R.O.S.L.A. wisdom or folly?

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EXOGEN ultrasound bone healing system for long bone fractures with non-union or delayed healing: a NICE medical technology guidance

Open Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.This article has been made available through the Brunel Open Access Publishing Fund.A routine part of the process for developing National Institute for Health and Care Excellence (NICE) medical technologies guidance is a submission of clinical and economic evidence by the technology manufacturer. The Birmingham and Brunel Consortium External Assessment Centre (EAC; a consortium of the University of Birmingham and Brunel University) independently appraised the submission on the EXOGEN bone healing system for long bone fractures with non-union or delayed healing. This article is an overview of the original evidence submitted, the EAC’s findings, and the final NICE guidance issued.The Birmingham and Brunel Consortium is funded by NICE to act as an External Assessment Centre for the Medical Technologies Evaluation Programme

Implementing pelvic floor muscle training in women's childbearing years: A critical interpretive synthesis of individual, professional, and service issues

Antenatal pelvic floor muscle training (PFMT) may be effective for the prevention and treatment of urinary and fecal incontinence both in pregnancy and postnatally, but it is not routinely implemented in practice despite guideline recommendations. This review synthesizes evidence that exposes challenges, opportunities, and concerns regarding the implementation of PFMT during the childbearing years, from the perspective of individuals, healthcare professionals (HCPs), and organizations.MethodsCritical interpretive synthesis of systematically identified primary quantitative or qualitative studies or research syntheses of women's and HCPs attitudes, beliefs, or experiences of implementing PFMT.ResultsFifty sources were included. These focused on experiences of postnatal urinary incontinence (UI) and perspectives of individual postnatal women, with limited evidence exploring the views of antenatal women and HCP or wider organizational and environmental issues. The concept of agency (people's ability to effect change through their interaction with other people, processes, and systems) provides an over?arching explanation of how PFMT can be implemented during childbearing years. This requires both individual and collective action of women, HCPs, maternity services and organizations, funders and policymakers.ConclusionNumerous factors constrain women's and HCPs capacity to implement PFMT. It is unrealistic to expect women and HCPs to implement PFMT without reforming policy and service delivery. The implementation of PFMT during pregnancy, as recommended by antenatal care and UI management guidelines, requires policymakers, organizations, HCPs, and women to value the prevention of incontinence throughout women's lives by using low?risk, low?cost, and proven strategies as part of women's reproductive health

Supported self-management for patients with COPD who have recently been discharged from hospital:a systematic review and meta-analysis

Purpose: Although many hospitals promote self-management to chronic obstructive pulmonary disease (COPD) patients post discharge from hospital, the clinical effectiveness of this is unknown. We undertook a systematic review of the evidence as part of a Health Technology Assessment review. Methods: A comprehensive search strategy with no language restrictions was conducted across relevant databases from inception to May 2012. Randomized controlled trials of patients with COPD, recently discharged from hospital after an acute exacerbation and comparing a self-management intervention with control, usual care or other intervention were included. Study selection, data extraction, and risk of bias assessment were undertaken by two reviewers independently. Results: Of 13,559 citations, 836 full texts were reviewed with nine randomized controlled trials finally included in quantitative syntheses. Interventions were heterogeneous. Five trials assessed highly supported multi-component interventions and four trials were less supported with fewer contacts with health care professionals and mainly home-based interventions. Total sample size was 1,466 (range 33–464 per trial) with length of follow-up 2–12 months. Trials varied in quality; poor patient follow-up and poor reporting was common. No evidence of effect in favor of self-management support was observed for all-cause mortality (pooled hazard ratio =1.07; 95% confidence interval [0.74 to 1.55]; I2=0.0%, [n=5 trials]). No clear evidence of effect on all-cause hospital admissions was observed (hazard ratio 0.88 [0.61, 1.27] I2=66.0%). Improvements in St George’s Respiratory Questionnaire score were seen in favor of self-management interventions (mean difference =3.84 [1.29 to 6.40]; I2=14.6%), although patient follow-up rates were low. Conclusion: There is insufficient evidence to support self-management interventions post-discharge. There is a need for good quality primary research to identify effective approaches

Development and psychometric evaluation of a new patient -reported outcome measure for stroke self -management: The Southampton Stroke Self - Management Questionnaire (SSSMQ).

BACKGROUND: Self-management is important to the recovery and quality of life of people following stroke. Many interventions to support self-management following stroke have been developed, however to date no reliable and valid outcome measure exists to support their evaluation. This study outlines the development and preliminary investigation of the psychometric performance of a newly developed patient-reported outcome measure (PROM) of self-management competency following stroke; the Southampton Stroke Self-Management Questionnaire (SSSMQ). METHODS: A convenience sample of 87 people who had had a stroke completed responses to the SSSMQ, the Stroke Self-Efficacy Questionnaire and the Stroke Impact Scale. Scaling properties were assessed using Mokken Scale Analysis. Reliability and construct validity were assessed using intra-class correlation coefficient (ICC), Mokken and Cronbach's reliability coefficients and Spearman rank order correlations with relevant measures. RESULTS: Mokken scaling refined the SSSMQ to 28 scalable items. Internal consistency reliability (Mokken r = 0.89) and test-retest reliability (ICC = 0.928) were excellent. Hypotheses of expected correlations with additional measures held, demonstrating good evidence for construct validity. CONCLUSIONS: Early findings suggest the Southampton Stroke Self-Management Questionnaire is a reliable and valid scale of self-management competency. The SSSMQ represents a potentially valid PROM for the evaluation of self-management following stroke

Reflectance confocal microscopy for diagnosising keratinocyte skin cancers in adults

Background Early accurate detection of all skin cancer types is important to guide appropriate management and to improve morbidity and survival. Basal cell carcinoma (BCC) is usually a localised skin cancer but with potential to infiltrate and damage surrounding tissue, whereas squamous cell carcinoma (cSCC) and melanoma are higher risk skin cancers with the potential to metastasise and ultimately lead to death. When used in conjunction with clinical or dermoscopic suspicion of malignancy, or both, reflectance confocal microscopy (RCM) may help to identify those eligible for non-surgical treatment without the need for a diagnostic biopsy, particularly in people with suspected BCC. Any potential benefit must be balanced against the risk of any misdiagnoses. Objectives 1) To determine the diagnostic accuracy of RCM for the detection of BCC, cSCC, or any skin cancer in adults with a) suspicious lesion and b) lesions that are difficult to diagnose (equivocal); and 2) to compare its accuracy with that of usual practice (visual inspection or dermoscopy, or both). Search methods We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; EMBASE; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles. Selection criteria Studies of any design that evaluated the accuracy of RCM alone, or RCM in comparison to visual inspection or dermoscopy, or both, in adults with lesions suspicious for skin cancer compared with a reference standard of either histological confirmation or clinical follow-up, or both. Data collection and analysis Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where information related to the target condition or diagnostic threshold were missing. We estimated summary sensitivities and specificities using the bivariate hierarchical model. For computation of likely numbers of true positive, false positive, false negative, and true negative findings in the'Summary of findings' tables, summary sensitivity and specificity estimates were applied to lower quartile, median and upper quartiles of the prevalence observed in the study groups. We also investigated the impact of observer experience. Main results Ten studies reporting on a total of 11 study cohorts were included. All 11 cohorts reported data for the detection of BCC, including 2037 lesions (464 with BCC); and four cohorts reported data for the detection of cSCC, including 834 lesions (71 with cSCC). Only one study also reported data for the detection of BCC or cSCC using dermoscopy, limiting comparisons between RCM and dermoscopy. Studies were at high or unclear risk of bias across almost all methodological quality domains, and were of high or unclear concern regarding applicability of the evidence. Selective participant recruitment, unclear blinding of the reference test, and exclusions due to image quality or technical difficulties were observed. It is unclear whether studies are representative of populations eligible for testing with RCM, and test interpretation was often undertaken using images, remotely from the patient and the interpreter blinded to clinical information that would normally be available in practice. Meta-analysis found RCM to be more sensitive but less specific for the detection of BCC in studies of participants with equivocal lesions (sensitivity 94%, 95% CI 79% to 98%; specificity 85%, 95% CI 72% to 92%; n = 3 studies) compared to studies that included any suspicious lesion (sensitivity 76%, 95% CI 45% to 92%; specificity 95%, 95% CI 66% to 99%; n = 4 studies), although confidence intervals were wide. At the median prevalence of disease of 12.5% observed in studies including any suspicious lesion, applying these results to a hypothetical population of 1000 lesions results in 30 BCCs missed with 44 false positive results (lesions misdiagnosed as BCCs). At the median prevalence of disease of 15% observed in studies of equivocal lesions, 9 BCCs would be missed with 128 false positive results in a population of 1000 lesions. Across both sets of studies, up to 15% of these false positive lesions were observed to be melanomas mistaken for BCCs. There was some suggestion of higher sensitivities in studies with more experienced observers. Summary sensitivity and specificity could not be estimated for the detection of cSCC due to paucity of data. Authors' conclusions There is insufficient evidence for the use of RCM for the diagnosis of BCC or cSCC in either population group. A possible role for RCM in clinical practice is as a tool to avoid diagnostic biopsies in lesions with a relatively high clinical suspicion of BCC. The potential for, and consequences of, misclassification of other skin cancers such as melanoma as BCCs requires further research. Importantly, data are lacking that compare RCM to standard clinical practice (with or without dermoscopy)

High frequency ultrasound for the diagnosis of skin cancer in adults

Background: Early accurate detection of all skin cancer types is essential to guide appropriate management and to improve morbidity and survival. Melanoma and squamous cell carcinoma (SCC) are high risk skin cancers which have the potential to metastasise and ultimately lead to death, whereas basal cell carcinoma (BCC) is usually localised with potential to infiltrate and damage surrounding tissue. Anxiety around missing early curable cases needs to be balanced against inappropriate referral and unnecessary excision of benign lesions. Ultrasound is a non-invasive imaging technique which relies on the measurement of sound wave reflections from the tissues of the body. At lower frequencies, the deeper structures of the body such as the internal organs can be visualised, while high frequency ultrasound (HFUS) with transducer frequencies of at least 20MHz, has a much lower depth of tissue penetration but produces a higher resolution image of tissues and structures closer to the skin surface. Used in conjunction with clinical or dermoscopic examination of suspected skin cancer, or both, HFUS may offer additional diagnostic information compared to other technologies. Objectives: To determine the diagnostic accuracy of HFUS to assist in the diagnosis of (a) melanoma and intraepidermal melanocytic variants, (b) cutaneous squamous cell carcinoma (cSCC), and (c) basal cell carcinoma (BCC) in adults. Search methods: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; EMBASE; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles. Selection criteria: Studies evaluating HFUS (>= 20 MHz) in adults with lesions suspicious for melanoma, cSCC or BCC, compared with a reference standard of histological confirmation or clinical follow-up. Data collection and analysis: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). Due to scarcity of data and poor quality of studies, no meta-analysis was undertaken for this review. For illustrative purposes, estimates of sensitivity and specificity were plotted on coupled forest plots. Main results: Six studies were included, providing 29 datasets, 20 for diagnosis of melanoma (1125 lesions and 242 melanomas) and 9 for diagnosis of BCC (993 lesions and 119 BCCs). No data relating to the diagnosis of cSCC were identified. Studies were generally poorly reported limiting judgements of methodological quality. Half of studies did not set out to establish test accuracy and all should be considered preliminary evaluations of the potential usefulness of HFUS. There were particularly high concerns for applicability of findings due to selective study populations and data driven thresholds for test positivity. Studies reporting qualitative assessments of HFUS images excluded up to 22% of lesions (including some melanomas) due to them not being visualised by the test. Derived sensitivities for qualitative HFUS characteristics were at least 83% (95% CI 75% to 90%) for the detection of melanoma; the combination of three features (lesions appearing hypoechoic, homogenous and well defined) demonstrating 100% sensitivity in two studies, with variable corresponding specificities of 33% (95% CI 20% to 48%) and 73% (95% CI 57% to 85%) (Lower limits of the 95% CIs for sensitivities were 94% and 82% respectively). Quantitative measurement of HFUS outputs in two studies enabled decision thresholds to be set to achieve 100% sensitivity; specificities were 93% (95% CI 77% to 99%) and 65% (95% CI 51% to 76%). It was not possible to make summary statements regarding HFUS accuracy for the diagnosis of BCC due to highly variable sensitivities and specificities. Authors' conclusions: Insufficient data are available on the potential value of HFUS in the diagnosis of melanoma or BCC. Given the between study heterogeneity, unclear to low methodological quality and limited volume of evidence, no implications for practice can be drawn. The main value of the preliminary studies included may be in provision of guidance on the possible components of future diagnostic rules for diagnosis of melanoma or BCC using HFUS that require future evaluation. A prospective evaluation of HFUS added to visual inspection and dermoscopy alone in a standard health care setting with a clearly defined and representative population of participants would be required for a full and proper evaluation of accuracy

Exfoliative cytology for the diagnosis of basal cell carcinoma and other skin cancers in adults

Background: Early accurate detection of all skin cancer types is essential to guide appropriate management and to reduce morbidity and improve survival. Basal cell carcinoma (BCC) is usually localised to the skin with potential to infiltrate and damage surrounding tissue, while cutaneous squamous cell carcinoma (cSCC) and melanoma have a much higher potential to metastasise and ultimately lead to death. Exfoliative cytology is a non–invasive test that uses the Tzanck smear technique to identify disease by examining the structure of cells obtained from scraped samples. This simple procedure is a less invasive diagnostic test than a skin biopsy, and for BCC has the potential to provide an immediate diagnosis that avoids an additional visit to clinic to receive skin biopsy results. This may benefit patients scheduled for either Mohs micrographic surgery or non–surgical treatments such as radiotherapy. A cytology scrape can never give the same information as a skin biopsy, however, so it is important to know more about which skin cancer situations it may be helpful. Objectives: The primary objective was to determine the diagnostic accuracy of exfoliative cytology for the detection of basal cell carcinoma (BCC) in adults. Secondary objectives were to determine diagnostic accuracy for the detection of i) cutaneous squamous cell carcinoma, ii) invasive melanoma and atypical intraepidermal melanocytic variants, and iii) any skin cancer, including keratinocyte skin cancer, invasive melanoma and atypical intraepidermal melanocytic variants, or any other skin cancer. Search methods: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; EMBASE; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We also studied the reference lists of published systematic review articles. Selection criteria: Studies evaluating exfoliative cytology in adults with lesions suspicious for BCC, cSCC or melanoma, compared with a reference standard of histological confirmation. Data collection and analysis: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). Where possible we estimated summary sensitivities and specificities using the bivariate hierarchical model. Main results: This review reports on nine studies with a total of 1655 lesions including 1120 BCCs (14 datasets), 401 lesions with 44 cSCCs (two datasets), and 200 lesions with 10 melanomas (one dataset). Three of these datasets (one each for BCC, melanoma, and any malignant condition) were derived from one study which also performed a direct comparison with dermoscopy. Studies were of moderate to poor quality providing inadequate descriptions of participant selection, thresholds used to make cytological and histological diagnoses, and blinding. Reporting of patients’ prior referral pathways was particularly poor, as were descriptions of the cytodiagnostic criteria used to make diagnoses. No studies evaluated the use of exfoliative cytology as a primary diagnostic test for detecting BCC or other skin cancers in lesions suspicious for skin cancer. Pooled data from seven studies using standard cytomorphological criteria (but various stain methods) to detect BCC in patients with a high clinical suspicion of BCC estimated the sensitivity and specificity of exfoliative cytology as 97.5% (95% CI: 94.5 to 98.9%) and 90.1% (95% CI: 81.1 to 95.1%) respectively. When applied to a hypothetical population of 1000 clinically suspected BCC lesions with a median observed BCC prevalence of 86%, exfoliative cytology would miss 21 BCCs and would lead to 14 false positive diagnoses of BCC. No false positive cases were histologically confirmed to be melanoma. Insufficient data are available to make summary statements regarding the accuracy of exfoliative cytology to detect melanoma or cSCC, or its accuracy compared to dermoscopy. Authors' conclusions: The utility of exfoliative cytology for the primary diagnosis of skin cancer is unknown, as all included studies focused on the use of this technique for confirming strongly suspected clinical diagnoses. For the confirmation of BCC in lesions with a high clinical suspicion, there is evidence of high sensitivity and specificity for exfoliative cytology. Since decisions to treat low risk BCCs are unlikely in practice to require diagnostic confirmation given that clinical suspicion is already high, exfoliative cytology might be most useful for cases of BCC where the treatments being contemplated require a tissue diagnosis (e.g. radiotherapy). The small number of included studies, poor reporting and varying methodological quality means that no strong conclusions can currently be drawn to guide clinical practice. Despite insufficient data on the use of cytology for cSCC or melanoma, it is unlikely that cytology would be useful in these scenarios since preservation of the architecture of the whole lesion that would be available from a biopsy provides crucial diagnostic information. Given the paucity of good quality data, appropriately designed prospective comparative studies may be required to evaluate both the diagnostic value of exfoliative cytology by comparison to dermoscopy, and its confirmatory value in adequately reported populations with a high probability of BCC scheduled for further treatment requiring a tissue diagnosis

Neurodevelopmental protein Musashi-1 interacts with the Zika genome and promotes viral replication.

A recent outbreak of Zika virus in Brazil has led to a simultaneous increase in reports of neonatal microcephaly. Zika targets cerebral neural precursors, a cell population essential for cortical development, but the cause of this neurotropism remains obscure. Here we report that the neural RNA-binding protein Musashi-1 (MSI1) interacts with the Zika genome and enables viral replication. Zika infection disrupts the binding of MSI1 to its endogenous targets, thereby deregulating expression of factors implicated in neural stem cell function. We further show that MSI1 is highly expressed in neural progenitors of the human embryonic brain and is mutated in individuals with autosomal recessive primary microcephaly. Selective MSI1 expression in neural precursors could therefore explain the exceptional vulnerability of these cells to Zika infection.The authors are indebted to Alain Kohl (Centre for Virus Research, University of Glasgow) and Lindomar J. Pena and Rafael Oliveira de Freitas França, Fiocruz Recife, Pernambuco, Brazil, for the provision of PE243 ZIKV RNA used to generate the virus stock. We would like to thank and acknowledge Steve Lisgo for the expert provision of human embryonic histology sections through the Human Developmental Biology Resource (HDBR) at the University of Newcastle funded by a joint UK MRC/Wellcome Trust grant (099175/Z/12/Z). We would like to thank Leanna Smith for her assistance with homology modeling, Guillaume van Zande for his help and the patients’ families for their participation. The National Research Ethics Service Committee, East of England - Cambridge Central, UK (C.G. Woods, REC 05/Q0108/402) approved the informed consent to enter the study. We are grateful for expert help by the CRUK CI Core Facilities. I.G. and A. E. F are Wellcome Trust Senior Fellows. I.G. was supported by research grants 097997/Z/11/A and 097997/Z/11/Z, whereas A. E. F by grant 106207. M.S.N was funded by the Wellcome Trust (200183/Z/15/Z) and T. R. S is a Wellcome Trust Henry Dale Fellow (202471/Z/16/Z). This work was made possible by funding from Cancer Research UK C14303/A17197 to FG and C24461/A12772 to R.B. F.G. and C.G.W. acknowledge support from NIHR Cambridge Biomedical Research Centre, the University of Cambridge and Hutchison Whampoa Ltd