BACKGROUND: School-based sexual health education has the potential to provide an inclusive and comprehensive approach to promoting sexual health among young people. We reviewed evaluations of school-based sexual health education interventions in sub-Saharan Africa to assess effectiveness in reducing sexually transmitted infections and promoting condom use. METHODS: We searched ten electronic databases, hand-searched key journals, and reference lists of included articles for potential studies. Data were extracted on outcomes, intervention characteristics, methods and study characteristics indicative of methodological quality. Where possible, data were synthesized using random effect meta-analysis. Intervention features found predominantly in effective interventions were noted. RESULTS: the initial search retrieved 21634 potentially relevant citations. of these, 51 papers reporting on 31 interventions were included. No evaluation reported statistically significant effects on the incidence or prevalence of Human Immunodeficiency Virus and Herpes Simplex Virus 2 infections. However, intervention participants reported statistically significant greater condom use in both randomised controlled trials and non-randomised trials for short (less than 6 months) follow-up periods (OR = 1.62, 95 % CI = 1.03-2.55 and OR = 2.88, 95 % CI = 1.41-5.90 respectively). For intermediate (6-10 months) and long-term (more than 10 months) follow-up periods, the effect was statistically significant (OR = 1.40, 95 % CI = 1.16-1.68) and marginally significant (OR = 1.22, 95 % CI = 0.99-1.50) among the randomised trials respectively. Only 12 of the 31 interventions reported implementation details, out of which seven reported on fidelity. CONCLUSION: School-based sexual health education has the potential to promote condom use among young people in sub-Saharan Africa. However, further work is needed to develop and evaluate interventions that have measurable effects on sexually transmitted infections.

Ebola virus (Zaire ebolavirus; EBOV) is a highly lethal hemorrhagic disease virus that most recently was responsible for two independent 2014 outbreaks in multiple countries in Western Africa, and the Democratic Republic of the Congo, respectively. Herein, we show that a cytomegalovirus (CMV)-based vaccine provides durable protective immunity from Ebola virus following a single vaccine dose. This study has implications for human vaccination against ebolaviruses, as well as for development of a 'disseminating' vaccine to target these viruses in wild African great apes.

BACKGROUND: the Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial aimed to determine whether or not oral Δ(9)-tetrahydrocannabinol (Δ(9)-THC) slowed the course of progressive multiple sclerosis (MS); evaluate safety of cannabinoid administration; and, improve methods for testing treatments in progressive MS. OBJECTIVES: There were three objectives in the CUPID study: (1) to evaluate whether or not Δ(9)-THC could slow the course of progressive MS; (2) to assess the long-term safety of Δ(9)-THC; and (3) to explore newer ways of conducting clinical trials in progressive MS. DESIGN: the CUPID trial was a randomised, double-blind, placebo-controlled, parallel-group, multicentre trial. Patients were randomised in a 2 : 1 ratio to Δ(9)-THC or placebo. Randomisation was balanced according to Expanded Disability Status Scale (EDSS) score, study site and disease type. Analyses were by intention to treat, following a pre-specified statistical analysis plan. A cranial magnetic resonance imaging (MRI) substudy, Rasch measurement theory (RMT) analyses and an economic evaluation were undertaken. SETTING: Twenty-seven UK sites. PARTICIPANTS: Adults aged 18-65 years with primary or secondary progressive MS, 1-year evidence of disease progression and baseline EDSS 4.0-6.5. INTERVENTIONS: Oral Δ(9)-THC (maximum 28 mg/day) or matching placebo. ASSESSMENT VISITS: Three and 6 months, and then 6-monthly up to 36 or 42 months. MAIN OUTCOME MEASURES: Primary outcomes were time to EDSS progression, and change in Multiple Sclerosis Impact Scale-29 version 2 (MSIS-29v2) 20-point physical subscale (MSIS-29phys) score. Various secondary patient- and clinician-reported outcomes and MRI outcomes were assessed. RMT analyses examined performance of MS-specific rating scales as measurement instruments and tested for a symptomatic or disease-modifying treatment effect. Economic evaluation estimated mean incremental costs and quality-adjusted life-years (QALYs). RESULTS: Effectiveness - recruitment targets were achieved. of the 498 randomised patients (332 to active and 166 to placebo), 493 (329 active and 164 placebo) were analysed. PRIMARY OUTCOMES: no significant treatment effect; hazard ratio EDSS score progression (active : placebo) 0.92 [95% confidence interval (CI) 0.68 to 1.23]; and estimated between-group difference in MSIS-29phys score (active-placebo) -0.9 points (95% CI -2.0 to 0.2 points). Secondary clinical and MRI outcomes: no significant treatment effects. Safety - at least one serious adverse event: 35% and 28% of active and placebo patients, respectively. RMT analyses - scale evaluation: MSIS-29 version 2, MS Walking Scale-12 version 2 and MS Spasticity Scale-88 were robust measurement instruments. There was no clear symptomatic or disease-modifying treatment effect. Economic evaluation - estimated mean incremental cost to NHS over usual care, over 3 years £27,443.20 per patient. No between-group difference in QALYs. CONCLUSIONS: the CUPID trial failed to demonstrate a significant treatment effect in primary or secondary outcomes. There were no major safety concerns, but unwanted side effects seemed to affect compliance. Participants were more disabled than in previous studies and deteriorated less than expected, possibly reducing our ability to detect treatment effects. RMT analyses supported performance of MS-specific rating scales as measures, enabled group- and individual person-level examination of treatment effects, but did not influence study inferences. The intervention had significant additional costs with no improvement in health outcomes; therefore, it was dominated by usual care and not cost-effective. Future work should focus on determining further factors to predict clinical deterioration, to inform the development of new studies, and modifying treatments in order to minimise side effects and improve study compliance. The absence of disease-modifying treatments in progressive MS warrants further studies of the cannabinoid pathway in potential neuroprotection. TRIAL REGISTRATION: Current Controlled Trials ISRCTN62942668. FUNDING: the National Institute for Health Research Health Technology Assessment programme, the Medical Research Council Efficacy and Mechanism Evaluation programme, Multiple Sclerosis Society and Multiple Sclerosis Trust. The report will be published in full in Health Technology Assessment; Vol. 19, No. 12. See the NIHR Journals Library website for further project information.

BACKGROUND: Laboratory evidence has shown that cannabinoids might have a neuroprotective action. We investigated whether oral dronabinol (Δ(9)-tetrahydrocannabinol) might slow the course of progressive multiple sclerosis. METHODS: in this multicentre, parallel, randomised, double-blind, placebo-controlled study, we recruited patients aged 18-65 years with primary or secondary progressive multiple sclerosis from 27 UK neurology or rehabilitation departments. Patients were randomly assigned (2:1) to receive dronabinol or placebo for 36 months; randomisation was by stochastic minimisation, using a computer-generated randomisation sequence, balanced according to expanded disability status scale (EDSS) score, centre, and disease type. Maximum dose was 28 mg per day, titrated against bodyweight and adverse effects. Primary outcomes were EDSS score progression (masked assessor, time to progression of ≥1 point from a baseline score of 4·0-5·0 or ≥0·5 points from a baseline score of ≥5·5, confirmed after 6 months) and change from baseline in the physical impact subscale of the 29-item multiple sclerosis impact scale (MSIS-29-PHYS). All patients who received at least one dose of study drug were included in the intention-to-treat analyses. This trial is registered as an International Standard Randomised Controlled Trial (ISRCTN 62942668). FINDINGS: of the 498 patients randomly assigned to a treatment group, 329 received at least one dose of dronabinol and 164 received at least one dose of placebo (five did not receive the allocated intervention). 145 patients in the dronabinol group had EDSS score progression (0·24 first progression events per patient-year; crude rate) compared with 73 in the placebo group (0·23 first progression events per patient-year; crude rate); HR for prespecified primary analysis was 0·92 (95% CI 0·68-1·23; p=0·57). Mean yearly change in MSIS-29-PHYS score was 0·62 points (SD 3·29) in the dronabinol group versus 1·03 points (3·74) in the placebo group. Primary analysis with a multilevel model gave an estimated between-group difference (dronabinol-placebo) of -0·9 points (95% CI -2·0 to 0·2). We noted no serious safety concerns (114 [35%] patients in the dronabinol group had at least one serious adverse event, compared with 46 [28%] in the placebo group). INTERPRETATION: Our results show that dronabinol has no overall effect on the progression of multiple sclerosis in the progressive phase. The findings have implications for the design of future studies of progressive multiple sclerosis, because lower than expected progression rates might have affected our ability to detect clinical change. FUNDING: UK Medical Research Council, National Institute for Health Research Efficacy and Mechanism Evaluation programme, Multiple Sclerosis Society, and Multiple Sclerosis Trust.

Background: the HemiSPAIRE trial is being conducted to determine whether a modified
muscle sparing technique (SPAIRE - “Save Piriformis and Internus, Repairing Externus”) in
hip hemiarthroplasty brings clinical benefits compared to the standard lateral technique in
adults aged 60 years or older, with a displaced intracapsular hip fracture. This article describes
the detailed statistical analysis plan for the trial.
Methods and design: HemiSPAIRE is a definitive, pragmatic, superiority, multicentre,
randomised controlled trial (with internal pilot) with two parallel groups. Participants, ward
staff and all research staff involved in post-operative assessments are blinded to allocation.
This article describes in detail (1) the primary and secondary outcomes, (2) the statistical
analysis principles, including: a survivor average causal effect (SACE) method chosen
specifically to address the issue of potential bias from differential survival between trial arms,
which was seen from data review by the Trial Steering Committee; the participants that will be
included in each analysis; the covariates that will be included in each analysis, and how the
results will be presented, (3) planned main analysis of the primary outcome; (4) planned
analyses of the secondary outcomes, (5) planned additional analyses of the primary and
secondary outcomes.

Abstract
. Background: Anxiety disorders are common among primary-school aged children, but few affected children receive evidence-based treatment. Identifying and supporting children who experience anxiety problems through schools would address substantial treatment access barriers that families and school staff often face. We have worked with families and school staff to co-design procedures that incorporate screening, feedback for parents, and the offer of a brief intervention in primary schools. This study sets out to assess the feasibility of a subsequent school-based cluster randomised controlled trial to evaluate these procedures. Our objectives are to ensure our procedures for identifying and supporting children with anxiety difficulties through primary schools are acceptable and there are no negative impacts, to estimate recruitment and retention rates, and to identify any changes needed to study procedures or measures. Methods: We will recruit six primary/junior schools in England (2 classes per school), and invite all children (aged 8-9) (n=360) and their parent/carer and class teacher in participating classes to take part. Children, parents and class teachers will complete questionnaires at baseline and 12-week follow-up. Children who ‘screen positive’ on a 2-item parent-report child anxiety screen at baseline will be the target population (expected n=43). Parents receive feedback on screening questionnaire responses, and where the child screens positive the family is offered support (OSI: Online Support and Intervention for child anxiety). OSI is a brief, parent-led online intervention, supported by short telephone sessions with a Children’s Wellbeing Practitioner. Participants’ experiences of study procedures will be assessed through qualitative interviews/discussion groups. Discussion:. Evidence-based procedures for identifying and supporting children with anxiety difficulties through primary schools would improve children’s access to timely, effective intervention for anxiety difficulties.Trial registration: ISRCTN registry: ISRCTN30032471. Retrospectively registered on 18.5.2021. https://www.isrctn.com/ISRCTN30032471

BACKGROUND: Parent carers of disabled children are at increased risk of physical and mental health problems. The Healthy Parent Carers (HPC) programme is a manualised peer-led group-based programme that aims to promote parent carer health and wellbeing. Previously, the programme had been delivered in person, with recruitment and delivery managed in a research context. This study explored implementation by two delivery partner organisations in the United Kingdom. Facilitator Training and Delivery Manuals were modified for online delivery using Zoom due to COVID-19. METHODS: the study methodology utilised the Replicating Effective Programs framework. A series of stakeholder workshops informed the development of the Implementation Logic Model and an Implementation Package. After delivering the programme, delivery partner organisations and facilitators participated in a workshop to discuss experiences of implementing the programme. A wider group of stakeholders, including commissioners, Parent Carer Forums and charity organisations representatives and researchers subsequently met to consider the sustainability and potential barriers to delivering the programme outside the research context. RESULTS: This study explored implementation by two delivery partner organisations in the United Kingdom that were able to recruit facilitators, who we trained, and they recruited participants and delivered the programme to parent carers in different localities using Zoom. The co-created Implementation Logic Model and Implementation Package were subsequently refined to enable the further roll-out of the programme with other delivery partner organisations. CONCLUSIONS: This study provides insight and understanding of how the HPC programme can be implemented sustainably outside of the research context. Further research will evaluate the effectiveness of the programme and refine the implementation processes. PATIENT AND PUBLIC CONTRIBUTION: Parent carers, delivery partner organisation staff and service commissioners were consulted on the design, delivery and reporting of the research.

BACKGROUND AND OBJECTIVES: Understanding how older people experience independence has implications for person-centred care. Existing understanding of older people's experience of independence, generated through methods that provide a 'snapshot' view of a person's independence at a given time point, provide little insight about the process of maintaining independence through time. The aim of this study was to explore older participants' perceptions to understand the processes and resources that were most important for maintaining independence. RESEARCH DESIGN AND METHODS: Two semi-structured interviews were conducted longitudinally to explore the perspectives of 12 community-dwelling, older people, aged 76-85 years. A social constructivist approach, using dramaturgical and descriptive codes, facilitated the interpretation of the data. Sixteen analytical questions guided exploration of participants' perceptions of independence through time. RESULTS: Older people suggested that objective representations underestimated, and omitted, important aspects of their independence through time. Some participants perceived 'snapshot' judgements of their independence as insensitive to their individual values and context. Change over time required some participants to adapt their methods for maintaining independence. The stability of participants' sense of independence was value-dependent and informed by the purpose a participant ascribed to maintaining independence. DISCUSSION AND IMPLICATIONS: This study augments the understanding of independence as a complex and multifaceted construct. The findings challenge the congruence of common interpretations of independence with older people's views, showing areas of commonality and discrepancy. Exploration of independence in terms of form and function provides important understanding about how function takes precedence to form in determining the maintenance of independence through time.

Abstract
. Approximately two-thirds of hospital admissions are older adults and almost half of these are likely to have some form of dementia. People with dementia are not only at an increased risk of adverse outcomes once admitted, but the unfamiliar environment and routinised practices of the wards and acute care can be particularly challenging for them, heightening their confusion, agitation and distress further impacting the ability to optimise their care. It is well established that a person-centred care approach helps alleviate some of the unfamiliar stress but how to embed this in the acute-care setting remains a challenge. In this article, we highlight the challenges that have been recognised in this area and put forward a set of evidence-based ‘pointers for service change’ to help organisations in the delivery of person-centred care. The DEMENTIA CARE pointers cover areas of: dementia awareness and understanding, education and training, modelling of person-centred care by clinical leaders, adapting the environment, teamwork (not being alone), taking the time to ‘get to know’, information sharing, access to necessary resources, communication, involving family (ask family), raising the profile of dementia care, and engaging volunteers. The pointers extend previous guidance, by recognising the importance of ward cultures that prioritise dementia care and institutional support that actively seeks to raise the profile of dementia care. The pointers provide a range of simple to more complex actions or areas for hospitals to help implement person-centred care approaches; however, embedding them within the organisational cultures of hospitals is the next challenge.

Abstract
. Background
. The COVID-19 pandemic dramatically influenced the delivery of healthcare. In line with the UK Royal Colleges’ advice the management of acute appendicitis (AA) changed with greater consideration for non-operative management (NOM) or open appendicectomy when operative management (OM) was sought. We describe our experience of the presentation, management and outcomes for these patients to inform care for future viral pandemics.
.
. Methods
. This retrospective, cohort study compared patients diagnosed with AA between March and July 2019 with those during the pandemic period of March to July 2020. Medical records were reviewed to obtain demographics, inflammatory markers, imaging, severity, management, histology, length of stay (LOS) and 90-day outcomes.
.
. Results
. There were 149 and 125 patients in the 2019 and 2020 cohorts respectively. 14 patients (9.4%) had NOM in 2019 versus 31 (24.8%) in 2020 (p = 0.001). In the 2019 operative management (OM) group 125 patients (92.6%) had laparoscopic appendicectomy versus 65 (69.1%) in 2020. 59 patients (39.6%) had a CT in 2019 versus 70 (56%) in 2020. The median LOS was 4 days in 2019 and 3 days in 2020 (p = 0.03). Two patients in each year who received NOM had treatment failure (14.3% in 2019 and 6.5% in 2020). Three patients in 2019 who received OM had treatment failure (2.2%). of 95 patients tested for COVID-19 all but one tested negative.
.
. Conclusion
. During the COVID-19 pandemic there was no observed increase in severity of AA, patients had a shorter LOS and were more likely to have imaging. NOM proportionally increased with no observed change in outcomes.
.

Realist evaluation has become widespread partly because of its sensitivity to the influence of contexts on policy implementation. In many such evaluations, the range of contexts considered relevant nevertheless remains disparate and under-conceptualised. This article uses findings from a realist evaluation of English Patient Safety Collaboratives during 2015–2018 to develop a realist taxonomy of contexts, differentiating contexts according to how they affect the corresponding policy mechanism. By analysing the main context-mechanism-outcome configurations that made up the English Patient Safety Collaboratives, we derive a taxonomy of the contexts that affected implementation and outcomes. The categories of context were structural (network, hierarchy, market and organisational contexts); resource-based (actors, material, financial); motivational (receptivity, outcome headroom), and temporal (continuity, history and convergence). To the categories found in previous studies, this study adds the three temporal contexts.

IntroductionCurrently National Institute for Health and Care Excellence clinical guidelines in the UK suggest that surgeons performing partial hip replacements (hemiarthroplasty) should consider using the lateral approach. Alternatively, a newer, modified posterior approach using a muscle sparing technique named ‘Save Piriformis and Internus, Repairing Externus’ (SPAIRE) can be used leaving the major muscles intact. This randomised controlled trial (RCT) aims to compare the SPAIRE approach to the standard lateral approach, to determine if it allows patients to mobilise better and experience improved function after surgery.Methods and analysisHemiSPAIRE is a two-arm, assessor-blinded, definitive pragmatic RCT with nested pilot and qualitative studies. Two hundred and twenty-eight participants with displaced intracapsular fractures requiring hip hemiarthroplasty will be individually randomised 1:1 to either the SPAIRE, or control (standard lateral approach) surgical procedure. Outcomes will be assessed at postoperative day 3 (POD3) and 120 (POD120). The primary outcome measure will be level of function and mobility using the Oxford Hip Score at POD120. Secondary outcomes include: De Morton Mobility Index (DEMMI), Cumulated Ambulatory Score and Numeric Pain Rating Scale (NPRS) at POD3; DEMMI, NPRS and EQ-5D-5L at POD120, complications, acute and total length of hospital stay, and mortality. Primary analysis will be on an intention-to-treat basis. Participant experiences of the impact of surgery and recovery period will be examined via up to 20 semi-structured telephone interviews.Ethics and disseminationThe protocol has been approved by Yorkshire and the Humber—Bradford Leeds Research Ethics Committee. Recruitment commenced in November 2019. Findings will be disseminated via research articles in peer-reviewed journals, presentations at conferences, public involvement events, patient groups and media releases. A summary of the trial findings will be shared with participants at the end of the study.Trial registration numberNCT04095611.

Objective:Poor vascular health is associated with reduced bone strength and increased risk of fragility fracture. However, direct measurement of intraosseous vascular health is difficult due to the density and mineral content of bone. We investigated the feasibility of using a commercially available continuous wave near infrared spectroscopy (NIRS) system for the investigation of vascular haemodynamics in human bonein vivo.Approach:An arterial occlusion (AO) protocol was developed for obtaining haemodynamic measurements of the proximal tibia and lateral calf, including assessment of the protocol’s intra operator reproducibility. For 36 participants, intraosseous haemodynamics derived by NIRS were compared to alternative tests of bone health based on dual x-ray absorptiometry (DXA) testing and MRI.Main Results:Near infrared spectroscopy markers of haemodynamics of the proximal tibia demonstrated acceptable reproducibility, comparable with reproducibility assessments of alternative modalities measuring intraosseous haemodynamics, and the use of NIRS for measuring muscle. Novel associations have been demonstrated between haemodynamic markers of bone measured with NIRS and body composition and bone mineral density (BMD) measurements obtained with both DXA and MRI.Significance:Near infrared spectroscopy provides inexpensive, non-invasive, safe, and real time data on changes in oxygenated and deoxygenated haemoglobin concentration in bone at the proximal tibia. This study has demonstrated the potential for NIRS to contribute to research investigating the pathophysiological role of vascular dysfunction within bone tissue, but also the limitations and need for further development of NIRS technology.

BACKGROUND: MYRIAD (My Resilience in Adolescence) is a superiority, parallel group, cluster randomised controlled trial designed to examine the effectiveness and cost-effectiveness of a mindfulness training (MT) programme, compared with normal social and emotional learning (SEL) school provision to enhance mental health, social-emotional-behavioural functioning and well-being in adolescence. The original trial protocol was published in Trials (accessible at https://doi.org/10.1186/s13063-017-1917-4 ). This included recruitment in two cohorts, enabling the learning from the smaller first cohort to be incorporated in the second cohort. Here we describe final amendments to the study protocol and discuss their underlying rationale. METHODS: Four major changes were introduced into the study protocol: (1) there were changes in eligibility criteria, including a clearer operational definition to assess the degree of SEL implementation in schools, and also new criteria to avoid experimental contamination; (2) the number of schools and pupils that had to be recruited was increased based on what we learned in the first cohort; (3) some changes were made to the secondary outcome measures to improve their validity and ability to measure constructs of interest and to reduce the burden on school staff; and (4) the current Coronavirus Disease 2019 (SARS-CoV-2 or COVID-19) pandemic both influences and makes it difficult to interpret the 2-year follow-up primary endpoint results, so we changed our primary endpoint to 1-year follow-up. DISCUSSION: These changes to the study protocol were approved by the Trial Management Group, Trial Steering Committee and Data and Ethics Monitoring Committees and improved the enrolment of participants and quality of measures. Furthermore, the change in the primary endpoint will give a more reliable answer to our primary question because it was collected prior to the COVID-19 pandemic in both cohort 1 and cohort 2. Nevertheless, the longer 2-year follow-up data will still be acquired, although this time-point will be now framed as a second major investigation to answer some new important questions presented by the combination of the pandemic and our study design. TRIAL REGISTRATION: International Standard Randomised Controlled Trials ISRCTN86619085. Registered on 3 June 2016.

BACKGROUND: an increasingly high number of patients admitted to hospital have dementia. Hospital environments can be particularly confusing and challenging for people living with dementia (Plwd) impacting their wellbeing and the ability to optimize their care. Improving the experience of care in hospital has been recognized as a priority, and non-pharmacological interventions including activity interventions have been associated with improved wellbeing and behavioral outcomes for Plwd in other settings. This systematic review aimed at evaluating the effectiveness of activity interventions to improve experience of care for Plwd in hospital. METHODS: Systematic searches were conducted in 16 electronic databases up to October 2019. Reference lists of included studies and forward citation searching were also conducted. Quantitative studies reporting comparative data for activity interventions delivered to Plwd aiming to improve their experience of care in hospital were included. Screening for inclusion, data extraction and quality appraisal were performed independently by two reviewers with discrepancies resolved by discussion with a third where necessary. Standardized mean differences (SMDs) were calculated where possible to support narrative statements and aid interpretation. RESULTS: Six studies met the inclusion criteria (one randomized and five non-randomized uncontrolled studies) including 216 Plwd. Activity interventions evaluated music, art, social, psychotherapeutic, and combinations of tailored activities in relation to wellbeing outcomes. Although studies were generally underpowered, findings indicated beneficial effects of activity interventions with improved mood and engagement of Plwd while in hospital, and reduced levels of responsive behaviors. Calculated SMDs ranged from very small to large but were mostly statistically non-significant. CONCLUSIONS: the small number of identified studies indicate that activity-based interventions implemented in hospitals may be effective in improving aspects of the care experience for Plwd. Larger well-conducted studies are needed to fully evaluate the potential of this type of non-pharmacological intervention to improve experience of care in hospital settings, and whether any benefits extend to staff wellbeing and the wider ward environment.

Rationale: Poor cardiovascular health is associated with reduced bone strength and increased risk of fragility fracture. However, direct measurement of intraosseous vascular health is difficult due to the density and mineral content of bone. The aim of this PhD project was to investigate the feasibility of near infrared spectroscopy (NIRS) for the investigation of vascular haemodynamics in human bone in vivo. NIRS provides inexpensive, non-invasive, safe, and real time data on changes in oxygenated and deoxygenated haemoglobin concentration at superficial anatomical sites. NIRS utilises a source optode of near infrared (NIR) light and detector optode that obtains representative data of the interactions of NIR photons with tissue.

Method: a systematic review was performed identifying the current existing applications of NIRS (and similar technologies) for measuring human bone tissue in vivo. This review informed the development of an arterial occlusion protocol for obtaining haemodynamic measurements of the proximal tibia and lateral calf, including assessment of the protocol’s reliability. For thirty-six participants, NIRS results were also compared to alternative tests of bone haemodynamics involving dynamic contrast enhanced MRI (DCE-MRI), and measures of general bone health based on dual x-ray absorptiometry testing and blood markers of bone metabolism.

Results: This thesis presents novel data demonstrating NIRS can obtain acceptably reliable markers of haemodynamics at the proximal tibia in vivo, comparable with reliability assessments of alternative modalities measuring intraosseous haemodynamics, and the use of NIRS for measuring muscle. Novel associations have been demonstrated between haemodynamic markers measured with NIRS and DCE-MRI, giving confidence NIRS truly represents bone haemodynamics. Increased NIRS markers of oxygen extraction during occlusion, and greater post-ischaemic vascular response to occlusion, were both associated with greater bone mineral density.

Conclusion: As a feasibility study, this PhD project has demonstrated the potential for NIRS to contribute to research around the potential pathophysiological role of vascular dysfunction within bone tissue, but also the limitations and need for further development of NIRS technology.

. Background
. Being in hospital can be particularly confusing and challenging not only for people living with dementia, but also for their carers and the staff who care for them. Improving the experience of care for people living with dementia in hospital has been recognised as a priority.
.
.
. Objectives
. To understand the experience of care in hospital for people living with dementia, their carers and the staff who care for them and to assess what we know about improving the experience of care.
.
.
. Review methods
. We undertook three systematic reviews: (1) the experience of care in hospital, (2) the experience of interventions to improve care in hospital and (3) the effectiveness and cost-effectiveness of interventions to improve the experience of care. Reviews 1 and 2 sought primary qualitative studies and were analysed using meta-ethnography. Review 3 sought comparative studies and economic evaluations of interventions to improve experience of care. An interweaving approach to overarching synthesis was used to integrate the findings across the reviews.
.
.
. Data sources
. Sixteen electronic databases were searched. Forwards and backwards citation chasing, author contact and grey literature searches were undertaken. Screening of title and abstracts and full texts was performed by two reviewers independently. A quality appraisal of all included studies was undertaken.
.
.
. Results
. Sixty-three studies (reported in 82 papers) were included in review 1, 14 studies (reported in 16 papers) were included in review 2, and 25 studies (reported in 26 papers) were included in review 3. A synthesis of review 1 studies found that when staff were delivering more person-centred care, people living with dementia, carers and staff all experienced this as better care. The line of argument, which represents the conceptual findings as a whole, was that ‘a change of hospital culture is needed before person-centred care can become routine’. From reviews 2 and 3, there was some evidence of improvements in experience of care from activities, staff training, added capacity and inclusion of carers. In consultation with internal and external stakeholders, the findings from the three reviews and overarching synthesis were developed into 12 DEMENTIA CARE pointers for service change: key institutional and environmental practices and processes that could help improve experience of care for people living with dementia in hospital.
.
.
. Limitations
. Few of the studies explored experience from the perspectives of people living with dementia. The measurement of experience of care across the studies was not consistent. Methodological variability and the small number of intervention studies limited the ability to draw conclusions on effectiveness.
.
.
. Conclusions
. The evidence suggests that, to improve the experience of care in hospital for people living with dementia, a transformation of organisational and ward cultures is needed that supports person-centred care and values the status of dementia care. Changes need to cut across hierarchies and training systems to facilitate working patterns and interactions that enable both physical and emotional care of people living with dementia in hospital. Future research needs to identify how such changes can be implemented, and how they can be maintained in the long term. To do this, well-designed controlled studies with improved reporting of methods and intervention details to elevate the quality of available evidence and facilitate comparisons across different interventions are required.
.
.
. Study registration
. This study is registered as PROSPERO CRD42018086013.
.
.
. Funding
. This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 8, No. 43. See the NIHR Journals Library website for further project information. Additional funding was provided by the NIHR Collaboration for Leadership in Applied Health Research and Care South West Peninsula.
.

Background:
Little research has been undertaken into the high rates of attrition from Diagnostic Radiography programmes. This two-phase study explored risk factors and experiences that may lead to attrition along with strategies that have enabled students to overcome these and continue their studies.
Methods:
Phase one – Quantitative, retrospective analysis of data from 2009-2014 for 579 past undergraduate student diagnostic radiographers from three English universities using non-parametric statistical tests and logistic regression. Data analysed included demographic and educational characteristics.
Phase two - Qualitative national online survey of 168 current undergraduate student diagnostic radiographers to further explore findings from phase one.
Results:
From the retrospective data, an attrition rate of 19% was reported with 45% non-completers leaving for personal reasons. Peak attrition was at 12 months. Increased age, non A-level entry qualifications and poor academic performance were identified as risk factors for attrition (p

INTRODUCTION: Parkinson's disease (PD) is a progressive neurodegenerative condition affecting approximately 185,000 people in the UK. No drug has been proven to slow disease progression. Epidemiological and pre-clinical data support simvastatin, a widely used cholesterol-lowering drug with a well-established safety profile, having neuroprotective properties. The aim of this study (Simvastatin as a neuroprotective treatment for PD (PD STAT)) is to determine whether simvastatin has the potential to slow PD progression. The study is part of the International Linked Clinical Trials initiative coordinated by the Cure Parkinson's Trust. This paper describes the protocol for the PD STAT study. METHODS AND ANALYSIS: PD STAT is a double-blind, randomised, placebo-controlled, multi-centre, parallel group, futility trial in patients with PD of mild-moderate severity. 235 participants have been recruited and randomly allocated in a 1:1 ratio to receive either oral simvastatin or matched placebo. Treatment involves a 1-month low-dose phase (40 mg daily), followed by a 23-month high-dose phase (80 mg daily) and ends with a 2-month washout period. Participants are reviewed at clinic visits at 1 month, 6, 12, 18, 24 and 26 months post-baseline, with interim telephone follow-up to monitor for adverse events.The primary outcome is the change in the Movement Disorder Society Unified Parkinson's Disease Rating Scale part III motor subscale score in the practically defined OFF medication state (OFF state) between baseline and 24 months. Primary analysis will be on a modified intention to treat basis and will include only those participants who progress to the high-dose phase of the study. ETHICS AND DISSEMINATION: the protocol has been approved by the North East-Newcastle and North Tyneside 2 Research Ethics Committee. The results will be disseminated via research articles in peer-reviewed journals and presentations at local, national and international scientific meetings, as well as disseminated via patient groups, websites and networks. A summary of the study findings will be posted to participants at the end of the study. TRIAL REGISTRATION: ISRCTN16108482 (prospectively registered); EudraCT 2015-000148-40; ClinicalTrials.gov NCT02787590; Pre-results.

This paper assesses the reliability and validity of the teacher-completed Pupil Behaviour Questionnaire (PBQ), by comparing it to the already extensively validated teacher-completed Strengths and Difficulties Questionnaire (SDQ). Participants included 2074 primary school children participating in a universal school-based trial and 41 vulnerable children who were taking part in a study exploring the impact of exclusion from school. Exploratory factor analysis results (first factor accounts for 80.8% of the variation in the items) and the high Cronbach’s alpha value of 0.85 indicate that the PBQ consists of one substantive factor/dimension. Strong correlations between the total PBQ score and the conduct sub-scale (Spearman’s correlation coefficient (rs) = 0.67) and total difficulties score (rs = 0.59) of the SDQ indicate convergent validity. This study suggests that the PBQ is a reliable measure, and provides some evidence of validity. Further work is needed to test the PBQ in an older, more diverse populations and to measure sensitivity to change.

BACKGROUND: School-based sexual health education has the potential to provide an inclusive and comprehensive approach to promoting sexual health among young people. We reviewed evaluations of school-based sexual health education interventions in sub-Saharan Africa to assess effectiveness in reducing sexually transmitted infections and promoting condom use. METHODS: We searched ten electronic databases, hand-searched key journals, and reference lists of included articles for potential studies. Data were extracted on outcomes, intervention characteristics, methods and study characteristics indicative of methodological quality. Where possible, data were synthesized using random effect meta-analysis. Intervention features found predominantly in effective interventions were noted. RESULTS: the initial search retrieved 21634 potentially relevant citations. of these, 51 papers reporting on 31 interventions were included. No evaluation reported statistically significant effects on the incidence or prevalence of Human Immunodeficiency Virus and Herpes Simplex Virus 2 infections. However, intervention participants reported statistically significant greater condom use in both randomised controlled trials and non-randomised trials for short (less than 6 months) follow-up periods (OR = 1.62, 95 % CI = 1.03-2.55 and OR = 2.88, 95 % CI = 1.41-5.90 respectively). For intermediate (6-10 months) and long-term (more than 10 months) follow-up periods, the effect was statistically significant (OR = 1.40, 95 % CI = 1.16-1.68) and marginally significant (OR = 1.22, 95 % CI = 0.99-1.50) among the randomised trials respectively. Only 12 of the 31 interventions reported implementation details, out of which seven reported on fidelity. CONCLUSION: School-based sexual health education has the potential to promote condom use among young people in sub-Saharan Africa. However, further work is needed to develop and evaluate interventions that have measurable effects on sexually transmitted infections.

Ebola virus (Zaire ebolavirus; EBOV) is a highly lethal hemorrhagic disease virus that most recently was responsible for two independent 2014 outbreaks in multiple countries in Western Africa, and the Democratic Republic of the Congo, respectively. Herein, we show that a cytomegalovirus (CMV)-based vaccine provides durable protective immunity from Ebola virus following a single vaccine dose. This study has implications for human vaccination against ebolaviruses, as well as for development of a 'disseminating' vaccine to target these viruses in wild African great apes.

BACKGROUND: Faecal calprotectin has been shown to be useful as a non-invasive screening test to differentiate functional from organic bowel disease, and it has been noted to be elevated in colorectal cancer. The aim of this study was to describe concentrations of faecal calprotectin in patients with oesophago-gastric cancer and investigate any potential discriminatory power of the test. PATIENTS: Faecal calprotectin was measured in samples from 39 patients with known oesophago-gastric cancer and in 191 samples from control subjects. RESULTS: the median calprotectin concentration was 

BACKGROUND: the Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial aimed to determine whether or not oral Δ(9)-tetrahydrocannabinol (Δ(9)-THC) slowed the course of progressive multiple sclerosis (MS); evaluate safety of cannabinoid administration; and, improve methods for testing treatments in progressive MS. OBJECTIVES: There were three objectives in the CUPID study: (1) to evaluate whether or not Δ(9)-THC could slow the course of progressive MS; (2) to assess the long-term safety of Δ(9)-THC; and (3) to explore newer ways of conducting clinical trials in progressive MS. DESIGN: the CUPID trial was a randomised, double-blind, placebo-controlled, parallel-group, multicentre trial. Patients were randomised in a 2 : 1 ratio to Δ(9)-THC or placebo. Randomisation was balanced according to Expanded Disability Status Scale (EDSS) score, study site and disease type. Analyses were by intention to treat, following a pre-specified statistical analysis plan. A cranial magnetic resonance imaging (MRI) substudy, Rasch measurement theory (RMT) analyses and an economic evaluation were undertaken. SETTING: Twenty-seven UK sites. PARTICIPANTS: Adults aged 18-65 years with primary or secondary progressive MS, 1-year evidence of disease progression and baseline EDSS 4.0-6.5. INTERVENTIONS: Oral Δ(9)-THC (maximum 28 mg/day) or matching placebo. ASSESSMENT VISITS: Three and 6 months, and then 6-monthly up to 36 or 42 months. MAIN OUTCOME MEASURES: Primary outcomes were time to EDSS progression, and change in Multiple Sclerosis Impact Scale-29 version 2 (MSIS-29v2) 20-point physical subscale (MSIS-29phys) score. Various secondary patient- and clinician-reported outcomes and MRI outcomes were assessed. RMT analyses examined performance of MS-specific rating scales as measurement instruments and tested for a symptomatic or disease-modifying treatment effect. Economic evaluation estimated mean incremental costs and quality-adjusted life-years (QALYs). RESULTS: Effectiveness - recruitment targets were achieved. of the 498 randomised patients (332 to active and 166 to placebo), 493 (329 active and 164 placebo) were analysed. PRIMARY OUTCOMES: no significant treatment effect; hazard ratio EDSS score progression (active : placebo) 0.92 [95% confidence interval (CI) 0.68 to 1.23]; and estimated between-group difference in MSIS-29phys score (active-placebo) -0.9 points (95% CI -2.0 to 0.2 points). Secondary clinical and MRI outcomes: no significant treatment effects. Safety - at least one serious adverse event: 35% and 28% of active and placebo patients, respectively. RMT analyses - scale evaluation: MSIS-29 version 2, MS Walking Scale-12 version 2 and MS Spasticity Scale-88 were robust measurement instruments. There was no clear symptomatic or disease-modifying treatment effect. Economic evaluation - estimated mean incremental cost to NHS over usual care, over 3 years £27,443.20 per patient. No between-group difference in QALYs. CONCLUSIONS: the CUPID trial failed to demonstrate a significant treatment effect in primary or secondary outcomes. There were no major safety concerns, but unwanted side effects seemed to affect compliance. Participants were more disabled than in previous studies and deteriorated less than expected, possibly reducing our ability to detect treatment effects. RMT analyses supported performance of MS-specific rating scales as measures, enabled group- and individual person-level examination of treatment effects, but did not influence study inferences. The intervention had significant additional costs with no improvement in health outcomes; therefore, it was dominated by usual care and not cost-effective. Future work should focus on determining further factors to predict clinical deterioration, to inform the development of new studies, and modifying treatments in order to minimise side effects and improve study compliance. The absence of disease-modifying treatments in progressive MS warrants further studies of the cannabinoid pathway in potential neuroprotection. TRIAL REGISTRATION: Current Controlled Trials ISRCTN62942668. FUNDING: the National Institute for Health Research Health Technology Assessment programme, the Medical Research Council Efficacy and Mechanism Evaluation programme, Multiple Sclerosis Society and Multiple Sclerosis Trust. The report will be published in full in Health Technology Assessment; Vol. 19, No. 12. See the NIHR Journals Library website for further project information.

INTRODUCTION: Secondary triage at a major incident allows for a more detailed assessment of the patient. In the UK, the Triage Sort (TSO) is the preferred method, combining GCS, systolic BP (SBP) and RR to categorise Priority 1 casualties. The Shock Index (SI) is calculated by dividing HR by SBP (HR/SBP). This study examines whether SI is better at predicting need for life-saving intervention (LSI) following trauma than TSO. METHODS: a prospective observational study was undertaken. Physiological data and interventions performed in the Emergency Department and operating theatre were prospectively collected for 482 consecutive adult trauma patients presenting to Camp Bastion, Afghanistan, over a 6-month period. A patient was deemed to have required LSI if they received any intervention from a set described previously. RESULTS: Complete data were available for 345 patients (71.6%). of these, 203 (58.8%) were gold standard P1, and 142 (41.2%) were non-P1. The TSO predicted need for LSI with a sensitivity of 58.6% (95% CI 51.8% to 65.4%) and specificity of 88.7% (95% CI 83.5% to 93.9%). Using an SI cut-off >0.75 provided greater sensitivity of 70.0% (95% CI 63.6% to 76.3%) while maintaining an acceptably high (although lower than TSO) specificity of 74.7% (95% CI 67.5% to 81.8%). At this SI cut-off, there was evidence of a difference between TSO and SI in terms of the way in which patients were triaged (p0.75 more accurately predicted the need for LSI, while maintaining acceptable specificity. SI may be more useful than TSO for secondary triage in a mass-casualty situation; this relationship in civilian trauma should be examined to clarify whether these results can be more widely translated into civilian practice. PROJECT REGISTRATION NUMBER: RCDM/Res/Audit/1036/12/0050.

INTRODUCTION: Major Incidents (MI) occur frequently and their unpredictable nature makes prospective research difficult and largely unethical. A key step in MI management is triage; the identification of the critically injured. Within a MI environment this is commonly performed using simple physiological ‘tools’, such as the Triage Sieve (TS). However the most commonly used tools appear to lack an evidence base. In a previous study, the authors used a military population to compare the performance of the TS to the Military Sieve (MS) at predicting need for Life-Saving Intervention (LSI). The MS differs only with the addition of a measurement of consciousness. The outcome from this study was that the MS outperformed the TS, but could be further improved with small changes to its physiological parameters, the Modified Military Sieve (MMS). MATERIALS AND METHODS: Physiological data and interventions performed within the Emergency Department (ED) and Operating Theatre were prospectively collected for consecutive adult trauma patients (>18years) presenting to the ED at Camp Bastion, Afghanistan between March and September 2011. All patients receiving a LSI were considered Gold Standard Priority One. Patients were triaged using the TS, MS, MMS, START (ST) and Careflight (CF) triage tools. Sensitivities and specificities were estimated with 95% confidence intervals and differences were checked for statistical significance using a McNemar test with Bonferroni correction. RESULTS: 482 patients presented to the ED during the study period, sufficient data was recorded for 335 (71%) with 199 (59%) P1s. The MMS (sensitivity 68.3%, specificity 79.4%) showed an absolute increase in sensitivity over existing tools ranging from 5.0% (MS) to 23.6% (CF). There was a statistically significant difference (P = 0.0005) between the MMS and MS. DISCUSSION: a key limitation to this study, is the use of a military cohort to validate the MMS, a tool which itself was developed using military data. The mechanism of injury also is unlikely to translate fully to the civilian population. CONCLUSIONS: Within a military population, the MMS outperforms existing MI triage tools. Before it is recommended as a replacement to the existing TS in UK civilian practice, it needs to be tested in a civilian environment.

BACKGROUND: Laboratory evidence has shown that cannabinoids might have a neuroprotective action. We investigated whether oral dronabinol (Δ(9)-tetrahydrocannabinol) might slow the course of progressive multiple sclerosis. METHODS: in this multicentre, parallel, randomised, double-blind, placebo-controlled study, we recruited patients aged 18-65 years with primary or secondary progressive multiple sclerosis from 27 UK neurology or rehabilitation departments. Patients were randomly assigned (2:1) to receive dronabinol or placebo for 36 months; randomisation was by stochastic minimisation, using a computer-generated randomisation sequence, balanced according to expanded disability status scale (EDSS) score, centre, and disease type. Maximum dose was 28 mg per day, titrated against bodyweight and adverse effects. Primary outcomes were EDSS score progression (masked assessor, time to progression of ≥1 point from a baseline score of 4·0-5·0 or ≥0·5 points from a baseline score of ≥5·5, confirmed after 6 months) and change from baseline in the physical impact subscale of the 29-item multiple sclerosis impact scale (MSIS-29-PHYS). All patients who received at least one dose of study drug were included in the intention-to-treat analyses. This trial is registered as an International Standard Randomised Controlled Trial (ISRCTN 62942668). FINDINGS: of the 498 patients randomly assigned to a treatment group, 329 received at least one dose of dronabinol and 164 received at least one dose of placebo (five did not receive the allocated intervention). 145 patients in the dronabinol group had EDSS score progression (0·24 first progression events per patient-year; crude rate) compared with 73 in the placebo group (0·23 first progression events per patient-year; crude rate); HR for prespecified primary analysis was 0·92 (95% CI 0·68-1·23; p=0·57). Mean yearly change in MSIS-29-PHYS score was 0·62 points (SD 3·29) in the dronabinol group versus 1·03 points (3·74) in the placebo group. Primary analysis with a multilevel model gave an estimated between-group difference (dronabinol-placebo) of -0·9 points (95% CI -2·0 to 0·2). We noted no serious safety concerns (114 [35%] patients in the dronabinol group had at least one serious adverse event, compared with 46 [28%] in the placebo group). INTERPRETATION: Our results show that dronabinol has no overall effect on the progression of multiple sclerosis in the progressive phase. The findings have implications for the design of future studies of progressive multiple sclerosis, because lower than expected progression rates might have affected our ability to detect clinical change. FUNDING: UK Medical Research Council, National Institute for Health Research Efficacy and Mechanism Evaluation programme, Multiple Sclerosis Society, and Multiple Sclerosis Trust.

OBJECTIVE: the aim of this study was to investigate gestational age-dependent effects of racial origin, smoking status and mode of conception on maternal serum levels of free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 7-14 weeks' gestation. METHODS: This was an analysis of data from prospective first-trimester combined screening for aneuploidies in singleton pregnancies, with β-hCG and PAPP-A measured at 7 + 1 to 14 + 3 weeks' gestation. We included 27,908 pregnancies from three centers in the U.K. and 125,461 pregnancies from 22 centers in Denmark, all with known normal fetal karyotype or resulting in the birth of a phenotypically normal neonate. Multiple regression modelling of log10 -transformed marker concentrations was used to produce log10 multiple of the median (MoM) values for free β-hCG and PAPP-A and to examine pregnancy characteristics that have significant effects on marker concentrations. RESULTS: Serum free β-hCG and PAPP-A concentrations were significantly affected by gestational age, maternal weight, racial origin, parity, smoking and mode of conception. There were significant gestational age-dependent effects attributed to Afro-Caribbean race, smoking and conception through in-vitro fertilization (IVF) on PAPP-A and free β-hCG levels. In women of Afro-Caribbean race there was a weekly increase in PAPP-A of 5.3% and in free β-hCG of 1.8%. In smokers there was a weekly decrease in PAPP-A of 2.4% and in free β-hCG of 1.6%. In cases of IVF conceptions there was a weekly increase in PAPP-A of 4.5% and in free β-hCG of 4.6%. CONCLUSIONS: Serum free β-hCG and PAPP-A concentrations at 7-14 weeks' gestation are affected by several pregnancy characteristics. The effects of Afro-Caribbean race, smoking and IVF conception change with gestational age.

INTRODUCTION: a key challenge at a major incident is to quickly identify those casualties most urgently needing treatment in order to survive - triage. The UK Triage Sieve (TS) advocated by the Major Incident Medical Management (MIMMS) Course categorises casualties by ability to walk, respiratory rate (RR) and heart rate (HR) or capillary refill time. The military version (MS) includes assessment of consciousness. We tested whether the MS better predicts need for life-saving intervention in a military trauma population. Ideal HR, RR and Glasgow Coma Score (GCS) thresholds were calculated. METHODS: a gold standard Priority 1 casualty was defined using resource-based criteria. Pre-hospital data from a military trauma database allowed calculation of triage category, which was compared with this standard, and presented as 2×2 tables. Sensitivity and specificity of each physiological parameter was calculated over a range of values to identify the ideal cut-offs. RESULTS: a gold standard could be ascribed in 1657 cases. In 1213 both the MS and TS could ascribe a category. MS was significantly more sensitive than TS (59% vs 53%, p

BACKGROUND: Accidental dural puncture has a quoted incidence of between 0.19% and 3.6% of obstetric epidurals and is associated with significant morbidity. We set out to determine possible factors associated with an increased risk of accidental dural puncture. METHODS: We performed a retrospective review of 18385 epidurals, performed over a 15-year period. Factors analysed were: time of day of insertion, loss-of-resistance technique, maternal position, cervical dilatation, grade of anaesthetist and depth to the epidural space. RESULTS: Using univariate analyses we found no association between the risk of accidental dural puncture and the following variables: time of day of insertion (P=0.71), loss-of-resistance technique (P=0.22), maternal position for insertion (P=0.83), degree of cervical dilatation (P=0.41) and grade of anaesthetist performing the epidural (P=0.34). Conversely, we found that the risk of accidental dural puncture increased with increasing depth to the epidural space. This was confirmed using a logistic regression analysis, from which it was estimated that, for every 1-cm increase in depth, the risk of accidental dural puncture increased by approximately 19% (P=0.019; 95% CI for OR: 1.029-1.38). CONCLUSION: We conclude that the risk of accidental dural puncture increases with increasing depth to the epidural space. We suggest further study is required to correlate this risk with increasing body mass index.

OBJECTIVE: it was the aim of this study to investigate the pregnancy characteristics that influence the measured concentrations of maternal serum-free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 9(+0)-13(+6) weeks' gestation. METHODS: in singleton pregnancies attending for routine care, serum-free β-hCG and PAPP-A were measured at 9(+0)-13(+6) weeks' gestation and fetal nuchal translucency was measured at 11(+0)-13(+6) weeks. The population included 27,908 chromosomally normal and 104 trisomy 21 pregnancies. Multiple regression analysis was used to examine the pregnancy characteristics that have a significant effect on the measured concentrations of free β-hCG and PAPP-A. We also examined the impact of incorporating temporal effects on performance of screening for trisomy 21. RESULTS: Serum-free β-hCG and PAPP-A concentrations were significantly affected by gestational age, maternal weight, racial origin, parity, preexisting diabetes mellitus type 2, smoking and conception by in vitro fertilization. There was a significant gestational age-dependent effect of Afro-Caribbean race on PAPP-A levels (p = 0.0005), with a weekly increase of 4.9% (95% CI 2.1-7.8). CONCLUSIONS: Serum-free β-hCG and PAPP-A concentrations at 9(+0)-13(+6) weeks' gestation are affected by several pregnancy characteristics and the effect of Afro-Caribbean race on PAPP-A increases with gestational age.

INTRODUCTION: Muscle biopsy is used in the diagnosis of mitochondrial disorders. There are limited data on the normal ranges, so interpretation of findings can be difficult. METHODS: We evaluated the percentage of fibers showing mitochondrial abnormalities using Gomori trichrome staining, succinate dehydrogenase, and cytochrome oxidase histochemistry in autopsy samples taken from 45 individuals without evidence of muscle disease and biopsies from 17 patients with mitochondrial disorders. RESULTS: in controls, mitochondrial abnormalities were rare before the fifth decade, and most had 0.5% abnormal fibers. CONCLUSIONS: Although some patients with mitochondrial disease have very few muscle fibers that show mitochondrial abnormalities, a rate of abnormality of >0.5% fibers, in the absence of a primary muscle disease this should raise the possibility of a mitochondrial disorder.

OBJECTIVES: to provide estimates and confidence intervals for the performance (detection and false-positive rates) of screening for Down's syndrome using repeated measures of biochemical markers from first and second trimester maternal serum samples taken from the same woman. DESIGN: Stored serum on Down's syndrome cases and controls was used to provide independent test data for the assessment of screening performance of published risk algorithms and for the development and testing of new risk assessment algorithms. SETTING: 15 screening centres across the USA, and at the North York General Hospital, Toronto, Canada. PARTICIPANTS: 78 women with pregnancy affected by Down's syndrome and 390 matched unaffected controls, with maternal blood samples obtained at 11-13 and 15-18 weeks' gestation, and women who received integrated prenatal screening at North York General Hospital at two time intervals: between 1 December 1999 and 31 October 2003, and between 1 October 2006 and 23 November 2007. INTERVENTIONS: Repeated measurements (first and second trimester) of maternal serum levels of human chorionic gonadotrophin (hCG), unconjugated estriol (uE3) and pregnancy-associated plasma protein a (PAPP-A) together with alpha-fetoprotein (AFP) in the second trimester. MAIN OUTCOME MEASURES: Detection and false-positive rates for screening with a threshold risk of 1 in 200 at term, and the detection rate achieved for a false-positive rate of 2%. RESULTS: Published distributional models for Down's syndrome were inconsistent with the test data. When these test data were classified using these models, screening performance deteriorated substantially through the addition of repeated measures. This contradicts the very optimistic results obtained from predictive modelling of performance. Simplified distributional assumptions showed some evidence of benefit from the use of repeated measures of PAPP-A but not for repeated measures of uE3 or hCG. Each of the two test data sets was used to create new parameter estimates against which screening test performance was assessed using the other data set. The results were equivocal but there was evidence suggesting improvement in screening performance through the use of repeated measures of PAPP-A when the first trimester sample was collected before 13 weeks' gestation. A Bayesian analysis of the combined data from the two test data sets showed that adding a second trimester repeated measurement of PAPP-A to the base test increased detection rates and reduced false-positive rates. The benefit decreased with increasing gestational age at the time of the first sample. There was no evidence of any benefit from repeated measures of hCG or uE3. CONCLUSIONS: If realised, a reduction of 1% in false-positive rate with no loss in detection rate would give important benefits in terms of health service provision and the large number of invasive tests avoided. The Bayesian analysis, which shows evidence of benefit, is based on strong distributional assumptions and should not be regarded as confirmatory. The evidence of potential benefit suggests the need for a prospective study of repeated measurements of PAPP-A with samples from early in the first trimester. A formal clinical effectiveness and cost-effectiveness analysis should be undertaken. This study has shown that the established modelling methodology for assessing screening performance may be optimistically biased and should be interpreted with caution.