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Severe acute malnutrition (SAM) remains a major global public health problem. SAM cases are treated using ready‐to‐use therapeutic food (RUTF) at a dosage of ∼200 kcal/kg/day per the standard treatment protocol (STD). Emerging evidence on simplifications to the standard protocol, which among other adaptations, includes reducing the daily RUTF dosage, indicates that it is effective and safe for treating children with SAM. In response to a foreseen stock shortage of RUTF, the government of Afghanistan endorsed the temporary use of a modified treatment protocol in which the daily RUTF dosage was prescribed at 1000 kcal/day (irrespective of body weight) until the child achieved moderate acute malnutrition status (weight‐for‐height z‐score ≥ −3 or mid‐upper arm circumference [MUAC] ≥ 115 mm), at which point 500 kcal/day was prescribed until cured (modified treatment protocol [MTP]). In this paper, we report the results of this nonweight‐based daily RUTF dosage experience. Data of 2042 children with SAM, treated using either the STD protocol (n = 269) or the MTP protocol (n = 1773) from August 2019 to March 2021 in five provinces, were analyzed. The per‐protocol analyses confirmed noninferiority of MTP protocol when compared to STD protocol for recovery rate [93.3% vs. 90.2%; ∆ (95% confidence interval, CI) = 3.1 (−0.9; 7.2) %] and length‐of‐stay [82.6 vs. 75.6 days; ∆ (95% CI) = 6.9 (3.3; 10.5) days], considering the margin of noninferiority of −10% and +14 days, respectively. Weight gain velocity was smaller in the MTP protocol group than in the STD protocol group [3.7 (1.7) vs. 5.2 (2.9) g/kg/day; ∆ (95% CI) = −1.5 (−1.8, −1.2); p < 0.001]. The STD group had a significantly higher mean than the MTP group for absolute MUAC gain [∆ (95% CI) = 1.7 (1.0; 2.3) mm; p < 0.001] and the MUAC velocity [∆ (95% CI) = 0.29 (0.20; 0.37) mm/week; p < 0.001]. Our results confirm the noninferiority of a nonweight‐based daily dosage and support the endorsement of this modification as an alternative to the standard protocol in resource‐constrained contexts. Key messages: More evidence supporting the use of the nonweight‐based daily ready‐to‐use therapeutic food (RUTF) dosage for treating uncomplicated severe acute malnutrition (SAM), in specific contexts, is needed.Our real‐world prospective nonrandomized study showed that the fixed nonweight‐based daily RUTF dosage protocol is as effective as the standard weight‐based protocol for treating uncomplicated SAM in children <5 in the Afghanistan context.Our findings support the reflection of a nonweight‐based daily RUTF dosage in resource‐constrained contexts in national and global policies and guidelines to improve coverage of all children in need of treatment. [ABSTRACT FROM AUTHOR]

Background: People with motor neuron disease (pwMND) are routinely offered gastrostomy feeding tube placement and (non‐invasive and invasive) ventilation to manage the functional decline associated with the disease. This study aimed to synthesise the findings from the qualitative literature to understand how individual, clinical team and organisational factors influence pwMND decisions about these interventions. Methods: The study design was guided by the enhancing transparency in reporting the synthesis of qualitative research (ENTREC) statement. The search of five bibliography databases and an extensive supplementary search strategy identified 27 papers that included qualitative accounts of pwMND, caregivers and healthcare professionals' (HCPs) experiences of making decisions about gastrostomy and ventilation. The findings from each study were included in a thematic synthesis. Findings: Making decisions about interventions is an emotional rather than simply a functional issue for pwMND. The interventions can signal an end to normality, and increasing dependence, where pwMND consider the balance between quality of life and extending survival. Interactions with multiple HCPs and caregivers can influence the process of decision‐making and the decisions made. These interactions contribute to the autonomy pwMND are able to exert during decision‐making. HCPs can both promote and threaten pwMND perceived agency over decisions through how they approach discussions about these interventions. Though there is uncertainty over the timing of interventions, pwMND who agree to interventions report reaching a tipping point where they accept the need for change. Conclusion: Discussion of gastrostomy and ventilation options generate an emotional response in pwMND. Decisions are the consequence of interactions with multiple external agents, including HCPs treading a complex ethical path when trying to improve health outcomes while respecting pwMND right to autonomy. Future decision support interventions that address the emotional response and seek to support autonomy have the potential to enable pwMND to make informed and timely decisions about gastrostomy placement and ventilation. Patient or Public Contribution: The lead author collaborated with several patient and participant involvement (PPI) groups with regards to the conceptualisation and design of this project. Decisions that have been influenced by discussions with multiple PPI panels include widening the scope of decisions about ventilation in addition to gastrostomy placement and the perceptions of all stakeholders involved (i.e., pwMND, caregivers and HCPs). [ABSTRACT FROM AUTHOR]

Background: CBT is an effective treatment for depression, but access varies across the United Kingdom. Online CBT increases access. The INTERACT platform was designed to support patient engagement in CBT, enabling therapists to deliver high‐intensity CBT via typed instant messaging and allowing patients and therapists access to an integrated online library of resources during and between sessions. Methods: The INTERACT trial aimed to evaluate this integrated approach to delivering CBT for primary care patients with depression. A nested qualitative study was conducted within the trial. Interviews were conducted with 20 patients who received the intervention, 9 therapists who delivered it and 3 therapist supervisors. Data were analysed using thematic analysis. Results: The combination of receiving support from a therapist and having access to integrated online CBT resources enabled patients to better manage their depression. Platform benefits included the opportunity to review transcripts to clarify how to complete homework tasks and track progress in managing their depression. The typing process allowed reflection and a focused discussion. However, less could be covered than during an in‐person session, which reduced therapists' expectations around goal setting. Patients who did not complete therapy struggled with the typing and found the CBT approach too demanding. Conclusion: Findings highlight the importance of establishing patient and therapist goals and expectations about what can be achieved in CBT mediated by typing. Some patients are comfortable communicating via typing and are motivated to utilise online resources in between sessions. Exploring the benefits and challenges of typed CBT with patients will enable them to make an informed choice about referral for this novel approach to therapy. Patient or Public Contribution: Patients, service users and members of the public were involved in the study design and management. Substantial pilot work gathered stakeholder feedback and informed the design of the intervention, before undertaking the RCT. Coauthor P.L. is a service user representative co‐applicant and member of the management group responsible for developing the intervention and the trial. Two PPI members sit on the Independent Steering Committee. PPI members provided valuable feedback on the study resources and documents. [ABSTRACT FROM AUTHOR]

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Introduction: Hearing loss is a chronic health condition that rises sharply with age. The way people respond to and cope with health conditions is influenced by their capacity to perform illness and treatment‐related work. The aim was to explore the cumulative burdens of living with hearing loss and the resources mobilised to ease the burdens. Methods: A qualitative design was used with semi‐structured interviews (online or in‐person) with participants recruited through audiology services and nonclinical services, such as lip‐reading classes. Forty‐six participants with hearing loss aged between 16 and 96 years were interviewed. An abductive approach, informed by May et al.'s burden of treatment theory, was used to analyse the data. Results: The illness burden involved participants working to make sense of their hearing loss, engaging in emotional work in response to changes in sound, social interactions and identity and coping with the daily frustrations required to communicate with others. Abandonment and uncertainty characterised the treatment burden; participants engaged in emotional work to adjust to hearing technology and deal with the uncertainty of how their hearing might progress. To ameliorate the burdens, participants drew on internal resources (psychological, health literacy, cognitive) and external resources (social support, financial, information, technology). Conclusions: The workload of hearing loss appears largely devolved to the patient and is not always visible. Our work indicates the need to widen approaches in audiological care through the implementation of lifeworld‐led care, family‐centred care and peer support to build support for those with hearing loss. Patient or Public Contribution: We developed the project in consultation with members of the public who have lived experience of hearing loss recruited through Aston University and volunteer links to audiology services. We also consulted people more likely to be affected by hearing loss adults including adults with learning disabilities, older adults in residential care and people from South Asia (Bangladeshi, Indian and Pakistani communities). These individuals commented on the study aims, interview schedule and participant recruitment practices. One of our co‐authors (expert by experience) contributed to the development and interpretation of themes and preparation of the final manuscript. [ABSTRACT FROM AUTHOR]

Although sucrose is widely administered to hospitalized infants for single painful procedures, total sucrose volume during the entire neonatal intensive care unit (NICU) stay and associated adverse events are unknown. In a longitudinal observation study, we aimed to quantify and contextualize sucrose administration during the NICU stay. Specifically, we investigated the frequency, nature, and severity of painful procedures; proportion of procedures where neonates received sucrose; total volume of sucrose administered for painful procedures; and incidence and type of adverse events. Neonates <32 weeks gestational age at birth and <10 days of life were recruited from four Canadian tertiary NICUs. Daily chart reviews of documented painful procedures, sucrose administration, and any associated adverse events were undertaken. One hundred sixty‐eight neonates underwent a total of 9093 skin‐breaking procedures (mean 54.1 [±65.2] procedures/neonate or 1.1 [±0.9] procedures/day/neonate) during an average NICU stay of 45.9 (±31.4) days. Pain severity was recorded for 5399/9093 (59.4%) of the painful procedures; the majority (5051 [93.5%]) were heel lances of moderate pain intensity. Sucrose was administered for 7839/9093 (86.2%) of painful procedures. The total average sucrose volume was 5.5 (±5.4) mL/neonate or 0.11 (±0.08) mL/neonate/day. Infants experienced an average of 7.9 (±12.7) minor adverse events associated with pain and/or sucrose administration that resolved without intervention. The total number of painful procedures, sucrose volume, and incidence of adverse events throughout the NICU stay were described addressing an important knowledge gap in neonatal pain. These data provide a baseline for examining the association between total sucrose volume during NICU stay and research on longer‐term behavioral and neurodevelopmental outcomes. [ABSTRACT FROM AUTHOR]

Background: Evidence shows that online interventions could prevent depression. However, to improve the effectiveness of preventive online interventions in individuals with subthreshold depression, it is worthwhile to study factors influencing intervention outcomes. Outcome expectancy has been shown to predict treatment outcomes in psychotherapy for depression. However, little is known about whether this also applies to depression prevention. The aim of this study was to investigate the role of participants' outcome expectancy in an online depression prevention intervention. Methods: A secondary data analysis was conducted using data from two randomised‐controlled trials (N = 304). Multilevel modelling was used to explore the effect of outcome expectancy on depressive symptoms and close‐to‐symptom‐free status postintervention (6–7 weeks) and at follow‐up (3–6 months). In a subsample (n = 102), Cox regression was applied to assess the effect on depression onset within 12 months. Explorative analyses included baseline characteristics as possible moderators. Outcome expectancy did not predict posttreatment outcomes or the onset of depression. Results: Small effects were observed at follow‐up for depressive symptoms (β = −.39, 95% confidence interval [CI]: [−0.75, −0.03], p =.032, padjusted =.130) and close‐to‐symptom‐free status (relative risk = 1.06, 95% CI: [1.01, 1.11], p =.013, padjusted = 0.064), but statistical significance was not maintained when controlling for multiple testing. Moderator analyses indicated that expectancy could be more influential for females and individuals with higher initial symptom severity. Conclusion: More thoroughly designed, predictive studies targeting outcome expectancy are necessary to assess the full impact of the construct for effective depression prevention. Patient or Public Contribution: This secondary analysis did not involve patients, service users, care‐givers, people with lived experience or members of the public. However, the findings incorporate the expectations of participants using the preventive online intervention, and these exploratory findings may inform the future involvement of participants in the design of indicated depression prevention interventions for adults. Clinical Trial Registration: Original studies: DRKS00004709, DRKS00005973; secondary analysis: osf.io/9xj6a. [ABSTRACT FROM AUTHOR]

Background and objective: End‐stage renal disease (ESRD) affects a multitude of aspects in the patient's daily life, often entailing their own involvement in various aspects of the treatment. Although patient participation is a core health‐care value, what the concept signifies is not yet fully known. The purpose of this paper is to conceptualize patient participation in dialysis care, depicting patients' and health‐care professionals' perspectives. Design: This explorative study employed qualitative interviews and content analysis. Setting and participants: Seven focus group discussions engaging 42 key informants were performed, including patients, staff and managers with experience of dialysis care. Results: In dialysis care, patient participation connotes a sharing of information and knowledge, the learning of and planning of care, including partaking in shared decisions with regards to treatment and management, and being involved in the management of one's own health‐care treatment and/or self‐care activities. Although these attributes were illustrated by all stakeholders, their significance varied: patients suggested that their preferences regarding primary aspects of participation vary, while staff considered patients' performance of dialysis to be the ultimate form of participation. Further, while patients considered multiple ways to execute participation, staff suggested that aspects such as sharing information were a route to, rather than actual, involvement. Conclusions: Without a common understanding to denote the idea of patient participation, staff and patients are exposed to a potential deficit in terms of facilitating patient participation in everyday encounters of dialysis treatment. Further studies and means to serve a mutual understanding are needed. [ABSTRACT FROM AUTHOR]

Background and Objective: To improve quality, child and adolescent mental health services (CAMHS) are expected to quantify families' views on healthcare with user satisfaction measures. As little is known about what influences satisfaction in CAMHS, this study aimed to examine predictors of adolescents' and parents' user satisfaction. Methods: Data from 231 adolescents and 495 parents in treatment at an outpatient clinic who returned a user satisfaction measure, the Experience of Service Questionnaire (ESQ), was analyzed. Registry data on background, clinical and service characteristics were predictors for the ESQ factors general satisfaction, satisfaction with care and satisfaction with environment. Results: In regression models, satisfaction with care for adolescents (r2 =.12) was significant and was predicted by low parent‐self‐reported mental health burden and low clinician‐rated overall symptom burden at intake. For parents, regression models for general satisfaction (r2 =.07), satisfaction with care (r2 =.06) and satisfaction with environment (r2 =.08) were significant. Parents general satisfaction was predicted by higher levels of hyperactivity, less family stress and longer travelling distances to the service. Satisfaction with care for parents was predicted by higher levels of hyperactivity at intake and longer travelling distances. Satisfaction with environment for parents was more likely if the adolescents was a boy, with low levels of family stress and longer travelling distances. Conclusion: Predictors for adolescent and parent user satisfaction in CAMHS differ. Hence, to improve quality CAMHS should enhance focus on collaborative practice with parents, and person‐centred care for adolescents with moderate to severe mental health illness. Patient or Public Contribution: Representatives from the hospitals' youth panel and the non‐governmental organization called The Change Factory have been consulted regarding study design and results. [ABSTRACT FROM AUTHOR]

According to the UN Convention on the Rights of the Child (UNCRC), children have the right to be involved in decisions about medical procedures affecting them. However, research has shown that healthcare professionals sometimes find this difficult to achieve and those procedures then are performed against the will of the child. The aim was to illuminate restraint from the perspective of children's and young people's experiences of feeling forced during medical procedures. Following the phenomenological hermeneutic method, a secondary qualitative analysis of narrative data from four datasets collected between 2001 and 2020 was performed. Twelve children and young people aged 6–19 years (three male, nine female) from central and northern Sweden narrated their experiences of restraint related to medical procedures in nine narrative interviews and three short written narratives. The analysis revealed that it hurts to get forced, this being illustrated in six themes: bodily misery, emotional rebellion, feeling disregarded, physically limited, desiring escape, and leaving deep traces. From the perspective of children and young people, restraint was interpreted with inspiration from the philosopher Michel Foucault, as being overpowered – not voluntary submission but offering resistance – and according to the theory of caring and uncaring, a relationship in which the healthcare professional is perceived as indifferent to the patient as a person. In conclusion restraint hurts and means powerlessness to the child, leaving deep traces that remain for a long time. The findings call the healthcare profession to take action to support children's self‐determination, participation, and integrity in healthcare. How children experience restraint in healthcare merits further investigation from the children's own perspective. [ABSTRACT FROM AUTHOR]

Background: Despite the demonstrated efficacy of approved COVID‐19 vaccines, high levels of hesitancy were observed in the first few months of the COVID‐19 vaccines' rollout. Factors contributing to vaccine hesitancy are well‐described in the literature. Among the various strategies for promoting vaccine confidence, educational interventions provide a foundationally and widely implemented set of approaches for supporting individuals in their vaccine decisions. However, the evidence around the measurable impact of various educational strategies to improve vaccine confidence is limited. We conducted a scoping review with the aim of exploring and characterizing educational interventions delivered during the pandemic to support COVID‐19 vaccine confidence in adults. Methods: We developed a search strategy with a medical information scientist and searched five databases, including Ovid MEDLINE and Web of Science, as well as grey literature. We considered all study designs and reports. Interventions delivered to children or adolescents, interventions on non‐COVID‐19 vaccines, as well as national or mass vaccination campaigns without documented interaction(s) between facilitator(s) and a specific audience were excluded. Articles were independently screened by three reviewers. After screening 4602 titles and abstracts and 174 full‐text articles across two rounds of searches, 22 articles met our inclusion criteria. Ten additional studies were identified through hand searching. Data from included studies were charted and results were described narratively. Results: We included 32 studies and synthesized their educational delivery structure, participants (i.e., facilitators and priority audience), and content. Formal, group‐based presentations were the most common type of educational intervention in the included studies (75%). A third of studies (34%) used multiple strategies, with many formal group‐based presentations being coupled with additional individual‐based interventions (29%). Given the novelty of the COVID‐19 vaccines and the unique current context, studies reported personalized conversations, question periods, and addressing misinformation as important components of the educational approaches reviewed. Conclusions: Various educational interventions were delivered during the COVID‐19 pandemic, with many initiatives involving multifaceted interventions utilizing both formal and informal approaches that leveraged community (cultural, religious) partnerships when developing and facilitating COVID‐19 vaccine education. Train‐the‐trainer approaches with recognized community members could be of value as trust and personal connections were identified as strong enablers throughout the review. [ABSTRACT FROM AUTHOR]

Introduction: Maternity services underwent much change during the COVID‐19 pandemic. Research on the impact on miscarriage care and experiences during this time is sparse. Within a national evaluation of recurrent miscarriage care, we qualitatively explored stakeholder views and experiences of recurrent miscarriage services in Ireland. This study describes the impact of the COVID‐19 pandemic on those experiences and perceptions of care. Methods: People with professional and lived experience of recurrent miscarriage and service engagement were actively involved in this qualitative study from idea generation to analysis and reporting. We recruited women and men with two or more consecutive first‐trimester miscarriages, and people involved in the management/delivery of recurrent miscarriage services and supports. We used purposive sampling to ensure that perspectives across disciplinary or lived experience, geographical, and health service administrative areas, were included. We conducted semi‐structured interviews, virtually all due to COVID‐19 restrictions, between June 2020 and February 2021. These were audio‐recorded, and data were transcribed, and subsequently analyzed using reflexive thematic analysis. Results: We interviewed 42 service providers and 13 women and 7 men with experience of recurrent miscarriage. We actively generated two central themes during data analysis. The first—'Disconnected'—describes how many women navigated miscarriage diagnosis and management and care in subsequent pregnancies alone; many felt that this resulted in increased trauma. At the same time, men struggled with not being present to support their partners and described feeling disconnected. The second theme highlighted 'The perceived dispensability of recurrent miscarriage services and supports'. Some service providers felt that service reduction and redeployment demonstrated a lack of value in the service. Virtual clinics facilitated access to services, but a preference for in‐person care was highlighted. Conclusion: Our analysis provides rich insights into the significant impacts that the COVID‐19 pandemic has had on the way recurrent miscarriage care is provided and experienced, with important implications for early pregnancy, miscarriage and recurrent miscarriage care. Services have undergone significant changes and, while these may be temporary, how services should be delivered in the future requires consideration, particularly given the deficits in care and care experiences highlighted prepandemic. Patient or Public Contribution: Members of the multidisciplinary RE:CURRENT Project Research Advisory Group (including four parent advocates, two of whom are co‐authors on this article) were actively involved throughout the study, including the generation of topic guides and the refining of themes. [ABSTRACT FROM AUTHOR]

Aim: To develop a set of evidence‐informed strategies to assist older people to improve swallowing functions and prevent further damage from complications. Design: A two‐round Delphi survey. Methods: An initial set of dysphagia care strategies with 74 relevant items for older people was formed based on a literature review by seven researchers. An online survey was conducted by 21 panellists, and data of experts' opinions were collected and analysed by improved Delphi method. Results: The positive coefficients in the two rounds of expert consultation were 85.71% and 83.33%, respectively. Consensus was reached with 53 items included and was allocated into the following five sections: (1) screening, (2) assessment, (3) training, (4) interventions and (5) management. These strategies were named with the acronym of each section—"SATIA". The management strategy can be applied to guide the management of older people with dysphagia. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study is to describe experiences of brief admission (BA) of people with borderline personality disorder and self‐harming behaviour, from the perspective of their relatives. Design: A descriptive qualitative design was chosen. Methods: Twelve relatives of people with borderline personality disorder and self‐harming behaviour who had access to BA were interviewed. Data were analysed with qualitative conventional content analysis. Results: One overarching category: Hope for the future and three categories occurred: Breathing space, Personal responsibility and Structure. BA created hope for the future and the relatives appreciated that BA is a freer and easily accessible form of care that enables help at an early stage, compared with usual care. When BA functions, the structure and pre‐determined days of care give relatives a breathing space, and the uncertainty diminishes for the children, as the parent can still be present during inpatient care. The lack of places was described as a disadvantage of BA. [ABSTRACT FROM AUTHOR]

Background and Purpose: Limited data on the brain penetration of potential stroke treatments have been cited as a major weakness contributing to numerous failed clinical trials. Thus, we tested whether interleukin-1 receptor antagonist (IL-1RA), established as a potent inhibitor of brain injury in animals and currently in clinical development, reaches the brain via a clinically relevant administration route, in experimental stroke.Experimental Approach: Male, Sprague-Dawley rats [either naïve or exposed to middle cerebral artery occlusion (MCAo)] were given a single s.c. dose of IL-1RA (100 mg*kg(-1)). The pharmacokinetic profile of IL-1RA was assessed in plasma and CSF up to 24 h post-administration. Brain tissue distribution of administered IL-1RA was assessed using immunohistochemistry. In a separate experiment, the neuroprotective effect of the single s.c. dose of IL-1RA in MCAo was assessed versus a placebo control group.Key Results: A single s.c. dose of IL-1RA reduced damage caused by MCAo by 33%. This dose resulted in sustained, high concentrations in plasma and CSF, penetrated brain tissue exclusively in areas of blood-brain barrier breakdown and co-localized with morphologically viable neurones. CSF concentrations did not reflect massive parenchymal infiltration of IL-1RA in MCAo animals compared to naïve.Conclusions and Implications: These data are the first to show that a potential treatment for stroke, IL-1RA, rapidly reaches salvageable brain tissue via an administration route that is clinically relevant. This allows confidence that IL-1RA, as a candidate for further clinical development, is able to confer its protective actions both peripherally and centrally. [ABSTRACT FROM AUTHOR]

Background and Purpose: Some neurosteroids, notably 3alpha-hydroxysteroids, positively modulate GABA(A) receptors, but sulphated steroids negatively modulate these receptors. Recently, other lipophilic amphiphiles have been suggested to positively modulate GABA receptors. We examined whether there was similarity among the actions of these agents and the mechanisms of neurosteroids. Significant similarity would affect theories about the specificity of steroid actions.Experimental Approach: Xenopus laevis oocytes were challenged with Triton X-100, octyl-beta-glucoside, capsaicin, docosahexaenoic acid and sodium dodecyl sulphate (SDS), along with different GABA concentrations.Key Results: These compounds have both positive and negative effects on GABA currents, which can be accentuated according to the degree of receptor activation. A low GABA concentration (1 microM) promoted potentiation and a high concentration (20 microM) promoted inhibition of current, except for SDS that inhibited function even at low GABA concentrations. Amphiphile inhibition was characterized by enhanced apparent desensitization and by weak voltage dependence, similar to pregnenolone sulphate antagonism. We then tested amphiphile effects on mutated receptor subunits that are insensitive to negative (alpha1V256S) and positive (alpha1Q241L or alpha1N407A/Y410F) steroid modulation. Negative regulation by amphiphiles was nearly abolished in alpha1V256S-mutated receptors, but potentiation was unaffected. In alpha1Q241L- or alpha1N407A/Y410F-mutated receptors, potentiation by amphiphiles remained intact.Conclusions and Implications: Structurally diverse amphiphiles have antagonist actions at GABA(A) receptors very similar to those of sulphated neurosteroids, while the potentiating mechanisms of these amphiphiles are distinct from those of neurosteroid-positive modulators. Thus, such antagonism at GABA(A) receptors does not have a clear pharmacophore requirement. [ABSTRACT FROM AUTHOR]

Background and Purpose: The functional characterization of secreted peptides can provide the basis for the development of novel therapeutic agents. Augurin is a recently identified secreted peptide of unknown function expressed in multiple endocrine tissues, and in regions of the brain including the hypothalamus. We therefore investigated the effect of hypothalamic injection of augurin on the hypothalamo-pituitary-adrenal (HPA) axis in male Wistar rats.Experimental Approach: Augurin was given as a single injection into the third cerebral ventricle (i.c.v.) or into the paraventricular nucleus (iPVN) of the hypothalamus. Circulating hormone levels were then measured by radioimmunoassay. The effect of augurin on the release of hypothalamic neuropeptides was investigated ex vivo using hypothalamic explants. The acute effects of iPVN augurin on behaviour were also assessed.Key Results: i.c.v. injection of augurin significantly increased plasma ACTH and corticosterone, compared with vehicle-injected controls, but had no effect on other hypothalamo-pituitary axes hormones. Microinjection of lower doses of augurin into the PVN caused a similar increase in plasma ACTH and corticosterone, without significant alteration in behavioural patterns. Incubation of hypothalamic explants with increasing doses of augurin significantly elevated corticotrophin-releasing factor (CRF) and arginine vasopressin release. In vivo, peripheral injection of a CRF(1/2) receptor antagonist prevented the rise in ACTH and corticosterone caused by i.c.v. augurin injection.Conclusions and Implications: These data suggest that augurin stimulates the release of ACTH via the release of hypothalamic CRF. Pharmacological manipulation of the augurin system may therefore be a novel target for regulation of the HPA axis. [ABSTRACT FROM AUTHOR]

Ready‐to‐use therapeutic foods (RUTF) used to treat children with severe acute malnutrition (SAM) are costly, and the prescribed dosage has not been optimized. The MANGO trial, implemented by Action Contre la Faim in Burkina Faso, proved the non‐inferiority of a reduced RUTF dosage in community‐based treatment of uncomplicated SAM. We performed a cost‐minimization analysis to assess the economic impact of transitioning from the standard to the reduced RUTF dose. We used a decision‐analytic model to simulate a cohort of 399 children/arm, aged 6–59 months and receiving SAM treatment. We adopted a societal perspective: direct medical costs (drugs, materials and staff time), non‐medical costs (caregiver expenses) and indirect costs (productivity loss) in 2017 international US dollar were included. Data were collected through interviews with 35 caregivers and 20 informants selected through deliberate sampling and the review trial financial documents. The overall treatment cost for 399 children/arm was $36,550 with the standard and $30,411 with the reduced dose, leading to $6,140 (16.8%) in cost savings ($15.43 saved/child treated). The cost/consultation was $11.6 and $9.6 in the standard and reduced arms, respectively, with RUTF accounting for 56.2% and 47.0% of the total. The savings/child treated was $11.4 in a scenario simulating the Burkinabè routine SAM treatment outside clinical trial settings. The reduced RUTF dose tested in the MANGO trial resulted in significant cost savings for SAM treatment. These results are useful for decision makers to estimate potential economic gains from an optimized SAM treatment protocol in Burkina Faso and similar contexts. [ABSTRACT FROM AUTHOR]

Background and Purpose: Niemann-Pick disease type C (NPC) is a lysosomal storage disorder with disrupted intracellular cholesterol trafficking. A cyclic heptasaccharide, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), is a cholesterol solubilizer that is being developed to treat NPC, but its ototoxicity and pulmonary toxicity remain important issues. We have characterized 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD), a cyclic octasaccharide with a larger cavity than HP-β-CD, as a candidate drug to treat NPC. However, the molecular target of HP-γ-CD with respect to NPC and its potential for clinical application are still unclear.Experimental Approach: We investigated the mode of interaction between HP-γ-CD and cholesterol by phase-solubility analysis, proton NMR spectroscopy and molecular dynamics simulations. We then evaluated the therapeutic effects of HP-γ-CD compared with HP-β-CD using cellular and murine NPC models. Mouse auditory and pulmonary function tests were also conducted.Key Results: HP-γ-CD solely formed a 1:1 inclusion complex with cholesterol with an affinity similar to that of HP-β-CD. In vitro, HP-γ-CD and HP-β-CD amelioration of NPC-related manifestations was almost equivalent at lower concentrations. However, at higher concentrations, the cholesterol inclusion mode of HP-β-CD shifted to the highly soluble 2:1 complex whereas that of HP-γ-CD maintained solely the 1:1 complex. The constant lower cholesterol solubilizing ability of HP-γ-CD conferred it with significantly reduced toxicity compared with HP-β-CD, but equal efficacy in treating a mouse model of NPC.Conclusions and Implications: HP-γ-CD can serve as a fine-tuned cholesterol solubilizer for the treatment of NPC with a wider safety margin than HP-β-CD in terms of ototoxicity and pulmonary toxicity. [ABSTRACT FROM AUTHOR]

Objective: This study examined the influence of physicians' recommendations and gender on the decision‐making process in a preference‐sensitive situation. Methods: N = 201 participants were put in a hypothetical scenario in which they suffered from a rupture of the anterior cruciate ligament (ACL). They received general information on two equally successful treatment options for this injury (surgery vs physiotherapy) and answered questions regarding their treatment preference, certainty and satisfaction regarding their decision and attitude towards the treatment options. Then, participants watched a video that differed regarding physician's recommendation (surgery vs physiotherapy) and physician's gender (female vs male voice and picture). Afterwards, they indicated again their treatment preference, certainty, satisfaction and attitude, as well as the physician's professional and social competence. Results: Participants changed their treatment preferences in the direction of the physician's recommendation (P <.001). Decision certainty (P <.001) and satisfaction (P <.001) increased more strongly if the physician's recommendation was congruent with the participant's prior attitude than if the recommendation was contrary to the participant's prior attitude. Finally, participants' attitudes towards the recommended treatment became more positive (surgery recommendation: P <.001; physiotherapy recommendation: P <.001). We found no influence of the physician's gender on participants' decisions, attitudes, or competence assessments. Conclusion: This research indicates that physicians should be careful with recommendations when aiming for shared decisions, as they might influence patients even if the patients have been made aware that they should take their personal preferences into account. This could be particularly problematic if the recommendation is not in line with the patient's preferences. [ABSTRACT FROM AUTHOR]

Objective: To examine the impact of Section 1115 waivers on Medicaid coverage and opioid agonist therapy (OAT) utilization among substance use treatment admissions.Data Source: Treatment Episode Data Set-Admissions (TEDS-A) (2001-2012).Study Design: We examined effects of 1115 waiver implementation on proportions of substance use treatment admissions with Medicaid and receiving OAT, using random intercept linear regression.Principal Findings: 1115 waiver implementation was associated with an average of a 6 percentage point increase in proportion of all admissions with Medicaid, and 4 percentage point increase among opioid outpatient admissions. Implementation was not associated with change in proportion of opioid outpatient admissions receiving OAT.Conclusions: 1115 waivers influence Medicaid coverage among substance use treatment admissions. The findings improve our understanding of how state policies impact substance use treatment utilization. [ABSTRACT FROM AUTHOR]

Background and Purpose: Diacetyl-bis(4-methyl-3-thiosemicarbazonato)copperII (CuII (atsm)) ameliorates neurodegeneration and delays disease progression in mouse models of amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD), yet the mechanism of action remains uncertain. Promising results were recently reported for separate Phase 1 studies in ALS patients and PD patients. Affected tissue in these disorders shares features of elevated Fe, low glutathione and increased lipid peroxidation consistent with ferroptosis, a novel form of regulated cell death. We therefore evaluated the ability of CuII (atsm) to inhibit ferroptosis.Experimental Approach: Ferroptosis was induced in neuronal cell models by inhibition of glutathione peroxidase-4 activity with RSL3 or by blocking cystine uptake with erastin. Cell viability and lipid peroxidation were assessed and the efficacy of CuII (atsm) was compared to the known antiferroptotic compound liproxstatin-1.Key Results: CuII (atsm) protected against lipid peroxidation and ferroptotic lethality in primary and immortalised neuronal cell models (EC50 : ≈130 nM, within an order of magnitude of liproxstatin-1). NiII (atsm) also prevented ferroptosis with similar potency, whereas ionic CuII did not. In cell-free systems, CuII (atsm) and NiII (atsm) inhibited FeII -induced lipid peroxidation, consistent with these compounds quenching lipid radicals.Conclusions and Implications: The antiferroptotic activity of CuII (atsm) could therefore be the disease-modifying mechanism being tested in ALS and PD trials. With potency in vitro approaching that of liproxstatin-1, CuII (atsm) possesses favourable properties such as oral bioavailability and entry into the brain that make it an attractive investigational product for clinical trials of ferroptosis-related diseases. [ABSTRACT FROM AUTHOR]

Arterial hypertension represents a serious public health problem, being a major cause of morbidity and mortality worldwide. The availability of many antihypertensive therapeutic strategies still fails to adequately treat around 20% of hypertensive patients, who are considered resistant to conventional treatment. In the pathogenesis of hypertension, immune system mechanisms are activated and both the innate and adaptive immune responses play a crucial role. However, what, when and how the immune system is triggered during hypertension development is still largely undefined. In this context, this review highlights scientific advances in the manipulation of the immune system in order to attenuate hypertension and end-organ damage. Here, we discuss the potential use of immunosuppressants and immunomodulators as pharmacological tools to control the activation of the immune system, by non-specific and specific mechanisms, to treat hypertension and improve end-organ damage. Nevertheless, more clinical trials should be performed with these drugs to establish their therapeutic efficacy, safety and risk-benefit ratio in hypertensive conditions. LINKED ARTICLES: This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc. [ABSTRACT FROM AUTHOR]

Aim: According to clinical guidelines, it is recommended that patients with heart failure (HF) receive structured multidisciplinary care at nurse-led HF clinics in order to optimise treatment and avoid preventable readmissions. Today, there are HF clinics with specialist-trained nurses at almost all Swedish hospitals, but HF clinics remain scarce in primary care (PC). The aim of this study was two-fold: firstly, to evaluate the effects of systematically implementing nurse-led HF clinics in PC settings with regard to hospital healthcare utilisation and evidence-based HF treatment, and secondly to explore patients' experiences of HF clinics in PC.Methods and Results: The study had a pre-post design. Annual measurement were done between 2010-2017 regarding in-hospital healthcare consumption and medical treatment. Data from 2011-2017 after the implementation of HF clinics in PC in one county council Sweden were compared with baseline data collected before the implementation in 2010. The implementation of HF clinics in PC significantly reduced the number of HF-related hospital admissions by 27% (P < 0.001), HF hospital days by 27.3% (P < 0.001) and HF emergency room visits by 24% (P < 0.001). Further, patients were to a higher extent medically treated according to guidelines and satisfied with the care they received at the PC HF clinic.Conclusion: Nurse-led HF clinics in PC seem to be effective in reducing the need for in-hospital care and provide high quality person-centred care. [ABSTRACT FROM AUTHOR]

Objectives: Compared with normal fetuses, fetuses with hypoplastic left heart syndrome (HLHS) have smaller brain volumes and are at higher risk of brain injury, possibly due to diminished cerebral blood flow and oxygen content. By increasing cerebral oxygen delivery, maternal hyperoxygenation (MH) might improve brain development and reduce the risk of brain injury in these fetuses. This study investigated whether gestational age and baseline cerebrovascular resistance affect the response to MH in fetuses with HLHS.Methods: The study population comprised 43 fetuses with HLHS or HLHS variant referred for fetal echocardiography between January 2004 and September 2008. Middle cerebral artery (MCA) pulsatility index (PI), a surrogate measure of cerebrovascular resistance, was assessed between 20 and 41 weeks' gestation at baseline in room air (RA) and after 10 min of MH. Z-scores of MCA-PI were generated. A mixed-effects model was used to determine whether change in MCA-PI depends upon gestational age and baseline MCA-PI.Results: In RA and following MH, MCA-PI demonstrated a curvilinear relationship with gestational age in fetuses with HLHS, peaking at around 28 weeks and then falling more steeply near term. MCA-PI Z-score declined in a linear manner, such that it was 1.4 SD below that in normal fetuses at 38 weeks. Increase in MCA-PI Z-score after MH was first seen at ≥ 28 weeks. A baseline MCA-PI Z-score ≤ -0.96 was predictive of an increase in cerebrovascular resistance in response to MH.Conclusion: In fetuses with HLHS, MCA-PI first increases in response to MH at ≥ 28 weeks' gestation. A baseline MCA-PI Z-score ≤ -0.96 predicts an increase in cerebrovascular resistance in response to MH. These results may have implications for clinical trials utilizing MH as a neuroprotective agent. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Aims: A network meta-analysis (NMA) of all recommended drug groups for the treatment of heart failure with reduced ejection fraction (HFrEF), including their combinations, was performed to assess the relative efficacy and incremental benefit.Methods and Results: A search was made in biomedical databases for randomized controlled trials published between 1987 and 2017 on angiotensin-converting enzyme inhibitors (ACEIs), beta-blockers (BBs), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), ivabradine (IVA), or angiotensin receptor-neprilysin inhibitors (ARNI). A total of 58 relevant trials were identified. The relative efficacy of each treatment group (or combination) in terms of all-cause mortality, cardiovascular mortality, all-cause hospitalizations and hospitalizations for heart failure, per patient-year of follow-up, were combined in a random-effects Bayesian NMA. The pairwise comparison between each regimen and for each outcome was estimated. The NMA was dominated by 15 large-scale trials with between 1984 and 18 898 patient-years of follow-up. Combinations of drug groups showed incremental benefits on outcomes over single groups. The most effective combinations were ARNI+BB + MRA and ACEI+BB + MRA + IVA, showing reductions in all-cause mortality (vs. placebo) of 62% and 59%, respectively; hazard ratios were 0.38 [credible interval (CrI) 0.20-0.65] and 0.41 (CrI 0.21-0.70); and in all-cause hospitalizations with reductions of 42% for both. These two combinations were also the most effective for the other outcomes studied.Conclusion: Our analysis shows that the incremental use of combinations of disease-modifying therapies has resulted in the progressive improvement in mortality and hospitalization outcomes in HFrEF. Our findings support the current guideline recommendations. [ABSTRACT FROM AUTHOR]

Background and Purpose: Recent crystal structures of GPCRs have emphasized the previously unappreciated role of the second extracellular (E2) loop in ligand binding and gating and receptor activation. Here, we have assessed the role of the E2 loop in the activation of the melatonin MT1 receptor and in the inactivation of the closely related orphan receptor GPR50.Experimental Approach: Chimeric MT1 -GPR50 receptors were generated and functionally analysed in terms of 2-[125 I]iodomelatonin binding, Gi /cAMP signalling and β-arrestin2 recruitment. We also used computational molecular dynamics (MD) simulations.Key Results: MD simulations of 300 ns revealed (i) the tight hairpin structure of the E2 loop of the MT1 receptor (ii) the most suitable features for melatonin binding in MT1 receptors and (iii) major predicted rearrangements upon MT1 receptor activation, stabilizing interaction networks between Phe179 or Gln181 in the E2 loop and transmembrane helixes 5 and 6. Functional assays confirmed these predictions, because reciprocal replacement of MT1 and GPR50 residues/domains led to the predicted loss- and gain-of-melatonin action of MT1 receptors and GPR50 respectively.Conclusions and Implications: Our work demonstrated the crucial role of the E2 loop for MT1 receptor and GPR50 function by proposing a model in which the E2 loop is important in stabilizing active MT1 receptor conformations and by showing how evolutionary processes appear to have selected for modifications in the E2 loop in order to make GPR50 unresponsive to melatonin.Linked Articles: This article is part of a themed section on Recent Developments in Research of Melatonin and its Potential Therapeutic Applications. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.16/issuetoc. [ABSTRACT FROM AUTHOR]

Background and Purpose: Antioxidants provide a promising therapeutic effect for the cardiovascular disease. Luteolin, a polyphenolic bioflavonoid, is known to confer cardioprotection, although the underlying mechanisms, especially the role of luteolin on the antioxidant enzymes, such as the peroxiredoxin family, remain unknown.Experimental Approach: We measured the effects of luteolin on myocardial ischaemia/reperfusion (MI/R) injury in vivo (Sprague-Dawley rats) and in vitro, together with the underlying mechanisms, with a focus on signalling by peroxiredoxins. H9c2 cells were used to assess the changes in peroxiredoxins and the other antioxidant enzymes. Oxidative stress, cardiac function, LDH release, ROS and infarct size were also assayed.Key Results: Luteolin exerted significant cardioprotective effects in vivo and in vitro via improving cardiac function, increasing the expression of anti-apoptotic protein Bcl-2 and decreasing the pro-apoptotic protein Bax and active caspases 3 and 9, associated with MI/R. Mechanistically, luteolin markedly enhanced expression of peroxiredoxin II, without significant effects on other forms of peroxiredoxin, catalase or SOD1. Molecular docking showed that luteolin could indeed bind to the enzymic active pocket of peroxiredoxin II. Furthermore, down-regulation of peroxiredoxin II by peroxiredoxin II-antisense, administered by adenovirus infection of H9c2 cardiomyocytes, and inhibition of peroxiredoxin II in vivo significantly reversed the cardioprotective effects of luteolin.Conclusions and Implications: Our findings, for the first time, demonstrate that luteolin protects against MI/R injury through promoting signalling through the endogenous antioxidant enzyme, peroxiredoxin II, indicating the important beneficial role of this antioxidant system in the heart. [ABSTRACT FROM AUTHOR]

Background and Purpose: An appropriate inflammatory response is necessary for cardiac healing after acute myocardial infarction (MI). Resolvin E1 (RvE1) is an anti-inflammatory and pro-resolution lipid mediator derived from eicosapentaenoic acid. Here we have investigated the effects of RvE1 on the recovery of cardiac function after MI in mice.Experimental Approach: Acute MI was induced by surgical ligation of the left anterior descending artery in male C57BL/6 mice. RvE1 (5 ng·g-1 ·day-1 ; i.p.) was given to mice at different times following MI. Cardiac function was monitored by transthoracic echocardiography at days 3, 7 and 14 after MI. Effects of RvE1 on the migration of subpopulations of monocytes/macrophages (Mos/Mps, Ly6Chi and Ly6Clow ) were examined by flow cytometry and transwell assay.Key Results: RvE1 administration from days 1 to 7 post-MI improved cardiac function, whereas treatment from days 7 to 14 markedly inhibited recovery of cardiac function. Early treatment with RvE1 post-MI suppressed the infiltration of dominant Ly6Chi Mos/Mps and secretion of pro-inflammatory cytokines in injured hearts, which protected cardiomyocytes against apoptosis in the peri-infarct zones. Contrastingly, treatment with RvE1 1 week after MI decreased infiltration of Ly6Clow Mos/Mps and expression of pro-angiogenic factors in cardiac tissue, consequently reducing neovascularization in the peri-infarct zones. Additionally, RvE1 inhibited Mp migration by activating ChemR23 receptors.Conclusion and Implications: Treatment with RvE1 during the initial 7 days after MI facilitated cardiac healing by suppressing pro-inflammatory cytokine secretion, indicating that RvE1 may serve as an early therapeutic agent for acute MI.Linked Articles: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc. [ABSTRACT FROM AUTHOR]

Objective: The ketones d-β-hydroxybutyrate (BHB) and acetoacetate are elevated during prolonged fasting or during a "ketogenic" diet. Although weight loss on a ketogenic diet may be associated with decreased appetite and altered gut hormone levels, it is unknown whether such changes are caused by elevated blood ketones. This study investigated the effects of an exogenous ketone ester (KE) on appetite.Methods: Following an overnight fast, subjects with normal weight (n = 15) consumed 1.9 kcal/kg of KE, or isocaloric dextrose (DEXT), in drinks matched for volume, taste, tonicity, and color. Blood samples were analyzed for BHB, glucose, insulin, ghrelin, glucagon-like peptide 1 (GLP-1), and peptide tyrosine tyrosine (PYY), and a three-measure visual analogue scale was used to measure hunger, fullness, and desire to eat.Results: KE consumption increased blood BHB levels from 0.2 to 3.3 mM after 60 minutes. DEXT consumption increased plasma glucose levels between 30 and 60 minutes. Postprandial plasma insulin, ghrelin, GLP-1, and PYY levels were significantly lower 2 to 4 hours after KE consumption, compared with DEXT consumption. Temporally related to the observed suppression of ghrelin, reported hunger and desire to eat were also significantly suppressed 1.5 hours after consumption of KE, compared with consumption of DEXT.Conclusions: Increased blood ketone levels may directly suppress appetite, as KE drinks lowered plasma ghrelin levels, perceived hunger, and desire to eat. [ABSTRACT FROM AUTHOR]

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Objective: The objective of this study was to test whether behavioral weight loss (BWL) intervention decreases headaches in women with comorbid migraine and overweight or obesity.Methods: This randomized, single-blind trial allocated women 18 to 50 years old with 4 to 20 migraine days per month and a BMI = 25.0-49.9 kg/m2 to 16 weeks of BWL (n = 54), which targeted exercise and eating behaviors for weight loss, or to migraine education control (ME, n = 56), which delivered didactic instruction on migraine and treatments. Participants completed a 4-week smartphone headache diary at baseline, posttreatment (16-20 wk), and follow-up (32-36 wk). The primary outcome was posttreatment change in migraine days per month, analyzed via linear mixed effects models.Results: Of 110 participants randomly assigned, 85 (78%) and 80 (73%) completed posttreatment and follow-up. Although the BWL group achieved greater weight loss (mean [95% CI] in kilograms) than the ME group at posttreatment (-3.8 [-2.5 to -5.0] vs. + 0.9 [-0.4 to 2.2], P < 0.001) and follow-up (-3.2 [-2.0 to -4.5] vs. + 1.1 [-0.2 to 2.4], P < 0.001), there were no significant group (BWL vs. ME) differences (mean [95% CI]) in migraine days per month at posttreatment (-3.0 [-2.0 to -4.0] vs. -4.0 [-2.9 to -5.0], P = 0.185) or follow-up (-3.8 [-2.7 to -4.8] vs. -4.4 [-3.4 to -5.5], P = 0.378).Conclusions: Contrary to hypotheses, BWL and ME yielded similar, sustained reductions in migraine headaches. Future research should evaluate whether adding BWL to standard pharmacological and/or nonpharmacological migraine treatment approaches yields greater benefits. [ABSTRACT FROM AUTHOR]

Background and Purpose: Sustained pulmonary vasoconstriction and excessive pulmonary vascular remodelling are two major causes of elevated pulmonary vascular resistance in patients with pulmonary arterial hypertension. The purpose of this study was to investigate whether chloroquine induced relaxation in the pulmonary artery (PA) and attenuates hypoxia-induced pulmonary hypertension (HPH).Experimental Approach: Isometric tension was measured in rat PA rings pre-constricted with phenylephrine or high K+ solution. PA pressure was measured in mouse isolated, perfused and ventilated lungs. Fura-2 fluorescence microscopy was used to measure cytosolic free Ca2+ concentration levels in PA smooth muscle cells (PASMCs). Patch-clamp experiments were performed to assess the activity of voltage-dependent Ca2+ channels (VDCCs) in PASMC. Rats exposed to hypoxia (10% O2 ) for 3 weeks were used as the model of HPH or Sugen5416/hypoxia (SuHx) for in vivo experiments.Key Results: Chloroquine attenuated agonist-induced and high K+ -induced contraction in isolated rat PA. Pretreatment with l-NAME or indomethacin and functional removal of endothelium failed to inhibit chloroquine-induced PA relaxation. In PASMC, extracellular application of chloroquine attenuated store-operated Ca2+ entry and ATP-induced Ca2+ entry. Furthermore, chloroquine also inhibited whole-cell Ba2+ currents through VDCC in PASMC. In vivo experiments demonstrated that chloroquine treatment ameliorated the HPH and SuHx models.Conclusions and Implications: Chloroquine is a potent pulmonary vasodilator that may directly or indirectly block VDCC, store-operated Ca2+ channels and receptor-operated Ca2+ channels in PASMC. The therapeutic potential of chloroquine in pulmonary hypertension is probably due to the combination of its vasodilator, anti-proliferative and anti-autophagic effects. [ABSTRACT FROM AUTHOR]

Background and Purpose: Atherosclerosis is characterized by a chronic non-resolving inflammation in the arterial wall. Aspirin-triggered lipoxin A4 (ATL) is a potent anti-inflammatory mediator, involved in the resolution of inflammation. However, the therapeutic potential of immune targeting by means of ATL in atherosclerosis has not previously been explored. The aim of the present study was to determine the effects of ATL and its receptor Fpr2 on atherosclerosis development and progression in apolipoprotein E deficient (ApoE-/- ) mice.Experimental Approach: ApoE-/-  × Fpr2+/+ and ApoE-/-  × Fpr2-/- mice were generated. Four-week-old mice fed a high-fat diet for 4 weeks and 16-week-old mice fed chow diet received osmotic pumps containing either vehicle or ATL for 4 weeks. Atherosclerotic lesion size and cellular composition were measured in the aortic root and thoracic aorta. Lipid levels and leukocyte counts were measured in blood and mRNA was isolated from abdominal aorta and spleen.Key Results: ATL blocked atherosclerosis progression in the aortic root and thoracic aorta of ApoE-/- mice. In addition, ATL reduced macrophage infiltration and apoptotic cells in atherosclerotic lesions. The mRNA levels of several cytokines and chemokines in the spleen and aorta were reduced by ATL, whereas circulating leukocyte levels were unchanged. The ATL-induced athero-protection was absent in ApoE-/- mice lacking the Fpr2 receptor.Conclusion and Implications: ATL blocked atherosclerosis progression by means of an Fpr2-mediated reduced local and systemic inflammation. These results suggest this anti-inflammatory and pro-resolving agent has therapeutic potential for the treatment of atherosclerosis.Linked Articles: This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc. [ABSTRACT FROM AUTHOR]

Objective: To examine whether medical homes have heterogeneous effects in different subpopulations, leveraging the interpretations from a variety of statistical techniques.Data Sources/study Setting: Secondary claims data from the NC Medicaid program for 2004-2007. The sample included all adults with diagnoses of schizophrenia, bipolar disorder, or major depression who were not dually enrolled in Medicare or in a nursing facility.Study Design: We modeled a number of monthly service use, adherence, and expenditure outcomes using fixed effects, generalized estimating equation with and without inverse probability of treatment weights, and instrumental variables analyses.Data Collection: Data were received from the Carolina Cost and Quality Initiative.Principal Findings: The four estimation techniques consistently revealed generally positive associations between medical homes and access to primary care, specialty mental health care, greater medication adherence, slightly lower emergency room use, and greater expenditures. These findings were consistent across all three major severe mental illness diagnostic groups. Some heterogeneity in effects were noted, especially in preventive screening.Conclusions: Expanding access to primary care-based medical homes for people with severe mental illness may not save money for insurance providers, due to greater access for important outpatient services with little cost offset. Health services research examining more of the treatment heterogeneity may contribute to more realistic projections about medical homes outcomes. [ABSTRACT FROM AUTHOR]

Objective: To develop and validate rates of potentially preventable emergency department (ED) visits as indicators of community health.Data Sources: Agency for Healthcare Research and Quality, Healthcare Cost and Utilization Project 2008-2010 State Inpatient Databases and State Emergency Department Databases.Study Design: Empirical analyses and structured panel reviews.Methods: Panels of 14-17 clinicians and end users evaluated a set of ED Prevention Quality Indicators (PQIs) using a Modified Delphi process. Empirical analyses included assessing variation in ED PQI rates across counties and sensitivity of those rates to county-level poverty, uninsurance, and density of primary care physicians (PCPs).Principal Findings: ED PQI rates varied widely across U.S. communities. Indicator rates were significantly associated with county-level poverty, median income, Medicaid insurance, and levels of uninsurance. A few indicators were significantly associated with PCP density, with higher rates in areas with greater density. A clinical and an end-user panel separately rated the indicators as having strong face validity for most uses evaluated.Conclusions: The ED PQIs have undergone initial validation as indicators of community health with potential for use in public reporting, population health improvement, and research. [ABSTRACT FROM AUTHOR]

Copyright of Developmental Medicine & Child Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background Shared decision making is an important component of patient-centred care and decision aids are tools designed to support patients' decision making and help patients with depression to make informed choices. Objective The study aim was to assess the effectiveness of a web-based decision aid for patients with unipolar depression. Design Randomized controlled trial. Setting and participants Adults diagnosed with a major depressive disorder and recruited in primary care centres were included and randomized to the decision aid (n=68) or usual care (n=79). Intervention Patients in the decision aid group reviewed the decision aid accompanied by a researcher. Outcome measures Knowledge about treatment options, decisional conflict, treatment intention and preference for participation in decision making. We also developed a pilot measure of concordance between patients' goals and concerns about treatment options and their treatment intention. Results Intervention significantly improved knowledge ( P<.001) and decisional conflict ( P<.001), and no differences were observed in treatment intention, preferences for participation, or concordance. One of the scales developed to measure goals and concerns showed validity issues. Conclusion The decision aid 'Decision making in depression' is effective improving knowledge of treatment options and reducing decisional conflict of patients with unipolar depression. More research is needed to establish a valid and reliable measure of concordance between patients' goals and concerns regarding pharmacological and psychological treatment, and the choice made. [ABSTRACT FROM AUTHOR]

Background and Purpose: Our initial aim was to generate cannabinoid agents that control spasticity, occurring as a consequence of multiple sclerosis (MS), whilst avoiding the sedative side effects associated with cannabis. VSN16R was synthesized as an anandamide (endocannabinoid) analogue in an anti-metabolite approach to identify drugs that target spasticity.Experimental Approach: Following the initial chemistry, a variety of biochemical, pharmacological and electrophysiological approaches, using isolated cells, tissue-based assays and in vivo animal models, were used to demonstrate the activity, efficacy, pharmacokinetics and mechanism of action of VSN16R. Toxicological and safety studies were performed in animals and humans.Key Results: VSN16R had nanomolar activity in tissue-based, functional assays and dose-dependently inhibited spasticity in a mouse experimental encephalomyelitis model of MS. This effect occurred with over 1000-fold therapeutic window, without affecting normal muscle tone. Efficacy was achieved at plasma levels that are feasible and safe in humans. VSN16R did not bind to known CB1 /CB2 /GPPR55 cannabinoid-related receptors in receptor-based assays but acted on a vascular cannabinoid target. This was identified as the major neuronal form of the big conductance, calcium-activated potassium (BKCa ) channel. Drug-induced opening of neuronal BKCa channels induced membrane hyperpolarization, limiting excessive neural-excitability and controlling spasticity.Conclusions and Implications: We identified the neuronal form of the BKCa channel as the target for VSN16R and demonstrated that its activation alleviates neuronal excitability and spasticity in an experimental model of MS, revealing a novel mechanism to control spasticity. VSN16R is a potential, safe and selective ligand for controlling neural hyper-excitability in spasticity. [ABSTRACT FROM AUTHOR]

Copyright of Tropical Medicine & International Health is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background and Purpose: Metformin, one of the most frequently prescribed medications for type 2 diabetes, reportedly exerts BP-lowering effects in patients with diabetes. However, the effects and underlying mechanisms of metformin on BP in non-diabetic conditions remain to be determined. The aim of the present study was to determine the effects of metformin on angiotensin II (Ang II) infusion-induced hypertension in vivo.Experimental Approach: The effects of metformin on BP were investigated in wild-type (WT) C57BL/6J mice and in mice lacking AMP-activated protein kinase α2 (AMPKα2) mice with or without Ang II infusion. Also, the effect of metformin on Ang II-induced endoplasmic reticulum (ER) stress was explored in cultured human vascular smooth muscle cells (hVSMCs).Key Results: Metformin markedly reduced BP in Ang II-infused WT mice but not in AMPKα2-deficient mice. In cultured hVSMCs, Ang II treatment resulted in inactivation of AMPK, as well as the subsequent induction of spliced X-box binding protein-1, phosphorylation of eukaryotic translation initiation factor 2α and expression of glucose-regulated protein 78 kDa, representing three well-characterized ER stress biomarkers. Moreover, AMPK activation by metformin ablated Ang II-induced ER stress in hVSMCs. Mechanistically, metformin-activated AMPKα2 suppressed ER stress by increasing phospholamban phosphorylation.Conclusion and Implications: Metformin alleviates Ang II-triggered hypertension in mice by activating AMPKα2, which mediates phospholamban phosphorylation and inhibits Ang II-induced ER stress in vascular smooth muscle cells. [ABSTRACT FROM AUTHOR]

Objective This study discusses the challenges and successes of engaging young people in a project aimed at developing an online counselling intervention for young people affected by cancer. Context For younger people with a diagnosis of cancer or who are caring for someone with cancer, the psychosocial consequences can create significant challenges for their social and educational development. Whilst young people have been shown to be reluctant to make use of traditional face-to-face counselling, research is beginning to suggest that effective therapeutic relationships can be formed with young people online. Design The first phase of the study involved working with a 'Young Persons' Panel' of healthy school pupils and university students to develop and pilot an online counselling intervention and study materials in preparation for a pilot evaluation of the intervention. Intervention An avatar-based virtual reality counselling world was created where young people can create their own avatar and receive counselling over the Internet from a qualified counsellor via an avatar in a virtual reality world. Findings The process of engaging young people in the C: EVOLVE project enabled a unique intervention to be developed and demonstrated positive developmental opportunities. However, despite the rigorous approach to the development of the intervention, initial attempts within the pilot evaluation phase of the study showed difficulties recruiting to the study, and this phase of the study has currently ceased whilst further exploratory work takes place. Conclusion This study has demonstrated the complexities of intervention development and evaluation research targeted at young people and the challenges created when attempting to bring clinical practice and research evaluation together. [ABSTRACT FROM AUTHOR]

Answer questions and earn CME/CNE Patients with breast cancer commonly use complementary and integrative therapies as supportive care during cancer treatment and to manage treatment-related side effects. However, evidence supporting the use of such therapies in the oncology setting is limited. This report provides updated clinical practice guidelines from the Society for Integrative Oncology on the use of integrative therapies for specific clinical indications during and after breast cancer treatment, including anxiety/stress, depression/mood disorders, fatigue, quality of life/physical functioning, chemotherapy-induced nausea and vomiting, lymphedema, chemotherapy-induced peripheral neuropathy, pain, and sleep disturbance. Clinical practice guidelines are based on a systematic literature review from 1990 through 2015. Music therapy, meditation, stress management, and yoga are recommended for anxiety/stress reduction. Meditation, relaxation, yoga, massage, and music therapy are recommended for depression/mood disorders. Meditation and yoga are recommended to improve quality of life. Acupressure and acupuncture are recommended for reducing chemotherapy-induced nausea and vomiting. Acetyl-L-carnitine is not recommended to prevent chemotherapy-induced peripheral neuropathy due to a possibility of harm. No strong evidence supports the use of ingested dietary supplements to manage breast cancer treatment-related side effects. In summary, there is a growing body of evidence supporting the use of integrative therapies, especially mind-body therapies, as effective supportive care strategies during breast cancer treatment. Many integrative practices, however, remain understudied, with insufficient evidence to be definitively recommended or avoided. CA Cancer J Clin 2017;67:194-232. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background and Purpose: Hyperglycaemia increases glucose concentrations in airway surface liquid and increases the risk of pulmonary Pseudomonas aeruginosa infection. We determined whether reduction of blood and airway glucose concentrations by the anti-diabetic drug dapagliflozin could reduce P. aeruginosa growth/survival in the lungs of diabetic mice.Experimental Approach: The effect of dapagliflozin on blood and airway glucose concentration, the inflammatory response and infection were investigated in C57BL/6J (wild type, WT) or leptin receptor-deficient (db/db) mice, treated orally with dapagliflozin prior to intranasal dosing with LPS or inoculation with P. aeruginosa. Pulmonary glucose transport and fluid absorption were investigated in Wistar rats using the perfused fluid-filled lung technique.Key Results: Fasting blood, airway glucose and lactate concentrations were elevated in the db/db mouse lung. LPS challenge increased inflammatory cells in bronchoalveolar lavage fluid from WT and db/db mice with and without dapagliflozin treatment. P. aeruginosa colony-forming units (CFU) were increased in db/db lungs. Pretreatment with dapagliflozin reduced blood and bronchoalveolar lavage glucose concentrations and P. aeruginosa CFU in db/db mice towards those seen in WT. Dapagliflozin had no adverse effects on the inflammatory response in the mouse or pulmonary glucose transport or fluid absorption in the rat lung.Conclusion and Implications: Pharmacological lowering of blood glucose with dapagliflozin effectively reduced P. aeruginosa infection in the lungs of diabetic mice and had no adverse pulmonary effects in the rat. Dapagliflozin has potential to reduce the use, or augment the effect, of antimicrobials in the prevention or treatment of pulmonary infection. [ABSTRACT FROM AUTHOR]

Objective: In-person lifestyle interventions for obesity treatment yield significant improvements in depression. These improvements may be attributed to the excellent weight losses produced by in-person interventions. In contrast, Internet programs yield more modest weight losses, and their effect on depression is unknown. This study is the first to examine whether Internet-delivered obesity treatment impacts depressive symptoms.Methods: Participants (N = 136) were randomized to either a community campaign plus Internet behavioral weight loss (IBWL) or community campaign alone (Control). IBWL did not include online social support components. A measure of depressive symptoms was administered, and weight was objectively assessed.Results: Of the total sample, 24% met the clinical cutoff for elevated depression risk at baseline. IBWL participants lost more weight during treatment (P = 0.005) and experienced significantly greater improvements in depressive symptoms (P = 0.02). Among participants who met the clinical cutoff for elevated risk for depression at baseline, those assigned to IBWL had greater improvements in depressive symptoms during treatment compared to Control (P = 0.033). Consequently, at post-treatment, a smaller percentage of IBWL participants were at elevated risk for depression.Conclusions: This study is the first to show that Internet-delivered obesity treatment improves depression risk and depressive symptoms in individuals with overweight or obesity. [ABSTRACT FROM AUTHOR]

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Background and Purpose: Myocardial cAMP elevation confers cardioprotection against ischaemia/reperfusion (I/R) injury. cAMP activates two independent signalling pathways, PKA and Epac. This study investigated the cardiac effects of activating PKA and/or Epac and their involvement in cardioprotection against I/R.Experimental Approach: Hearts from male rats were used either for determination of PKA and PKC activation or perfused in the Langendorff mode for either cardiomyocyte isolation or used to monitor functional activity at basal levels and after 30 min global ischaemia and 2 h reperfusion. Functional recovery and myocardial injury during reperfusion (LDH release and infarct size) were evaluated. Activation of PKA and/or Epac in perfused hearts was induced using cell permeable cAMP analogues in the presence or absence of inhibitors of PKA, Epac and PKC. H9C2 cells and cardiomyocytes were used to assess activation of Epac and effect on Ca2+ transients.Key Results: Selective activation of either PKA or Epac was found to trigger a positive inotropic effect, which was considerably enhanced when both pathways were simultaneously activated. Only combined activation of PKA and Epac induced marked cardioprotection against I/R injury. This was accompanied by PKCε activation and repressed by inhibitors of PKA, Epac or PKC.Conclusion and Implications: Simultaneous activation of both PKA and Epac induces an additive inotropic effect and confers optimal and marked cardioprotection against I/R injury. The latter effect is mediated by PKCε activation. This work has introduced a new therapeutic approach and targets to protect the heart against cardiac insults. [ABSTRACT FROM AUTHOR]

Aim: Jaundice may cause auditory toxicity (auditory neuropathy and hearing loss). However, total serum bilirubin (TSB) does not discriminate neonates at risk for auditory toxicity. We compared TSB, bilirubin:albumin molar ratio (BAMR), and unbound bilirubin for their association with auditory toxicity in neonates with severe jaundice (TSB ≥342μmol/L, or that met exchange transfusion).Method: Neonates greater or equal to 34 weeks gestational age with severe jaundice during the first 2 postnatal weeks were eligible for prospective cohort study, unless they had craniofacial malformations, chromosomal disorders, toxoplasmosis, other infections, rubella, cytomegalovirus, herpes simplex infections, surgery, or family history of congenital deafness.Results: Twenty-eight out of 100 neonates (mean gestational age 37.4wks; 59 males, 41 females) had auditory toxicity. Peak unbound bilirubin, but not peak TSB and BAMR, was associated with auditory toxicity (p<0.05) in neonates with severe (TSB <427.5μmol/L) and extreme hyperbilirubinemia (TSB ≥427.5μmol/L). Area under the receiver operating characteristic curve for unbound bilirubin (0.78) was significantly greater (p=0.03) than TSB (0.54) among neonates with severe but not extreme hyperbilirubinemia.Interpretation: Unbound bilirubin is more strongly associated with auditory toxicity than TSB and/or BAMR in greater or equal to 34 weeks gestational age neonates with severe jaundice. Unbound bilirubin is a better predictor than TSB in neonates with severe hyperbilirubinemia. [ABSTRACT FROM AUTHOR]

Aim: To assess changes over time in parents' expectations of adult milestone achievement (college attendance, full-time job attainment, independent living, marriage, parenthood) for young people with spina bifida, to examine how expectancies relate to actual milestone achievement, and to compare milestone achievement in emerging adults with spina bifida with that of peers with typical development.Method: Sixty-eight families of children with spina bifida (mean age 8y 4mo, 37 males, 31 females) and 68 families of children with typical development (mean age 8y 6mo, 37 males, 31 females) participated at Time 1. At all subsequent timepoints, parents of young people with spina bifida were asked to rate their expectations of emerging adulthood milestone achievement. At Time 7, when participants were 22 to 23 years old, milestone achievement was assessed.Results: Parents of young people with spina bifida lowered their expectations over time for most milestones; parents of children with higher cognitive ability reported decreases of lower magnitude. Parent expectancies were optimistic and unrelated to actual milestone achievement. Emerging adults with spina bifida were less likely than individuals with typical development to achieve all milestones.Interpretation: Optimistic parental expectations may be adaptive for children with spina bifida and their families, although it is important for families to set realistic goals. Healthcare providers serve a key role in helping families of young people with spina bifida prepare for emerging adulthood. [ABSTRACT FROM AUTHOR]

Objective: To determine the effect of prebiotic supplementation on metabolic endotoxemia and systemic inflammation in adults with overweight and obesity.Methods: Samples from a previously conducted randomized, double-blind, placebo-controlled trial were used for analysis. Participants were randomized to 21 g of oligofructose (n = 20; BMI 30.4 kg/m2 ) or a maltodextrin placebo (n = 17; BMI 29.5 kg/m2 ) for 12 weeks. A total of 37 participants had samples available for the current analysis. Resistin, adiponectin, plasminogen activator inhibitor-1 (PAI-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and macrophage chemoattractant protein-1 (MCP-1) were quantified using MILLIPLEX® assays. Lipopolysaccharide (LPS) was measured using PyroGene™ Recombinant Factor C Assay.Results: Plasma LPS concentrations were reduced by 40% in the oligofructose group over 12 weeks compared to a 48% increase in the placebo group (P = 0.04). PAI-1, a risk factor for thrombosis, was reduced to a greater extent in the oligofructose group (-17.3 ± 2.6 ng/ml) compared to the placebo group (-9.7 ± 1.8 ng/ml; P = 0.03). Oligofructose did not affect IL-6, TNF-α, MCP-1, adiponectin, or resistin.Conclusions: Oligofructose reduces metabolic endotoxemia and PAI-1. Incorporating prebiotics into the diet through supplements or functional foods may help mitigate some markers of obesity-associated inflammation. [ABSTRACT FROM AUTHOR]