LncRNA DLEU2 regulates sirtuins and mitochondrial respiratory chain complex IV: a novel pathway in obesity and offspring's health.

BACKGROUND: Long non-coding RNAs (lncRNAs) have emerged as a rapidly expanding area of interest in chronic diseases. They are mostly unknown for roles in metabolic regulation. Sirtuins, an epigenetic modulator class, regulate metabolic pathways. However, how sirtuins are regulated via lncRNA is unknown. We hypothesized that a high-fat high-fructose diet (HFD-HF) during pregnancy would increase the risk for obesity via lncRNA-Sirtuin pathways. METHODS: Female C57Bl/6 mice (F0) were fed either chow diet (CD) or HFD-HF for 6 weeks till birth. The pups (F1) were fed either CD or HFD-HF for 20 weeks. Expression of Dleu2, sirtuins, mitochondrial respiratory complexes, and oxidative stress were investigated in the F1 livers. Fasting blood glucose, insulin sensitivity, glucose tolerance, body and tissues weight were measured. A mechanistic interaction was then carried out using a DLEU2 knockdown experiment in the HepG2 cell. RESULTS: Dleu2 and sirtuins were both significantly decreased in the livers of HFD-HF fed male F1 whose mothers were either fed CD or HFD-HF during reproductive and pregnancy windows. Confirming this connection, upon silencing DLEU2, transcription levels of SIRT1 through 6 and translational levels of SIRT1, 3, 5, and 6 were significantly downregulated. Knockdown of DLEU2 significantly decreased the protein level of cytochrome-c oxidase (complex IV, MTCO1) without altering other mitochondrial complexes, decreased mitochondrial membrane potential, decreased ATP, and increased reactive oxygen species. Interestingly, in F1 livers, the protein level of MTCO1 was also significantly decreased under an HFD-HF diet or even under chow diet if the mother was exposed to HFD-HF. CONCLUSION: Our findings reveal for the first time that one lncRNA can regulate sirtuins and a specific mitochondrial complex. Furthermore, diet or maternal diet can modulate Dleu2 and its downstream regulators in offspring, suggesting a potential role of DLEU2 in metabolic disorders over one or more generations.

Pilot phase results of a prospective, randomized controlled trial of narrowband ultraviolet B phototherapy in hospitalized COVID-19 patients.

COVID-19 morbidity and mortality are driven by poor immune regulation. Narrowband ultraviolet B (NB-UVB) phototherapy is standard of care in a number of immune-dysregulated diseases. To assess the efficacy of NB-UVB phototherapy for improving COVID-19 outcomes in high-risk, hospitalized, we developed the Adaptive Photo-Protection Trial. This is a multi-center, prospective, double-blinded, randomized, placebo-controlled trial. The pilot phase results are reported here. Consecutive patients admitted with a positive COVID-19 PCR were screened for eligibility. Enrolled subjects were computer randomized 1:1 to NB-UVB or placebo phototherapy. Subjects were treated daily with escalating doses on 27% of their body surface area for up to 8 consecutive days. Primary outcomes were safety and efficacy, defined as persistent or painful erythema and 28-day mortality. Comparisons were made via non-parametric exact tests. Patients in treatment (n = 15) and placebo (n = 15) arms had similar demographics. No adverse events occurred. Twenty eight-day mortality was 13.3% in treatment vs. 33.3% in placebo arms (p = 0.39). NB-UVB phototherapy in hospitalized COVID-19 patients was safe. Decreased mortality was observed in treated patients but this was statistically non-significant. Given its low-cost, scalability, and adjunctive nature, NB-UVB has the potential to improve COVID-19 outcomes. Continuation of this trial is warranted.

Interventions for self-management of medicines for community-dwelling people with dementia and mild cognitive impairment and their family carers: a systematic review.

BACKGROUND: people with dementia or mild cognitive impairment (MCI) and their family carers face challenges in managing medicines. How medicine self-management could be supported for this population is unclear. This review identifies interventions to improve medicine self-management for people with dementia and MCI and their family carers, and the core components of medicine self-management that they address. METHODS: a database search was conducted for studies with all research designs and ongoing citation search from inception to December 2021. The selection criteria included community-dwelling people with dementia and MCI and their family carers, and interventions with a minimum of one medicine self-management component. The exclusion criteria were wrong population, not focusing on medicine management, incorrect medicine self-management components, not in English and wrong study design. The results are presented and analysed through narrative synthesis. The review is registered [PROSPERO (CRD42020213302)]. Quality assessment was carried out independently applying the QATSDD quality assessment tool. RESULTS: 13 interventions were identified. Interventions primarily addressed adherence. A limited number focused on a wider range of medicine self-management components. Complex psychosocial interventions with frequent visits considered the person's knowledge and understanding, supply management, monitoring effects and side effects and communicating with healthcare professionals, and addressed more resilience capabilities. However, these interventions were delivered to family carers alone. None of the interventions described patient and public involvement. CONCLUSION: interventions, and measures to assess self-management, need to be developed which can address all components of medicine self-management to better meet the needs of people with dementia and MCI and their family carers.

Experiences of patients with heart failure with medicines at transition intervention: Findings from the process evaluation of the Improving the Safety and Continuity of Medicines management at Transitions of care (ISCOMAT) programme.

BACKGROUND: Medicines are often suboptimally managed for heart failure patients across the transition from hospital to home, potentially leading to poor patient outcomes. The Improving the Safety and Continuity Of Medicines management at Transitions of care programme included: understanding the problems faced by patients and healthcare professionals; developing and co-designing the Medicines at Transitions of care Intervention (MaTI); a cluster randomized controlled trial testing the effectiveness of a complex behavioural MaTI aimed at improving medicines management at the interface between hospitals discharge and community care for patients with heart failure; and a process evaluation. The MaTI included a patient-held My Medicines Toolkit; enhanced communication between the hospital and the patient's community pharmacist and increased engagement of the community pharmacist postdischarge. This paper reports on the patients' experiences of the MaTI and its implementation from the process evaluation. DESIGN: Twenty one-to-one semi-structured patient interviews from six intervention sites were conducted between November 2018 and January 2020. Data were analysed using the Framework method, involving patients as co-analysts. Interview data were triangulated with routine trial data, the Consolidated Framework for Implementation Research and a logic model. RESULTS: Within the hospital setting patients engaged with the toolkit according to whether staff raised awareness of the My Medicines Toolkit's importance and the time and place of its introduction. Patients' engagement with community pharmacy depended on their awareness of the community pharmacist's role, support sources and perceptions of involvement in medicines management. The toolkit's impact on patients' medicines management at home included reassurance during gaps in care, increased knowledge of medicines, enhanced ability to monitor health and seek support and supporting sharing medicines management between formal and informal care networks. CONCLUSION: Many patients perceived that the MaTI offered them support in their medicines management when transitioning from hospital into the community. Importantly, it can be incorporated into and built upon patients' lived experiences of heart failure. Key to its successful implementation is the quality of engagement of healthcare professionals in introducing the intervention. PATIENT OR PUBLIC CONTRIBUTION: Patients were involved in the study design, as qualitative data co-analysts and as co-authors.

Effect of Chronic Western Diets on Non-Alcoholic Fatty Liver of Male Mice Modifying the PPAR-γ Pathway via miR-27b-5p Regulation.

Western diets contribute to metabolic diseases. However, the effects of various diets and epigenetic mechanisms are mostly unknown. Here, six week-old C57BL/6J male and female mice were fed with a low-fat diet (LFD), high-fat diet (HFD), and high-fat high-fructose diet (HFD-HF) for 20 weeks. We determined that HFD-HF or HFD mice experienced significant metabolic dysregulation compared to the LFD. HFD-HF and HFD-fed male mice showed significantly increased body weight, liver size, and fasting glucose levels with downregulated PPARγ, SCD1, and FAS protein expression. In contrast, female mice were less affected by HFD and HFD-HF. As miR-27b contains a seed sequence in PPARγ, it was discovered that these changes are accompanied by male-specific upregulation of miR-27b-5p, which is even more pronounced in the HFD-HF group (p < 0.01 vs. LFD) compared to the HFD group (p < 0.05 vs. LFD). Other miR-27 subtypes were increased but not significantly. HFD-HF showed insignificant changes in fibrosis markers when compared to LFD. Interestingly, fat ballooning in hepatocytes was increased in HFD-fed mice compared to HFD-HF fed mice, however, the HFD-HF liver showed an increase in the number of small cells. Here, we concluded that chronic Western diet-composition administered for 20 weeks may surpass the non-alcoholic fatty liver (NAFL) stage but may be at an intermediate stage between fatty liver and fibrosis via miR-27b-5p-induced PPARγ downregulation.

Advancing metabolism research to overcome low litter survival in metabolically stressed mice.

Elucidating the mechanism underlying the transmission of metabolic disease to subsequent generations requires robust preclinical mouse breeding strategies. Western diets rich in fat and carbohydrates are contributing factors in the rise of diabetes and obesity rates worldwide. Therefore, determining the impact of Western diets consumed by parents on offspring and future generations is critical for understanding the perpetuation of these diseases. Specifically, epigenetic regulation and transgenerational inheritance of metabolic disease is an emerging field of study requiring robust murine models. However, a major challenge to transgenerational studies is offspring mortality, exacerbated by maternal stress during pregnancy. Here, we describe a challenge experienced in our metabolic research in Western diet-fed female mice leading to the loss of litters via pup mortality and cannibalism by the mother. Furthermore, our study evaluates various breeding schemes with pregnancy efficiency and refined husbandry techniques to overcome pup mortality and infanticide, to characterize dams' and pups' metabolic characteristics, and to determine the impact on physiology of dams under detailed breeding schemes.

Family involvement in timely detection of changes in health of nursing homes residents: A qualitative exploratory study.

AIMS AND OBJECTIVES: To explore family perspectives on their involvement in the timely detection of changes in their relatives' health in UK nursing homes. BACKGROUND: Increasingly, policy attention is being paid to the need to reduce hospitalisations for conditions that, if detected and treated in time, could be managed in the community. We know that family continue to be involved in the care of their family members once they have moved into a nursing home. Little is known, however, about family involvement in the timely detection of changes in health in nursing home residents. DESIGN: Qualitative exploratory study with thematic analysis. METHODS: A purposive sampling strategy was applied. Fourteen semi-structured one-to-one interviews with family members of people living in 13 different UK nursing homes. Data were collected from November 2015-March 2016. RESULTS: Families were involved in the timely detection of changes in health in three key ways: noticing signs of changes in health, informing care staff about what they noticed and educating care staff about their family members' changes in health. Families suggested they could be supported to detect timely changes in health by developing effective working practices with care staff. CONCLUSION: Families can provide a special contribution to the process of timely detection in nursing homes. Their involvement needs to be negotiated, better supported, as well as given more legitimacy and structure within the nursing home. RELEVANCE TO CLINICAL PRACTICE: Families could provide much needed support to nursing home nurses, care assistants and managers in timely detection of changes in health. This may be achieved through communication about their preferred involvement on a case-by-case basis as well as providing appropriate support or services.

CXCR3 deficiency enhances tumor progression by promoting macrophage M2 polarization in a murine breast cancer model.

Tumor associated macrophages play a vital role in determining the outcome of breast cancer. We investigated the contribution of the chemokine receptor CXCR3 to antitumor immune responses using a cxcr3 deficient mouse orthotopically injected with a PyMT breast cancer cell line. We observed that cxcr3 deficient mice displayed increased IL-4 production and M2 polarization in the tumors and spleens compared to WT mice injected with PyMT cells. This was accompanied by larger tumor development in cxcr3(-/-) than in WT mice. Further, tumor-promoting myeloid derived immune cell populations accumulated in higher proportions in the spleens of cxcr3 deficient mice. Interestingly, cxcr3(-/-) macrophages displayed a deficiency in up-regulating inducible nitric oxide synthase after stimulation by either IFN-γ or PyMT supernatants. Stimulation of bone marrow derived macrophages by PyMT supernatants also resulted in greater induction of arginase-1 in cxcr3(-/-) than WT mice. Further, cxcr3(-/-) T cells activated with CD3/CD28 in vitro produced greater amounts of IL-4 and IL-10 than T cells from WT mice. Our data suggests that a greater predisposition of cxcr3 deficient macrophages towards M2 polarization contributes to an enhanced tumor promoting environment in cxcr3 deficient mice. Although CXCR3 is known to be expressed on some macrophages, this is the first report that demonstrates a role for CXCR3 in macrophage polarization and subsequent breast tumor outcomes. Targeting CXCR3 could be a potential therapeutic approach in the management of breast cancer tumors.

Smoking cessation counseling for Asian immigrants with serious mental illness: using RE-AIM to understand challenges and lessons learned in primary care-behavioral health integration.

Engagement in modifiable risk behaviors, such as tobacco use, substantially contributes to early mortality rates in individuals with serious mental illness (SMI). There is an alarmingly high prevalence of tobacco use among subgroups of Asian Americans, such as immigrants and individuals with SMI, yet there are no empirically supported effective smoking cessation interventions that have been tailored to meet the unique cultural, cognitive, and psychological needs of Asian immigrants with SMI. In this article, we share the experiences of clinicians in the delivery of smoking cessation counseling to Asian American immigrants with SMI, in the context of an Asian-focused integrated primary care and behavioral health setting. Through a qualitative analysis of clinician perspectives organized with the RE-AIM framework, we outline challenges, lessons learned, and promising directions for delivering smoking cessation counseling to Asian American immigrant clients with SMI.

Pyrroloquinoline quinone attenuated benzyl butyl phthalate induced metabolic aberration and a hepatic metabolomic analysis.

Benzyl butyl phthalate (BBP) has recently been implicated as an obesogen. Our recent study demonstrated that BBP can exacerbate high fat diet (HFD) induced diabesity in male mice. Here, we explored if pyrroloquinoline quinone (PQQ), a natural antioxidant andphytochemical, can attenuate metabolic aberrations induced by HFD or HFD-BBPcombination. C57Bl/6 male and female mice were fed either a chow diet (CD) or HFD with or without BBP (3 mg/kg body weight/day)and/or PQQ (20 mg/kg/day)for 16 weeks. The mice's body and tissue weight, fasting blood glucose, glucose and insulin tolerance test, and liver metabolites level weremeasured. In HFD-fed male mice, PQQ significantly attenuated the increased body weight, liver weight, fasting blood glucose, and insulin intolerance under BBP exposure.Even though female mice did show some reversal of metabolic characteristics by PQQ, the response was not similar nor consistent with the male population. Amongthe 14 hepatic metabolites that were significantly altered by HFD compared to CD, only three major metabolites (acetyl-L-carnitine, DL-stachytine, and propionylcarnitine) were decreased. These three were shown to have more reduction under BBP exposure in the presence of HFD whereas with addition of PQQ, these metabolites were restored. Pathway analysis and literature search revealed that these metabolites were negatively associated with obesity and were involved in several pathways including beta-oxidation, oxidative stress, and mitochondrial function. Overall,this finding indicated the potential use of PQQ to restore thewide range of aberrant metabolic effectinduced by an obesogen in the presence of a western diet.

Using routine healthcare data to evaluate the impact of the Medicines at Transitions Intervention (MaTI) on clinical outcomes of patients hospitalised with heart failure: protocol for the Improving the Safety and Continuity Of Medicines management at Transitions of care (ISCOMAT) cluster randomised controlled trial with embedded process evaluation, health economics evaluation and internal pilot.

INTRODUCTION: Heart failure affects 26 million people globally, approximately 900 thousand people in the UK, and is increasing in incidence. Appropriate management of medicines for heart failure at the time of hospital discharge reduces readmissions, improves quality of life and increases survival. The Improving the Safety and Continuity Of Medicines management at Transitions (ISCOMAT) trial tests the effectiveness of the Medicines at Transition Intervention (MaTI), which aims to enhance self-care and increase community pharmacy involvement in the medicines management of heart failure patients. METHODS AND ANALYSIS: ISCOMAT is a parallel-group cluster randomised controlled trial, randomising 42 National Health Service trusts with cardiology wards in England on a 1:1 basis to implement the MaTI or treatment as usual. Around 2100 patients over the age of 18 admitted to hospital with heart failure with at least moderate left ventricular systolic dysfunction within the last 5 years, and planned discharge to the geographical area of the cluster will be recruited. The MaTI consists of training for staff, a toolkit for participants, transfer of discharge information to community pharmacies and a medicines reconciliation/review. Treatment as usual is determined by local policy and practices. The primary outcome is a composite of all-cause mortality and heart failure-related hospitalisation at 12 months postregistration obtained from national electronic health records. The key secondary outcome is continued prescription of guideline-indicated therapies at 12 months measured via patient-reported data and Hospital Episode Statistics. The trial contains a parallel mixed-methods process evaluation and an embedded health economics study. ETHICS AND DISSEMINATION: The study obtained approval from the Yorkshire and the Humber-Bradford Leeds Research Ethics Committee; REC reference 18/YH/0017. Findings will be disseminated via academic and policy conferences, peer-reviewed publications and social media. Amendments to the protocol are disseminated to all relevant parties as required. TRIAL REGISTRATION NUMBER: ISRCTN66212970; Pre-results.

Developing effective child death review: a study of 'early starter' child death overview panels in England.

AIM: This qualitative study of a small number of child death overview panels aimed to observe and describe their experience in implementing new child death review processes, and making prevention recommendations. METHODS: Nine sites reflecting a geographic and demographic spread were selected from Local Safeguarding Children Boards across England. Data were collected through a combination of questionnaires, interviews, structured observations, and evaluation of documents. Data were subjected to qualitative analysis. RESULTS: Data analysis revealed a number of themes within two overarching domains: the systems and structures in place to support the process; and the process and function of the panels. The data emphasised the importance of child death review being a multidisciplinary process involving senior professionals; that the process was resource and time intensive; that effective review requires both quantitative and qualitative information, and is best achieved through a structured analytic framework; and that the focus should be on learning lessons, not on trying to apportion blame. In 17 of the 24 cases discussed by the panels, issues were raised that may have indicated preventable factors. A number of examples of recommendations relating to injury prevention were observed including public awareness campaigns, community safety initiatives, training of professionals, development of protocols, and lobbying of politicians. CONCLUSIONS: The results of this study have helped to inform the subsequent establishment of child death overview panels across England. To operate effectively, panels need a clear remit and purpose, robust structures and processes, and committed personnel. A multi-agency approach contributes to a broader understanding of and response to children's deaths.

A moderate physiological dose of benzyl butyl phthalate exacerbates the high fat diet-induced diabesity in male mice.

Exposure to endocrine disrupting chemicals (EDCs) used in plastic manufacturing processes may be contributing to the current increase in metabolic disorders. Here, we determined that benzyl butyl phthalate (BBP), a common EDC and food packaging plasticizer, mixed into chow diet (CD) and high fat diets (HFD) at varying concentrations (4 µg/kg body weight (bw)/day, 169 µg/kg bw/day, 3 mg/kg bw/day, 50 mg/kg bw/day) produced a number of detrimental and sex-specific metabolic effects in C57BL/6 male and female mice after 16 weeks. Male mice exposed to moderate (3 mg/kg bw/day) concentrations of BBP in an HFD were especially affected, with significant increases in body weight due to significant increases in weight of liver and adipose tissue. Other doses did not show any significant changes when compared to only CD or HFD alone. HFD in the presence of 3 mg/kg bw/day BBP showed significant increases in fasting blood glucose, glucose intolerance, and insulin intolerance when compared to HFD alone. Furthermore, this group significantly alters transcriptional regulators involved in hepatic lipid synthesis and its downstream pathway. Interestingly, most of the BBP doses had no phenotypic effect when mixed with CD and compared to CD alone. The female mice did not show a similar response as the male population even though they consumed a similar amount of food. Overall, these data establish a dose which can be used for a BBP-induced metabolic research model and suggest that a moderate dosage level of EDC exposure can contribute to widely ranging metabolic effects.

Improving the Safety and Continuity Of Medicines management at Transitions of care (ISCOMAT): protocol for a process evaluation of a cluster randomised control trial.

INTRODUCTION: A key priority for the UK National Health Service and patients is to ensure that medicines are used safely and effectively. However, medication changes are not always optimally communicated and implemented when patients transfer from hospital into community settings. Heart failure is a common reason for admission to hospital. Patients with heart failure have a high burden of morbidity, mortality and complex pharmacotherapeutic regimens. The Improving the Safety and Continuity Of Medicines management at Transitions of care programme comprises a cluster randomised controlled trial which will test the effectiveness of a complex behavioural intervention aimed at improving medications management at the interface between hospitals discharge and community care. We will conduct a rigorous process evaluation to inform interpretation of the trial findings, inform implementation of the intervention on a wider scale and aid dissemination of the intervention. METHODS AND ANALYSIS: The process evaluation will be conducted in six purposively selected intervention sites (ie, hospital trusts and associated community pharmacies) using a mixed-methods design. Fidelity and barriers/enablers of implementation of the Medicines at Transitions Intervention (MaTI) will be explored using observation, interviews (20 patients, 40 healthcare professionals), surveys and routine trial data collection on adherence to MaTI. A parallel mixed analysis will be applied. Qualitative data will be thematically analysed using Framework analysis and survey data will be analysed descriptively. Data will be synthesised, triangulated and mapped to the Consolidated Framework for Implementation Research where appropriate. The process evaluation commenced on June 2018 and is due to end on February 2021. ETHICS AND DISSEMINATION: Approved by Research Ethics Committee and the UK Health Research Authority REC: 18/YH/0017/IRAS: 231 431. Findings will be disseminated via academic and policy conferences, peer-reviewed publications and social media. TRIAL REGISTRATION NUMBER: ISRCTN66212970.

Pilot cluster randomised trial of an evidence-based intervention to reduce avoidable hospital admissions in nursing home residents (Better Health in Residents of Care Homes with Nursing-BHiRCH-NH Study).

OBJECTIVES: To pilot a complex intervention to support healthcare and improve early detection and treatment for common health conditions experienced by nursing home (NH) residents. DESIGN: Pilot cluster randomised controlled trial. SETTING: 14 NHs (7 intervention, 7 control) in London and West Yorkshire. PARTICIPANTS: NH residents, their family carers and staff. INTERVENTION: Complex intervention to support healthcare and improve early detection and treatment of urinary tract and respiratory infections, chronic heart failure and dehydration, comprising: (1) 'Stop and Watch (S&W)' early warning tool for changes in physical health, (2) condition-specific care pathway and (3) Situation, Background, Assessment and Recommendation tool to enhance communication with primary care. Implementation was supported by Practice Development Champions, a Practice Development Support Group and regular telephone coaching with external facilitators. OUTCOME MEASURES: Data on NH (quality ratings, size, ownership), residents, family carers and staff demographics during the month prior to intervention and subsequently, numbers of admissions, accident and emergency visits, and unscheduled general practitioner visits monthly for 6 months during intervention. We collected data on how the intervention was used, healthcare resource use and quality of life data for economic evaluation. We assessed recruitment and retention, and whether a full trial was warranted. RESULTS: We recruited 14 NHs, 148 staff, 95 family carers and 245 residents. We retained the majority of participants recruited (95%). 15% of residents had an unplanned hospital admission for one of the four study conditions. We were able to collect sufficient questionnaire data (all over 96% complete). No NH implemented intervention tools as planned. Only 16 S&W forms and 8 care pathways were completed. There was no evidence of harm. CONCLUSIONS: Recruitment, retention and data collection processes were effective but the intervention not implemented. A full trial is not warranted. TRIAL REGISTRATION NUMBER: ISRCTN74109734 (https://doi.org/10.1186/ISRCTN74109734). ORIGINAL PROTOCOL: BMJ Open. 2019;9(5):e026510. doi:10.1136/bmjopen-2018-026510.

Evidence-based intervention to reduce avoidable hospital admissions in care home residents (the Better Health in Residents in Care Homes (BHiRCH) study): protocol for a pilot cluster randomised trial.

INTRODUCTION: Acute hospital admission is distressing for care home residents. Ambulatory care sensitive conditions, such as respiratory and urinary tract infections, are conditions that can cause unplanned hospital admission but may have been avoidable with timely detection and intervention in the community. The Better Health in Residents in Care Homes (BHiRCH) programme has feasibility tested and will pilot a multicomponent intervention to reduce these avoidable hospital admissions. The BHiRCH intervention comprises an early warning tool for noting changes in resident health, a care pathway (clinical guidance and decision support system) and a structured method for communicating with primary care, adapted for use in the care home. We use practice development champions to support implementation and embed changes in care. METHODS AND ANALYSIS: Cluster randomised pilot trial to test study procedures and indicate whether a further definitive trial is warranted. Fourteen care homes with nursing (nursing homes) will be randomly allocated to intervention (delivered at nursing home level) or control groups. Two nurses from each home become Practice Development Champions trained to implement the intervention, supported by a practice development support group. Data will be collected for 3 months preintervention, monthly during the 12-month intervention and 1 month after. Individual-level data includes resident, care partner and staff demographics, resident functional status, service use and quality of life (for health economic analysis) and the extent to which staff perceive the organisation supports person centred care. System-level data includes primary and secondary health services contacts (ie, general practitioner and hospital admissions). Process evaluation assesses intervention acceptability, feasibility, fidelity, ease of implementation in practice and study procedures (ie, consent and recruitment rates). ETHICS AND DISSEMINATION: Approved by Research Ethics Committee and the UK Health Research Authority. Findings will be disseminated via academic and policy conferences, peer-reviewed publications and social media (eg, Twitter). TRIAL REGISTRATION NUMBER: ISRCTN74109734; Pre-results.

The role of stress in symptom exacerbation among IBS patients.

Over 200 treatment-seeking irritable bowel syndrome (IBS) patients completed 4 weeks of daily prospective measures of stress and gastrointestinal symptoms as well as retrospective measures of stress (life events over 12 months, hassles over 1 month). We also obtained the stress measures on 66 nonill controls. Irritable bowel syndrome patients report more frequent hassles than controls and a greater stress impact than controls. Using structural equation modeling, we found that the data were consistent with a model of robust autocorrelation effects of both week-to-week gastrointestinal (GI) symptom indices (r=.84) and stress indices (r=.73), as well as strong concurrent effects of stress on IBS symptoms (r=.90) and vice versa (r=.41). The data also were consistent with a model where there were effects of stress in Week t upon GI symptoms in Week t+1 and t+2, but they were mediated through the concurrent week effects and/or autocorrelation effects. There were no statistically significant independent pathways from stress in Week t to GI symptoms in Week t+1 or t+2. Thus, there is more support for a reciprocal relation between stress and symptoms than there is for a causal relation.

The contribution of cholesterol and epigenetic changes to the pathophysiology of breast cancer.

Breast cancer​ is one of the most commonly diagnosed cancers in women. Accumulating evidence suggests that cholesterol plays an important role in the development of breast cancer. Even though the mechanistic link between these two factors is not well understood, one possibility is that dysregulated cholesterol metabolism may affect lipid raft and membrane fluidity and can promote tumor development. Current studies have shown oxysterol 27-hydroxycholesterol (27-HC) as a critical regulator of cholesterol and breast cancer pathogenesis. This is supported by the significantly higher expression of CYP27A1 (cytochrome P450, family 27, subfamily A, polypeptide 1) in breast cancers. This enzyme is responsible for 27-HC synthesis from cholesterol. It has been shown that 27-HC can not only increase the proliferation of estrogen receptor (ER)-positive breast cancer cells but also stimulate tumor growth and metastasis in several breast cancer models. This phenomenon is surprising since 27-HC and other oxysterols generally reduce intracellular cholesterol levels by activating the liver X receptors (LXRs). Resolving this paradox will elucidate molecular pathways by which cholesterol, ER, and LXR are connected to breast cancer. These findings will also provide the rationale for evaluating pharmaceutical approaches that manipulate cholesterol or 27-HC synthesis in order to mitigate the impact of cholesterol on breast cancer pathophysiology. In addition to cholesterol, epigenetic changes including non-coding RNAs, and microRNAs, DNA methylation, and histone modifications, have all been shown to control tumorigenesis. The purpose of this review is to discuss the link between altered cholesterol metabolism and epigenetic modification during breast cancer progression.

Measuring health-related quality of life in patients with irritable bowel syndrome: can less be more?

OBJECTIVE: This study assessed the ability of a brief, well-validated generic health-related quality of life (HRQOL) measure to characterize the symptom burden of patients with irritable bowel syndrome (IBS) with reference to a large survey of U.S. community-living adults. METHODS: One hundred four Rome II diagnosed patients with IBS completed measures of pain, psychological dysfunction (neuroticism, somatization, distress, abuse), and HRQOL (SF-36, IBS-QOL, CDC HRQOL-4) during baseline assessment of a National Institutes of Health-funded clinical trial. The four-item CDC HRQOL-4 assesses global health and the number of days in the past 30 days resulting from poor physical health, poor mental health, and activity limitation. RESULTS: Patients with IBS averaged 15 of 30 days with poor physical or mental health. These average overall unhealthy days exceeded those of respondents with arthritis, diabetes, heart disease/stroke, cancer, and class III obesity (body mass index > or =40 kg/m2) from the U.S. survey. Fifteen percent of patients identified musculoskeletal disorders, not IBS symptoms, as the major cause of their activity limitation. Overall unhealthy days among patients with IBS varied directly with IBS symptom severity, abuse, pain, and psychological distress. Controlling for personality variables that influence perception and reporting HRQOL did not diminish the statistical significance of associations between the CDC HRQOL-4 and other study measures. CONCLUSIONS: The CDC HRQOL-4 is a psychometrically sound, rapid, and efficient instrument whose HRQOL profile reflects the symptom burden of moderate-to-severe IBS, is sensitive to treatment effects associated with cognitive behavior therapy, and is not a proxy for personality variables identified as potential confounders of HRQOL. HRQOL is related to but not redundant with psychological distress.

Children's missed healthcare appointments: professional and organisational responses.

AIM: This National Society for the Prevention of Cruelty to Children (NSPCC) funded UK study sought to examine organisational and professional responses to children's missed healthcare appointments. DESIGN/METHODS: The study comprised two parts: phase I was a web-based scoping and systematic analysis of UK National Health Service healthcare organisations' internal policies on missed appointments. Phase II involved a case study of how missed appointments were managed within one hospital trust, including interviews with hospital-based staff, review of organisational data and examination of policies and 'systems' in place. RESULTS: Policies accessed were of variable quality when benchmarked against a predetermined set of evidence-based standards. Additional material (eg, board minutes) gleaned through the searches found an apparent disconnect between nationally determined safeguarding requirements and strategies to reduce the cost pressures arising from missed appointments. Findings from the case study included the continuing use of the adult-centric term 'did not attend' (DNA), the challenges that may be inherent in attending appointments (with concomitant sympathy for parents) and a need to further explore general practitioner responses to DNA notifications, particularly given the acknowledged association between missed appointments and child maltreatment. CONCLUSIONS: The web-based scoping exercise yielded a small number of organisational policies. These were of variable quality when rated against predetermined standards. Other material gathered through the search strategy found evidence that 'missed appointment' strategies aimed at reducing costs did not always acknowledge the discrete needs of children. The case study findings contribute to an understanding of the complexities and challenges of responding to a missed appointment and the importance of taking a child-centred approach.