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Biology education plays a vital role in nurturing the understanding of learners about the intricacy of life. Various efforts have emerged to strengthen learning biological concepts but there were still studies that showed that learners have low mastery in some aspects. To determine how well students understood various biological topics, including human physiology, Concept inventory tests (CIT) were used. The concept inventory test may be able to spot students' misconceptions and ultimately lead to improved comprehension. The crafted CIT developed with the aid of a table of specifications based on Bloom’s taxonomy of cognitive domain was assessed according to its validity and reliability. In validation, content validity and item analysis were considered while reliability test was employed through Cronbach’s alpha. Distractor analysis was also performed to determine possible source of misconception per item. The CIT was administered to 120 senior high school STEM students (50.8% from the private schools, 37.5% in regular public schools and 11.7% from public schools with special programs in science). The results displayed high content validity with a mean of 4.83 for content validity and an average Aiken’s validity coefficient of 0.98. It also highlighted that the test is moderately difficult with the test difficulty of 0.58, as well as, discriminatory with a discriminating level of 0.46. After item classification, 63 items were retained (39 accepted, 24 for revisions) and Chronbach’s alpha (α=0.74) indicated good internal consistency. The concept inventory test propounds to be a good classroom test with minor items to be revised.

Introduction Randomised controlled trials (RCTs) inform healthcare decisions. It is now apparent that some published RCTs contain false data and some appear to have been entirely fabricated. Systematic reviews are performed to identify and synthesise all RCTs that have been conducted on a given topic. While it is usual to assess methodological features of the RCTs in the process of undertaking a systematic review, it is not usual to consider whether the RCTs contain false data. Studies containing false data therefore go unnoticed and contribute to systematic review conclusions. The INveStigating ProblEmatic Clinical Trials in Systematic Reviews (INSPECT-SR) project will develop a tool to assess the trustworthiness of RCTs in systematic reviews of healthcare-related interventions.Methods and analysis The INSPECT-SR tool will be developed using expert consensus in combination with empirical evidence, over five stages: (1) a survey of experts to assemble a comprehensive list of checks for detecting problematic RCTs, (2) an evaluation of the feasibility and impact of applying the checks to systematic reviews, (3) a Delphi survey to determine which of the checks are supported by expert consensus, culminating in, (4) a consensus meeting to select checks to be included in a draft tool and to determine its format and (5) prospective testing of the draft tool in the production of new health systematic reviews, to allow refinement based on user feedback. We anticipate that the INSPECT-SR tool will help researchers to identify problematic studies and will help patients by protecting them from the influence of false data on their healthcare.Ethics and dissemination The University of Manchester ethics decision tool was used, and this returned the result that ethical approval was not required for this project (30 September 2022), which incorporates secondary research and surveys of professionals about subjects relating to their expertise. Informed consent will be obtained from all survey participants. All results will be published as open-access articles. The final tool will be made freely available.

Purpose: The etiopathogenesis of coronal nonsyndromic craniosynostosis (cNCS), a congenital condition defined by premature fusion of 1 or both coronal sutures, remains largely unknown. Methods: We conducted the largest genome-wide association study of cNCS followed by replication, fine mapping, and functional validation of the most significant region using zebrafish animal model. Results: Genome-wide association study identified 6 independent genome-wide-significant risk alleles, 4 on chromosome 7q21.3 SEM1-DLX5-DLX6 locus, and their combination conferred over 7-fold increased risk of cNCS. The top variants were replicated in an independent cohort and showed pleiotropic effects on brain and facial morphology and bone mineral density. Fine mapping of 7q21.3 identified a craniofacial transcriptional enhancer (eDlx36) within the linkage region of the top variant (rs4727341; odds ratio [95% confidence interval], 0.48[0.39-0.59]; P = 1.2E−12) that was located in SEM1 intron and enriched in 4 rare risk variants. In zebrafish, the activity of the transfected human eDlx36 enhancer was observed in the frontonasal prominence and calvaria during skull development and was reduced when the 4 rare risk variants were introduced into the sequence. Conclusion: Our findings support a polygenic nature of cNCS risk and functional role of craniofacial enhancers in cNCS susceptibility with potential broader implications for bone health.

Abstract Background Concerns regarding reduced fetal movements (RFM) are reported in 5–15% of pregnancies, and RFM are associated with adverse pregnancy outcomes including fetal growth restriction and stillbirth. Studies have aimed to improve pregnancy outcomes by evaluating interventions to raise awareness of RFM in pregnancy, such as kick counting, evaluating interventions for the clinical management of RFM, or both. However, there is not currently a core outcome set (COS) for studies of RFM. This study aims to create a COS for use in research studies that aim to raise awareness of RFM and/or evaluate interventions for the clinical management of RFM. Methods A systematic review will be conducted, to identify outcomes used in randomised and non-randomised studies with control groups that aimed to raise awareness of RFM (for example by using mindfulness techniques, fetal movement counting, or other tools such as leaflets or mobile phone applications) and/or that evaluated the clinical management of RFM. An international Delphi consensus will then be used whereby stakeholders will rate the importance of the outcomes identified in the systematic review in (i) awareness and (ii) clinical management studies. The preliminary lists of outcomes will be discussed at a consensus meeting where one final COS for awareness and management, or two discrete COS (one for awareness and one for management), will be agreed upon. Discussion A well-developed COS will provide researchers with the minimum set of outcomes that should be measured and reported in studies that aim to quantify the effects of interventions.

Objectives To investigate factors that promote and prevent the use of compression therapy in people with venous leg ulcers.Design Qualitative interview study with nurses using the Theoretical Domains Framework (TDF).Setting Three National Health Service Trusts in England.Participants Purposive sample of 15 nurses delivering wound care.Results Nurses described factors which made provision of compression therapy challenging. Organisational barriers (TDF domains environmental context and resources/knowledge, skills/behavioural regulation) included heavy/increasing caseloads; lack of knowledge/skills and the provision of training; and prescribing issues (variations in bandaging systems/whether nurses could prescribe). Absence of specialist leg ulcer services to refer patients into was perceived as a barrier to providing optimal care by some community-based nurses. Compression use was perceived to be facilitated by clinics for timely initial assessment; continuity of staff and good liaison between vascular/leg ulcer clinics and community teams; clear local policies and care pathways; and opportunities for training such as ‘shadowing’ in vascular/leg ulcer clinics. Patient engagement barriers (TDF domains goals/beliefs about consequences) focused on getting patients ‘on board’ with compression, and supporting them in using it. Clear explanations were seen as key in promoting compression use.Conclusions Rising workload pressures present significant challenges to enhancing leg ulcer services. There may be opportunities to develop facilitated approaches to enable community nursing teams to make changes to practice, enhancing quality of patient care. The majority of venous leg ulcers could be managed in the community without referral to specialist community services if issues relating to workloads/skills/training are addressed. Barriers to promoting compression use could also be targeted, for example, through the development of clear patient information leaflets. While the patient engagement barriers may be easier/quicker to address than organisational barriers, unless organisational barriers are addressed it seems unlikely that all people who would benefit from compression therapy will receive it.

Biology education plays a vital role in nurturing the understanding of learners about the intricacy of life. Various efforts have emerged to strengthen learning biological concepts but there were still studies that showed that learners have low mastery in some aspects. To determine how well students understood various biological topics, including human physiology, Concept inventory tests (CIT) were used. The concept inventory test may be able to spot students' misconceptions and ultimately lead to improved comprehension. The crafted CIT developed with the aid of a table of specifications based on Bloom's taxonomy of cognitive domain was assessed according to its validity and reliability. In validation, content validity and item analysis were considered while reliability test was employed through Cronbach's alpha. Distractor analysis was also performed to determine possible source of misconception per item. The CIT was administered to 120 senior high school STEM students (50.8% from the private schools, 37.5% in regular public schools and 11.7% from public schools with special programs in science). The results displayed high content validity with a mean of 4.83 for content validity and an average Aiken's validity coefficient of 0.98. It also highlighted that the test is moderately difficult with the test difficulty of 0.58, as well as, discriminatory with a discriminating level of 0.46. After item classification, 63 items were retained (39 accepted, 24 for revisions) and Chronbach's alpha ([alpha]=0.74) indicated good internal consistency. The concept inventory test propounds to be a good classroom test science with minor items to be revised.

Muscle fibers are the largest cells in the body and contain less DNA per unit volume than other cells even if they have multiple nuclei. Here, the authors show that the number of nuclei regulates the cell size with similar scaling properties in mice and humans.

Objectives To estimate and examine the direct healthcare costs of treating people with open venous leg ulcers in the UK.Design Cost-of-illness study.Setting A cross-sectional survey of nine National Health Service community locales over 2-week periods in 2015/2016.Methods We examined the resource use and prevalence of venous leg ulcer treatment in the community. Examination of variation in these obtained costs was performed by ordinary least squares regression. We used additional resource use information from a randomised control trial and extrapolated costs to the UK for an annual period.Results The average 2-week per person cost of treating patients where a venous leg ulceration was the primary (most severe) wound was estimated at £166.39 (95% CI £157.78 to £175.00) with community staff time making up over half of this amount. Costs were higher where antimicrobial dressings were used and where wound care was delivered in the home. Among those with any recorded venous leg ulcer (primary and non-primary), we derived a point prevalence of 3.2 per 10 000 population and estimated that the annual prevalence could be no greater than 82.4 per 10 000 population. We estimated that the national cost of treating a venous leg ulcer was £102 million with a per person annual cost at £4787.70.Conclusion Our point prevalence figures are in line with the literature. However, our annual prevalence estimations and costs are far lower than those reported in recent literature which suggests that the costs of treating venous leg ulcers are lower than previously thought. Movement towards routinely collected and useable community care activity would help provide a transparent and deeper understanding of the scale and cost of wound care in the UK.

Objectives To investigate the period prevalence of complex wounds among the overall inpatients, and the impact of complex wounds on inpatient health expense and length of hospital stay (LOS).Design An observational study.Setting 6056 healthcare institutions across Sichuan province in China.Participants This study included 4 033 763 people admitted to healthcare institutions during 1 September 2018 and 31 December 2018.Results The point prevalence of complex wounds was 4.07 per 1000 among inpatients in Sichuan. The most common complex wounds were pressure ulcers (1.47 per 1000 among inpatients). Older, male, Han ethnic groups and retired people were most likely to suffer from complex wounds. The median LOS was longer for those with complex wounds as their main condition of treatment compared with all-cause admissions in Sichuan (12 days compared with 7 days; p

Abstract Background Surgical site infections (SSIs) are common, occurring in up to 25% of > 4 million operations performed in England each year. Previous trials of the effect of wound dressings on the risk of developing a SSI are of poor quality and underpowered. Methods/Design This study is a feasibility and pilot trial to examine the feasibility of a full trial that will compare simple dressings, no dressing and tissue-glue as a dressing. It is examining the overall acceptability of trial participation, identifying opportunities for refinement, testing the feasibility of and validating new outcome tools to assess SSI, wound management issues and patients’ wound symptom experiences. It is also exploring methods for avoiding performance bias and blinding outcome assessors by testing the feasibility of collecting wound photographs taken in theatre immediately after wound closure and, at 4–8 weeks after surgery, taken by participants themselves or their carers. Finally, it is identifying the main cost drivers for an economic evaluation of dressing types. Integrated qualitative research is exploring acceptability and reasons for non-adherence to allocation. Adults undergoing primary elective or unplanned abdominal general surgery or Caesarean section are eligible. The main exclusion criteria are abdominal or other major surgery less than three months before the index operation or contraindication to dressing allocation. The trial is scheduled to recruit for nine months. The findings will be used to inform the design of a main trial. Discussion This pilot trial is the first pragmatic study to randomise participants to no dressing or tissue-glue as a dressing versus a simple dressing. Early evidence from the ongoing pilot shows that recruitment is proceeding well and that the interventions are acceptable to participants. Combined with the qualitative findings, the findings will inform whether a main, large trial is feasible and, if so, how it should be designed. Trial registration ISRCTN49328913 . Registered on 20 October 2015.

Background: Surgical site infection (SSI) affects up to 20% of people with a primary closed wound after surgery. Wound dressings may reduce SSI. Objective: To assess the feasibility of a multicentre randomised controlled trial (RCT) to evaluate the effectiveness and cost-effectiveness of dressing types or no dressing to reduce SSI in primary surgical wounds. Design: Phase A – semistructured interviews, outcome measure development, practice survey, literature reviews and value-of-information analysis. Phase B – pilot RCT with qualitative research and questionnaire validation. Patients and the public were involved. Setting: Usual NHS care. Participants: Patients undergoing elective/non-elective abdominal surgery, including caesarean section. Interventions: Phase A – none. Phase B – simple dressing, glue-as-a-dressing (tissue adhesive) or ‘no dressing’. Main outcome measures: Phase A – pilot RCT design; SSI, patient experience and wound management questionnaires; dressing practices; and value-of-information of a RCT. Phase B – participants screened, proportions consented/randomised; acceptability of interventions; adherence; retention; validity and reliability of SSI measure; and cost drivers. Data sources: Phase A – interviews with patients and health-care professionals (HCPs), narrative data from published RCTs and data about dressing practices. Phase B – participants and HCPs in five hospitals. Results: Phase A – we interviewed 102 participants. HCPs interpreted ‘dressing’ variably and reported using available products. HCPs suggested practical/clinical reasons for dressing use, acknowledged the weak evidence base and felt that a RCT including a ‘no dressing’ group was acceptable. A survey showed that 68% of 1769 wounds (727 participants) had simple dressings and 27% had glue-as-a-dressing. Dressings were used similarly in elective and non-elective surgery. The SSI questionnaire was developed from a content analysis of existing SSI tools and interviews, yielding 19 domains and 16 items. A main RCT would be valuable to the NHS at a willingness to pay of £20,000 per quality-adjusted life-year. Phase B – from 4 March 2016 to 30 November 2016, we approached 862 patients for the pilot RCT; 81.1% were eligible, 59.4% consented and 394 were randomised (simple, n = 133; glue, n = 129; no dressing, n = 132); non-adherence was 3 out of 133, 8 out of 129 and 20 out of 132, respectively. SSI occurred in 51 out of 281 participants. We interviewed 55 participants. All dressing strategies were acceptable to stakeholders, with no indication that adherence was problematic. Adherence aids and patients’ understanding of their allocated dressing appeared to be key. The SSI questionnaire response rate overall was 67.2%. Items in the SSI questionnaire fitted a single scale, which had good reliability (test–retest and Cronbach’s alpha of > 0.7) and diagnostic accuracy (c-statistic = 0.906). The key cost drivers were hospital appointments, dressings and redressings, use of new medicines and primary care appointments. Limitations: Multiple activities, often in parallel, were challenging to co-ordinate. An amendment took 4 months, restricting recruitment to the pilot RCT. Only 67% of participants completed the SSI questionnaire. We could not implement photography in theatres. Conclusions: A main RCT of dressing strategies is feasible and would be valuable to the NHS. The SSI questionnaire is sufficiently accurate to be used as the primary outcome. A main trial with three groups (as in the pilot) would be valuable to the NHS, using a primary outcome of SSI at discharge and patient-reported SSI symptoms at 4–8 weeks. Trial registration: Phase A – Current Controlled Trials ISRCTN06792113; Phase B – Current Controlled Trials ISRCTN49328913. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 39. See the NIHR Journals Library website for further project information. Funding was also provided by the Medical Research Council ConDuCT-II Hub (reference number MR/K025643/1).

ObjectiveTo develop, with nurse specialists and nursing home care staff, a theory and evidence-informed pressure injury prevention care bundle for use in nursing home settings.DesignThe development of a care bundle.MethodsWe undertook a detailed, multistaged and theoretically driven development process. First, we identified evidence-informed pressure injury prevention practices: these formed an initial set of possible target behaviours to be considered for inclusion in the bundle. During a 4-hour workshop and supplemental email consultation with a total of 13 healthcare workers, we agreed the key target behaviours for the care bundle. We explored with staff the barriers and facilitators to prevention activity and defined intervention functions and behaviour change practices using the Behaviour Change Wheel.SettingNorth West England.ResultsThe target behaviours consisted of three elements: support surfaces, skin inspection and repositioning. We identified capability, opportunity and reflective motivation as influencing the pressure injury prevention behaviours of nursing home care staff. The intervention functions (education, training, modelling) and behaviour change techniques (information about social and environmental consequences, information on health consequences, feedback on behaviour, feedback on the outcome of behaviour, prompts/cues, instruction on how to perform the behaviour, demonstration of behaviour) were incorporated into the care bundle.ConclusionThis is the first description of a pressure injury prevention care bundle for nursing homes developed using the Behaviour Change Wheel. Key stakeholders identified and prioritised the appropriate target behaviours to aid pressure injury prevention in a nursing home setting.

To help guide school mental health policy and practice, we evaluated patterns of mental health help-seeking across lifetime adversity among sixth-grade adolescents. An ethnically/socioeconomically diverse sample of sixth-graders (N = 751) self-completed assessments of help-seeking and indicators of lifetime adversities: violence victimization, poverty, parent loss/divorce, mental illness/substance abuse at home, and stressors related to social identity. Logistic regression models adjusting for family/personal factors examined adversity factors on help-seeking outcomes overall and across subgroups with mental health perceived problems and high-symptoms. Overall, odds increased between perceived problem and formal service use, poverty and formal service/school counselor use, and high-symptoms/victimization and talking to a friend (p < 0.05). Among those with perceived problems, odds increased between mental illness/substance abuse at home and formal service use, victimization and talking to a friend, and poverty and school counselor use (p < 0.05). Among those with no mental health problems, odds increased between victimization and formal service/school counselor use, and poverty and formal service use (p < 0.05). No significant patterns were observed in the high-symptom subgroup. Understanding how adversity shapes help-seeking can help guide school mental health policies and practices. Study findings point to areas for expansion of supports for students with adversity to create a mental health safety net and help mitigate future risk.

BACKGROUND:Complex wounds such as leg and foot ulcers are common, resource intensive and have negative impacts on patients' wellbeing. Evidence-based decision-making, substantiated by high quality evidence such as from systematic reviews, is widely advocated for improving patient care and healthcare efficiency. Consequently, we set out to classify and map the extent to which up-to-date systematic reviews containing robust evidence exist for wound care uncertainties prioritised by community-based healthcare professionals. METHODS:We asked healthcare professionals to prioritise uncertainties based on complex wound care decisions, and then classified 28 uncertainties according to the type and level of decision. For each uncertainty, we searched for relevant systematic reviews. Two independent reviewers screened abstracts and full texts of reviews against the following criteria: meeting an a priori definition of a systematic review, sufficiently addressing the uncertainty, published during or after 2012, and identifying high quality research evidence. RESULTS:The most common uncertainty type was 'interventions' 24/28 (85%); the majority concerned wound level decisions 15/28 (53%) however, service delivery level decisions (10/28) were given highest priority. Overall, we found 162 potentially relevant reviews of which 57 (35%) were not systematic reviews. Of 106 systematic reviews, only 28 were relevant to an uncertainty and 18 of these were published within the preceding five years; none identified high quality research evidence. CONCLUSIONS:Despite the growing volume of published primary research, healthcare professionals delivering wound care have important clinical uncertainties which are not addressed by up-to-date systematic reviews containing high certainty evidence. These are high priority topics requiring new research and systematic reviews which are regularly updated. To reduce clinical and research waste, we recommend systematic reviewers and researchers make greater efforts to ensure that research addresses important clinical uncertainties and is of sufficient rigour to inform practice.

Pressure ulcers are a prevalent and global issue and support surfaces are widely used for preventing ulceration. However, the diversity of available support surfaces and the lack of direct comparisons in RCTs make decision-making difficult.To determine, using network meta-analysis, the relative effects of different support surfaces in reducing pressure ulcer incidence and comfort and to rank these support surfaces in order of their effectiveness.We conducted a systematic review, using a literature search up to November 2016, to identify randomised trials comparing support surfaces for pressure ulcer prevention. Two reviewers independently performed study selection, risk of bias assessment and data extraction. We grouped the support surfaces according to their characteristics and formed evidence networks using these groups. We used network meta-analysis to estimate the relative effects and effectiveness ranking of the groups for the outcomes of pressure ulcer incidence and participant comfort. GRADE was used to assess the certainty of evidence.We included 65 studies in the review. The network for assessing pressure ulcer incidence comprised evidence of low or very low certainty for most network contrasts. There was moderate-certainty evidence that powered active air surfaces and powered hybrid air surfaces probably reduce pressure ulcer incidence compared with standard hospital surfaces (risk ratios (RR) 0.42, 95% confidence intervals (CI) 0.29 to 0.63; 0.22, 0.07 to 0.66, respectively). The network for comfort suggested that powered active air-surfaces are probably slightly less comfortable than standard hospital mattresses (RR 0.80, 95% CI 0.69 to 0.94; moderate-certainty evidence).This is the first network meta-analysis of the effects of support surfaces for pressure ulcer prevention. Powered active air-surfaces probably reduce pressure ulcer incidence, but are probably less comfortable than standard hospital surfaces. Most prevention evidence was of low or very low certainty, and more research is required to reduce these uncertainties.

People with complex wounds are more likely to be elderly, living with multimorbidity and wound related symptoms. A variety of products are available for managing complex wounds and a range of healthcare professionals are involved in wound care, yet there is a lack of good evidence to guide practice and services. These factors create uncertainty for those who deliver and those who manage wound care. Formal priority setting for research and implementation topics is needed to more accurately target the gaps in treatment and services. We solicited practitioner and manager uncertainties in wound care and held a priority setting workshop to facilitate a collaborative approach to prioritising wound care-related uncertainties.We recruited healthcare professionals who regularly cared for patients with complex wounds, were wound care specialists or managed wound care services. Participants submitted up to five wound care uncertainties in consultation with their colleagues, via an on-line survey and attended a priority setting workshop. Submitted uncertainties were collated, sorted and categorised according professional group. On the day of the workshop, participants were divided into four groups depending on their profession. Uncertainties submitted by their professional group were viewed, discussed and amended, prior to the first of three individual voting rounds. Participants cast up to ten votes for the uncertainties they judged as being high priority. Continuing in the professional groups, the top 10 uncertainties from each group were displayed, and the process was repeated. Groups were then brought together for a plenary session in which the final priorities were individually scored on a scale of 0-10 by participants. Priorities were ranked and results presented. Nominal group technique was used for generating the final uncertainties, voting and discussions.Thirty-three participants attended the workshop comprising; 10 specialist nurses, 10 district nurses, seven podiatrists and six managers. Participants had been qualified for a mean of 20.7 years with a mean of 16.8 years of wound care experience. One hundred and thirty-nine uncertainties were submitted electronically and a further 20 were identified on the day of the workshop following lively, interactive group discussions. Twenty-five uncertainties from the total of 159 generated made it to the final prioritised list. These included six of the 20 new uncertainties. The uncertainties varied in focus, but could be broadly categorised into three themes: service delivery and organisation, patient centred care and treatment options. Specialist nurses were more likely to vote for service delivery and organisation topics, podiatrists for patient centred topics, district nurses for treatment options and operational leads for a broad range.This collaborative priority setting project is the first to engage front-line clinicians in prioritising research and implementation topics in wound care. We have shown that it is feasible to conduct topic prioritisation in a short time frame. This project has demonstrated that with careful planning and rigor, important questions that are raised in the course of clinicians' daily decision making can be translated into meaningful research and implementation initiatives that could make a difference to service delivery and patient care.

A central tenet of skeletal muscle biology is the existence of an inverse relationship between the oxidative fibre capacity and its size. However, robustness of this relationship is unknown. We show that superimposition of Estrogen-related receptor gamma (Errγ) on the myostatin (Mtn) mouse null background (Mtn-/-/ErrγTg/+) results in hypertrophic muscle with a high oxidative capacity thus violating the inverse relationship between fibre size and oxidative capacity. We also examined the canonical view that oxidative muscle phenotype positively correlate with Satellite cell number, the resident stem cells of skeletal muscle. Surprisingly, hypertrophic fibres from Mtn-/-/ErrγTg/+ mouse showed satellite cell deficit which unexpectedly did not affect muscle regeneration. These observations 1) challenge the concept of a constraint between fibre size and oxidative capacity and 2) indicate the important role of the microcirculation in the regenerative capacity of a muscle even when satellite cell numbers are reduced.

Background: Compression is an effective and recommended treatment for venous leg ulcers. Although the four-layer bandage (4LB) is regarded as the gold standard compression system, it is recognised that the amount of compression delivered might be compromised by poor application technique. Also the bulky nature of the bandages might reduce ankle or leg mobility and make the wearing of shoes difficult. Two-layer compression hosiery systems are now available for the treatment of venous leg ulcers. Two-layer hosiery (HH) may be advantageous, as it has reduced bulk, which might enhance ankle or leg mobility and patient adherence. Some patients can also remove and reapply two-layer hosiery, which may encourage self-management and could reduce costs. However, little robust evidence exists about the effectiveness of two-layer hosiery for ulcer healing and no previous trials have compared two-layer hosiery delivering ‘high’ compression with the 4LB. Objectives: Part I To compare the clinical effectiveness and cost-effectiveness of HH and 4LB in terms of time to complete healing of venous leg ulcers. Part II To synthesise the relative effectiveness evidence (for ulcer healing) of high-compression treatments for venous leg ulcers using a mixed-treatment comparison (MTC). Part III To construct a decision-analytic model to assess the cost-effectiveness of high-compression treatments for venous leg ulcers. Design: Part I A multicentred, pragmatic, two-arm, parallel, open randomised controlled trial (RCT) with an economic evaluation. Part II MTC using all relevant RCT data – including Venous leg Ulcer Study IV (VenUS IV). Part III A decision-analytic Markov model. Settings: Part I Community nurse teams or services, general practitioner practices, leg ulcer clinics, tissue viability clinics or services and wound clinics within England and Northern Ireland. Participants: Part I Patients aged ≥ 18 years with a venous leg ulcer, who were willing and able to tolerate high compression. Interventions: Part I Participants in the intervention group received HH. The control group received the 4LB, which was applied according to standard practice. Both treatments are designed to deliver 40 mmHg of compression at the ankle. Part II and III All relevant high-compression treatments including HH, the 4LB and the two-layer bandage (2LB). Main outcome measures: Part I The primary outcome measure was time to healing of the reference ulcer (blinded assessment). Part II Time to ulcer healing. Part III Quality-adjusted life-years (QALYs) and costs. Results: Part I A total of 457 participants were recruited. There was no evidence of a difference in time to healing of the reference ulcer between groups in an adjusted analysis [hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.79 to 1.25; p = 0.96]. Time to ulcer recurrence was significantly shorter in the 4LB group (HR = 0.56, 95% CI 0.33 to 0.94; p = 0.026). In terms of cost-effectiveness, using QALYs as the measure of benefit, HH had a > 95% probability of being the most cost-effective treatment based on the within-trial analysis. Part II The MTC suggests that the 2LB has the highest probability of ulcer healing compared with other high-compression treatments. However, this evidence is categorised as low to very low quality. Part III Results suggested that the 2LB had the highest probability of being the most cost-effective high-compression treatment for venous leg ulcers. Conclusions: Trial data from VenUS IV found no evidence of a difference in venous ulcer healing between HH and the 4LB. HH may reduce ulcer recurrence rates compared with the 4LB and be a cost-effective treatment. When all available high-compression treatments were considered, the 2LB had the highest probability of being clinically effective and cost-effective. However, the underpinning evidence was sparse and more research is needed. Further research should thus focus on establishing, in a high-quality trial, the effectiveness of this compression system in particular. Trial registration: Current Controlled Trials ISRCTN49373072. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 57. See the NIHR Journals Library website for further project information.

Vaccination with naked DNA holds great promise but immunogenicity needs to be improved. DNA constructs encoding bivalent proteins that bind antigen-presenting cells (APC) for delivery of antigen have been shown to enhance T and B cell responses and protection in tumour challenge experiments. However, the mechanism for the increased potency remains to be determined. Here we have constructed DNA vaccines that express the fluorescent protein mCherry, a strategy which allowed tracking of vaccine proteins. Transfected muscle fibres in mice were visualized, and their relationship to infiltrating mononuclear cells could be determined. Interestingly, muscle fibers that produced MHC class II-specific dimeric vaccine proteins with mCherry were for weeks surrounded by a localized intense cellular infiltrate composed of CD45+, MHC class II+ and CD11b+ cells. Increasing numbers of eosinophils were observed among the infiltrating cells from day 7 after immunization. The local infiltrate surrounding mCherry+ muscle fibers was dependent on the MHC II-specificity of the vaccine proteins since the control, a non-targeted vaccine protein, failed to induce similar infiltrates. Chemokines measured on day 3 in immunized muscle indicate both a DNA effect and an electroporation effect. No influence of targeting was observed. These results contribute to our understanding for why targeted DNA vaccines have an improved immunogenicity.

Mechanical factors such as stretch are thought to be important in the regulation of muscle phenotype. Small muscle protein X-linked (SMPX) is upregulated by stretch in skeletal muscle and has been suggested to serve both as a transcription factor and a mechanosensor, possibly giving rise to changes in both fiber size and fiber type. We have used in vivo confocal imaging to study the subcellular localization of SMPX in skeletal muscle fibers of adult rats using a SMPX-EGFP fusion protein. The fusion protein was localized predominantly in repetitive double stripes flanking the Z-disc, and was excluded from all nuclei. This localization would be consistent with SMPX being a mechanoreceptor, but not with SMPX playing a role as a transcription factor. In vivo overexpression of ectopic SMPX in skeletal muscle of adult mice gave no significant changes in fiber type distribution or cross sectional area, thus a role of SMPX in regulating muscle phenotype remains unclear.

Recent studies in our laboratory have shown that PCP (phencyclidine) and d-amphetamine induce a cognitive deficit in rats, in a paradigm of potential relevance for the pathology of schizophrenia. Atypical, but not classical antipsychotics and the anticonvulsant, lamotrigine have been shown to prevent a selective reversal learning deficit induced by PCP. In contrast, only haloperidol reversed the d-amphetamine-induced deficit. The present study aimed to explore the ability of two anticonvulsants with differing mechanism of action, valproate and phenytoin to attenuate the cognitive deficits induced by PCP and d-amphetamine in the reversal learning paradigm. PCP at 1.5mg/kg and d-amphetamine at 0.5mg/kg both produced a selective and significant reduction in performance of the reversal phase with no effect on the initial phase of the task in female-hooded Lister rats. Valproate (25-200mg/kg) and phenytoin (25-50mg/kg) had no effect on performance when administered alone. Valproate (100-200mg/kg), whose principle action is thought to be the enhancement of GABA transmission, was unable to prevent the cognitive deficit induced by either PCP or d-amphetamine. Conversely, phenytoin (50mg/kg), a use-dependent sodium channel inhibitor, significantly prevented the deficit induced by PCP, but not d-amphetamine. These results add to our earlier work with lamotrigine, and suggest that sodium channel blockade may be a mechanism by which some anticonvulsant drugs can prevent the PCP-induced deficit. These data have implications for the use of anticonvulsant drugs in the treatment of cognitive or psychotic disorders.

To determine the effectiveness of a school-based curriculum, Eliminating the Stigma of Differences (ESD), in improving attitudinal and/or behavioral contexts regarding mental illness in schools and increasing the likelihood that youth seek treatment for mental health problems when needed. We conducted a cluster randomized trial in sixth-grade classes from 14 schools in 2011 and 2012 with follow-up at 6-month intervals through 24 months (2012-2015). Using a fully crossed 2 × 2 × 2 factorial design, we compared ESD to a no-intervention control and to 2 comparator interventions: (1) contact with 2 young adults with a history of mental illness and (2) exposure to antistigma printed materials. We implemented interventions in classrooms in an ethnically and socioeconomically diverse school district. There were 416 youth who participated in the follow-up, and 312 (75%) of these participated for the full 2 years. Outcome measures were knowledge and positive attitudes, social distance from peers with mental illness, and mental health treatment seeking. Youth assigned to ESD reported greater knowledge and positive attitudes and reduced social distance (Cohen's d = 0.35 and 0.16, respectively) than youth in the comparator interventions and no-intervention groups across the 2-year follow-up. Youth with high levels of mental health symptoms were more likely (odds ratio = 3.51; confidence interval = 1.08-11.31) to seek treatment during follow-up if assigned to ESD than if they were assigned to comparator interventions or no intervention. ESD shows potential for improving the social climate related to mental illnesses in schools and increasing treatment seeking when needed. ESD and interventions like it show promise as part of a public mental health response to youth with mental health needs in schools.

Our previous genome-wide association study (GWAS) for sagittal nonsyndromic craniosynostosis (sNCS) provided important insights into the genetics of midline CS. In this study, we performed a GWAS for a second midline NCS, metopic NCS (mNCS), using 215 non-Hispanic white case-parent triads. We identified six variants with genome-wide significance (P ≤ 5 × 10–8): rs781716 (P = 4.71 × 10–9; odds ratio [OR] = 2.44) intronic to SPRY3; rs6127972 (P = 4.41 × 10–8; OR = 2.17) intronic to BMP7; rs62590971 (P = 6.22 × 10–9; OR = 0.34), located ~ 155 kb upstream from TGIF2LX; and rs2522623, rs2573826, and rs2754857, all intronic to PCDH11X (P = 1.76 × 10–8, OR = 0.45; P = 3.31 × 10–8, OR = 0.45; P = 1.09 × 10–8, OR = 0.44, respectively). We performed a replication study of these variants using an independent non-Hispanic white sample of 194 unrelated mNCS cases and 333 unaffected controls; only the association for rs6127972 (P = 0.004, OR = 1.45; meta-analysis P = 1.27 × 10–8, OR = 1.74) was replicated. Our meta-analysis examining single nucleotide polymorphisms common to both our mNCS and sNCS studies showed the strongest association for rs6127972 (P = 1.16 × 10–6). Our imputation analysis identified a linkage disequilibrium block encompassing rs6127972, which contained an enhancer overlapping a CTCF transcription factor binding site (chr20:55,798,821–55,798,917) that was significantly hypomethylated in mesenchymal stem cells derived from fused metopic compared to open sutures from the same probands. This study provides additional insights into genetic factors in midline CS.

ObjectiveTo compare current analgesia and sedation management practices between critically ill children with pre-existing cognitive impairment and critically ill neurotypical children, including possible indicators of therapeutic efficacy.Study designThis study used secondary analysis of prospective data from the RESTORE clinical trial, with 2449 children admitted to the pediatric intensive care unit and receiving mechanical ventilation for acute respiratory failure. Subjects with a baseline Pediatric Cerebral Performance Category ≥3 were defined as subjects with cognitive impairment, and differences between groups were explored using regression methods accounting for pediatric intensive care unit as a cluster variable.ResultsThis study identified 412 subjects (17%) with cognitive impairment. Compared with neurotypical subjects, subjects with cognitive impairment were older (median, years, 6.2 vs 1.4; P

RationaleParents are one of several key gatekeepers to mental health (MH) services for adolescents with MH problems. Parental MH stigma is a significant barrier to treatment, yet little is known about how stigma may bias parental recognition of mental illness in youth.ObjectiveThis study examines how stigma influences a critical and early stage of the help-seeking process-the recognition of MH problems in preadolescents by their parents.MethodParents from a school-based anti-stigma intervention study were analyzed. Logistic regressions examined the association of stigma with parental recognition of MH problems in their preadolescent child (10-12 years old) and that of two preadolescent vignette characters described as having bipolar disorder and social anxiety disorder.ResultsThe more parents desired their preadolescent child to avoid interaction with individuals with a mental illness-that is, to be more socially distant-the less likely these parents believed their child had a MH problem, controlling for parent-reported MH symptoms and other covariates. This pattern was prominent among parents who reported high symptoms in their child. Social distance had no bearing on whether parents recognized the vignette characters as having a problem. Avoidance of individuals with a mental illness and knowledge/positive MH attitudes were not associated with problem recognition.ConclusionStigmatizing attitudes of parents may be detrimental when trying to understand the psychopathology of their own preadolescent children but not preadolescents outside their family. Stigma may present itself as a barrier to problem recognition because it may impose a significant personal cost on the family, thereby affecting the help-seeking process earlier than considered by previous work.

Background: Addressing school violence is an important public health goal. To assess the role of school mental health curricula in violence prevention, we evaluated effects of an anti-stigma curriculum on violence victimization/perpetration. Methods: An ethnically/socioeconomically diverse sample of 751 sixth-graders (mean age 11.5 years) across 14 schools in Texas were block-randomized by school (2011-2012) to receive singly or in combination: (1) a mental illness anti-stigma curriculum; (2) contact with 2 young adults with mental illness; or (3) merged control (printed materials/no intervention). Pre- and post-test assessments were self-completed during health education classes; prior to randomization, 484 (64.5%) agreed to 2-year, home-based longitudinal assessments. Statistical models tested short- and long-term effects on physical, verbal, and relational/social violence victimization/perpetration. Results: At 1-month post-test, students who received the "curriculum" versus control made fewer verbal threats (p < 0.05). Those with high-level mental health symptoms in the "curriculum" group versus control used less violence overall and received fewer verbal threats from peers short-term (p < 0.05). "Curriculum" effects of reducing violence perpetration sustained long-term among adolescents with high-symptoms (p < 0.01). The comparator "contact" intervention was ineffective short- and long-term. Conclusions: Implementing efficacious mental health curricula can serve as a multi-pronged strategy with anti-bulling efforts to prevent violence and improve mental health.

ObjectiveSchool-based interventions for preadolescents provide the opportunity, in a ubiquitous institutional setting, to attack stigmatizing attitudes before they are firmly entrenched, and thus they may reduce mental illness stigma in the overall population. This study evaluated the effectiveness of classroom-based interventions in reducing stigma and increasing understanding of mental illness and positive attitudes toward treatment seeking among sixth-grade students.MethodsIn an ethnically and racially diverse sample (N=721), 40% of participants were Latino, 26% were white, and 24% were African American; the mean age was 11.5. In a fully crossed design, classrooms from a school district in Texas were randomly assigned to receive all three, two, one, or none of the following interventions: a PowerPoint- and discussion-based curriculum, contact with two college students who described their experiences with mental illness, and exposure to antistigma printed materials. Standard and vignette-based quantitative measures of mental health knowledge and attitudes, social distance, and help-seeking attitudes were assessed pre- and postintervention.ResultsPrinted materials had no significant effects on outcomes and were grouped with the control condition for analysis. For eight of 13 outcomes, the curriculum-only group reported significantly more positive outcomes than the control group; the largest between-group differences were for stigma awareness and action, recognition of mental illness in the vignettes, and positive orientation to treatment. The contact-alone group reported significantly more positive outcomes on three vignette-based measures.ConclusionsResults were most promising for a classroom-based curriculum that can be relatively easily disseminated to and delivered by teachers, offering the potential for broad application in the population.