— revelaron amplias inequidades de género. El abandono por parte de los hombres y el deseo de evitar la revelación del embarazo a los hombres debido al temor de sus reacciones o interferencias, influyeron de manera importante tanto en las decisiones de algunas mujeres a la hora de buscar un aborto, como en el secreto y urgencia con que se procuró el aborto y el nivel de riesgo asumido. Sin embargo, otras mujeres hablaron acerca de la influencia positiva de los hombres en su búsqueda de atención relativa al aborto. En este entorno de baja conciencia sobre la legalidad y disponibilidad del aborto, algunos hombres utilizaron sus amplios recursos sociales y económicos para facilitar el aborto seguro al proporcionar información y pagar por los servicios. Conclusiones: Aumentar el conocimiento sobre la legalidad y disponibilidad del aborto seguro es vital, no solo entre las mujeres sexualmente activas, sino también entre las personas en las que ellas confían, incluidos los hombres.Contexte: Étant donné la persistance de la morbidité et de la mortalité maternelles entourant l'avortement non médicalisé, en Afrique surtout, le besoin de comprendre le processus décisionnel de l'avortement est impérieux. On en sait cependant peu sur l'influence des hommes et leur implication dans la décision des femmes d'avorter et leur recherche de soins. Méthodes: Une étude qualitative a été effectuée dans les locaux du plus grand prestataire public de soins liés à l'avortement en Zambie. L'étude a procédé par analyse de cadre thématique pour catégoriser et synthétiser les données d'entretiens en profondeur menés en 2013 avec 71 femmes qui avaient obtenu un avortement médicalisé et 41 ayant reçu des soins suite à un avortement incomplet (non médicalisé). Résultats: La décision d'obtenir un avortement, médicalisé ou non, est influencée par les hommes. Leurs actes, leur inaction et leurs actes anticipés—négatifs comme positifs—sont le reflet de plus vastes inégalités de genre. L'abandon par les hommes, de même que le désir d'éviter de révéler une grossesse aux hommes de peur de leur réaction ou ingérence, influencent fortement la décision prise par certaines femmes de se faire avorter, le secret et l'urgence de l'obtention de l'avortement et le niveau de risque assumé. D'autres femmes décrivent cependant l'influence positive des hommes sur leur recherche de soins suite à un avortement. Dans ce contexte de faible sensibilisation à la légalité et à la disponibilité de l'avortement, certains hommes utilisent leurs plus grandes ressources sociales et économiques pour faciliter l'avortement médicalisé, par l'apport d'information et l'acquittement du coût des soins.La connaissance accrue de la légalité et de la disponibilité de l'avortement médicalisé est vitale, non seulement parmi les femmes sexuellement actives, mais aussi parmi les personnes à qui elles se confient, y compris les hommes.

Research on HIV infection and sexual behaviour in sub-Saharan Africa typically focuses on individuals aged 15–49 years, under the assumption that both become less relevant for older individuals. We test this assumption using data from rural Malawi to compare sexual behaviour and HIV infection among individuals aged 15–49 with individuals aged 50–64 and 65 years and over. Although general declines with age were observed, levels of sexual activity and HIV remained considerable: 26.7 percent and 73.8 percent of women and men aged 65 and older reported having sex in the last year, respectively; men’s average number of sexual partners remained above one; and HIV prevalence is significantly higher for men aged 50–64 (8.9 percent) than men aged 15–49 (4.1 percent). We conclude that older populations are relevant to studies of sexual behaviour and HIV risk. Their importance is likely to increase as access to antiretrovirals in Africa increases. We recommend inclusion of adults aged over 49 years in African HIV/AIDS research and prevention efforts.

Network based technology, either private or public networks, are continuing to bear dramatic impact on enterprises around the world, and a growing number of risk managers are recognizing the importance of understanding how these technologies are transforming every aspect of the business infrastructure.

El interés en la toma de decisión médica compartida y en las ayudas a la toma de decisión se desarrollaron en los años ochenta y noventa con un foco inicial en pacientes con cáncer, y en particular, en mujeres con cáncer de mama. Este interés con el tiempo ha experimentado un cambio en énfasis desde la curiosidad acerca del significado de estos conceptos y su potencial para mejorar la participación del paciente en la toma de decisión a una promoción a gran escala, intentos de expansión, implementación en una variedad de situaciones clínicas, medición de resultados múltiples en niveles clínicos y de política pública y el desarrollo de criterios estandarizados para evaluar las ayudas a la toma de decisión. En este artículo planteamos la cuestión: ¿estamos moviéndonos demasiado rápido en la promoción de la decisión médica compartida y de la ayuda a la toma de decisión antes de resolver los importantes desafíos que todavía existen acerca del significado y los méritos de estas iniciativas? Discutimos cuatro desafíos: i) ambigüedad e inconsistencia en la definición de la decisión médica compartida; ii) variaciones en las preferencias de médicos y pacientes sobre la decisión médica compartida; iii) el incremento en el número y rango de metas definidas para lograr con la toma de decisión compartida y/o la ayuda a la decisión; iv) la carencia de apoyo teórico y empírico bien documentado para los criterios usados en la evaluación de la calidad de las ayudas a la decisión, y potencialmente para los propósitos de la certificación de la ayuda a la decisión. Estos hallazgos sugieren la necesidad de precaución, un análisis más meditado e investigación adicional en los desafíos mencionados previamente a la promoción a gran escala de la decisión compartida y las ayudas a la decisión en la práctica clínica habitual. Clinical and research interest in shared treatment decision making (STDM) and decision aids (DA) evolved in the 1980’s and 1990’s with an initial focus on patients with cancer, and particularly, women with breast cancer. This interest has undergone a shift in emphasis over time from curiosity about the meaning of these concepts and their potential to improve patient participation in treatment decision making to wide scale endorsement, attempts to expand implementation in a variety of clinical settings, measurement of multiple outcomes at the clinical and public policy level, and the development of standardized criteria for evaluating DA. In this chapter we raise the question: are we moving too fast to promote implementation of STDM and DA before resolving important challenges that still exist about the meaning and merits of these initiatives? We discuss four such challenges: i) ambiguity and inconsistency in the definition of STDM, ii) variations in patient and physician preferences for STDM, iii) the increase in the number and range of goals defined for STDM and /or DA to achieve, and iv) the lack of well documented theoretical and empirical support for criteria to be used in evaluating DA quality, and potentially for purposes of DA certification. These findings suggest the need for caution, for more thoughtful analysis, and additional research on the challenges raised above prior to wide scale endorsement of STDM and DA in routine clinical practice.

In the search for new antibacterial agents, the enzyme FabI has been identified as an attractive target. Employing a structure guided approach, the previously reported ene-amide series of FabI inhibitors were expanded to include 2,3,4,5-tetrahydro-1H-pyrido[2,3-b and e][1,4]diazepines. These novel series incorporate additional H-bonding functions and can be more water soluble than their naphthyridinone progenitors; diazepine 16c is shown to be efficacious in a mouse infection model.

Major bottlenecks in systems biology studies arise from limitations of current sample preparation techniques. Multiple mutually exclusive sample preparation methods, which are often required to extract distinct classes of molecules from cells and tissues, are incompatible with studies of precious or very limited samples. Moreover, the strong detergents and chaotropic agents commonly required to solubilize sample constituents often interfere with subsequent separation and analysis. Here we describe a rapid, detergent-free sample preparation technique that allows efficient concurrent isolation and fractionation of protein, DNA, RNA, and lipids from biological samples, eliminating the need for multiple replicates. The method relies on a synergistic combination of physical disruption of the cellular material by hydrostatic pressure (pressure cycling technology) and novel extraction conditions to dissolve and partition distinct classes of molecules into separate fractions. We demonstrate parallel recovery of proteins, lipids, and intact DNA and RNA, from animal cells and tissues, for proteomic, lipidomic, and genomic analyses. The protein extracts require minimal cleanup and are compatible with 1D and 2D PAGE, liquid chromatography coupled with tandem mass spectrometry, and Western blotting. The lipid fractions have been profiled by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry without further processing. The isolated DNA and RNA were shown to be intact by agarose gel visualization, and the presence of intact mRNA was confirmed by real time reverse transcription polymerase chain reaction. Analysis and comparison of samples extracted using this method and a more traditional extraction technique revealed several protein species preferentially extracted by the new method.