Oxandrolone for growth hormone-treated girls aged up to 18 years with Turner syndrome.

BACKGROUND: The final adult height of untreated girls aged up to 18 years with Turner syndrome (TS) is approximately 20 cm shorter compared with healthy females. Treatment with growth hormone (GH) increases the adult height of people with TS. The effects of adding the androgen, oxandrolone, in addition to GH are unclear. Therefore, we conducted this systematic review to investigate the benefits and harms of oxandrolone as an adjuvant therapy for people with TS treated with GH. OBJECTIVES: To assess the effects of oxandrolone on growth hormone-treated girls aged up to 18 years with Turner syndrome. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, the ICTRP Search Portal and ClinicalTrials.gov. The date of the last search was October 2018. We applied no language restrictions. SELECTION CRITERIA: We included randomised controlled clinical trials (RCTs) that enrolled girls aged up to 18 years with TS who were treated with GH and oxandrolone compared with GH only treatment. DATA COLLECTION AND ANALYSIS: Three review authors independently screened titles and abstracts for relevance, selected trials, extracted data and assessed risk of bias. We resolved disagreements by consensus, or by consultation with a fourth review author. We assessed trials for overall certainty of the evidence using the GRADE instrument. MAIN RESULTS: We included six trials with 498 participants with TS, 267 participants were randomised to oxandrolone plus GH treatment and 231 participants were randomised to GH only treatment. The individual trial sample size ranged between 22 and 133 participants. The included trials were conducted in 65 different paediatric endocrinology healthcare facilities including clinics, centres, hospitals and academia in the USA and Europe. The duration of interventions ranged between 3 and 7.6 years. The mean age of participants at start of therapy ranged from 9 to 12 years. Overall, we judged only one trial at low risk of bias in all domains and another trial at high risk of bias in most domains. We downgraded the level of evidence mainly because of imprecision (low number of trials, low number of participants or both). Comparing oxandrolone plus GH with GH only for final adult height showed a mean difference (MD) of 2.7 cm in favour of oxandrolone plus GH treatment (95% confidence interval (CI) 1.3 to 4.1; P < 0.001; 5 trials, 270 participants; moderate-quality evidence). The 95% prediction interval ranged between 0.3 cm and 5.1 cm. For adverse events, we based our main analysis on reliable date from two trials with overall low risk of bias. There was no evidence of a difference between oxandrolone plus GH and GH for adverse events (RR 1.81, 95% CI 0.83 to 3.96; P = 0.14; 2 trials, 170 participants; low-quality evidence). Six out of 86 (18.6%) participants receiving oxandrolone plus GH compared with 8/84 (9.5%) participants receiving GH only reported adverse events, mainly signs of virilisation (e.g. deepening of the voice). One trial each investigated the effects of treatments on speech (voice frequency; 88 participants), cognition (51 participants) and psychological status (106 participants). The overall results for these comparisons were inconclusive (very low-quality evidence). No trial reported on health-related quality of life or all-cause mortality. AUTHORS' CONCLUSIONS: Addition of oxandrolone to the GH therapy led to a modest increase in the final adult height of girls aged up to 18 years with TS. Adverse effects identified included virilising effects such as deepening of the voice, but reporting was inadequate in some trials.

Global burden of diseases, injuries, and risk factors for young people's health during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.

BACKGROUND: Young people's health has emerged as a neglected yet pressing issue in global development. Changing patterns of young people's health have the potential to undermine future population health as well as global economic development unless timely and effective strategies are put into place. We report the past, present, and anticipated burden of disease in young people aged 10-24 years from 1990 to 2013 using data on mortality, disability, injuries, and health risk factors. METHODS: The Global Burden of Disease Study 2013 (GBD 2013) includes annual assessments for 188 countries from 1990 to 2013, covering 306 diseases and injuries, 1233 sequelae, and 79 risk factors. We used the comparative risk assessment approach to assess how much of the burden of disease reported in a given year can be attributed to past exposure to a risk. We estimated attributable burden by comparing observed health outcomes with those that would have been observed if an alternative or counterfactual level of exposure had occurred in the past. We applied the same method to previous years to allow comparisons from 1990 to 2013. We cross-tabulated the quantiles of disability-adjusted life-years (DALYs) by quintiles of DALYs annual increase from 1990 to 2013 to show rates of DALYs increase by burden. We used the GBD 2013 hierarchy of causes that organises 306 diseases and injuries into four levels of classification. Level one distinguishes three broad categories: first, communicable, maternal, neonatal, and nutritional disorders; second, non-communicable diseases; and third, injuries. Level two has 21 mutually exclusive and collectively exhaustive categories, level three has 163 categories, and level four has 254 categories. FINDINGS: The leading causes of death in 2013 for young people aged 10-14 years were HIV/AIDS, road injuries, and drowning (25·2%), whereas transport injuries were the leading cause of death for ages 15-19 years (14·2%) and 20-24 years (15·6%). Maternal disorders were the highest cause of death for young women aged 20-24 years (17·1%) and the fourth highest for girls aged 15-19 years (11·5%) in 2013. Unsafe sex as a risk factor for DALYs increased from the 13th rank to the second for both sexes aged 15-19 years from 1990 to 2013. Alcohol misuse was the highest risk factor for DALYs (7·0% overall, 10·5% for males, and 2·7% for females) for young people aged 20-24 years, whereas drug use accounted for 2·7% (3·3% for males and 2·0% for females). The contribution of risk factors varied between and within countries. For example, for ages 20-24 years, drug use was highest in Qatar and accounted for 4·9% of DALYs, followed by 4·8% in the United Arab Emirates, whereas alcohol use was highest in Russia and accounted for 21·4%, followed by 21·0% in Belarus. Alcohol accounted for 9·0% (ranging from 4·2% in Hong Kong to 11·3% in Shandong) in China and 11·6% (ranging from 10·1% in Aguascalientes to 14·9% in Chihuahua) of DALYs in Mexico for young people aged 20-24 years. Alcohol and drug use in those aged 10-24 years had an annual rate of change of >1·0% from 1990 to 2013 and accounted for more than 3·1% of DALYs. INTERPRETATION: Our findings call for increased efforts to improve health and reduce the burden of disease and risks for diseases in later life in young people. Moreover, because of the large variations between countries in risks and burden, a global approach to improve health during this important period of life will fail unless the particularities of each country are taken into account. Finally, our results call for a strategy to overcome the financial and technical barriers to adequately capture young people's health risk factors and their determinants in health information systems. FUNDING: Bill & Melinda Gates Foundation.

Using patient values and preferences to inform the importance of health outcomes in practice guideline development following the GRADE approach.

BACKGROUND: There are diverse opinions and confusion about defining and including patient values and preferences (i.e. the importance people place on the health outcomes) in the guideline development processes. This article aims to provide an overview of a process for systematically incorporating values and preferences in guideline development. METHODS: In 2013 and 2014, we followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to adopt, adapt and develop 226 recommendations in 22 guidelines for the Ministry of Health of the Kingdom of Saudi Arabia. To collect context-specific values and preferences for each recommendation, we performed systematic reviews, asked clinical experts to provide feedback according to their clinical experience, and consulted patient representatives. RESULTS: We found several types of studies addressing the importance of outcomes, including those reporting utilities, non-utility measures of health states based on structured questionnaires or scales, and qualitative studies. Guideline panels used the relative importance of outcomes based on values and preferences to weigh the balance of desirable and undesirable consequences of alternative intervention options. However, we found few studies addressing local values and preferences. CONCLUSIONS: Currently there are different but no firmly established processes for integrating patient values and preferences in healthcare decision-making of practice guideline development. With GRADE Evidence-to-Decision (EtD) frameworks, we provide an empirical strategy to find and incorporate values and preferences in guidelines by performing systematic reviews and eliciting information from guideline panel members and patient representatives. However, more research and practical guidance are needed on how to search for relevant studies and grey literature, assess the certainty of this evidence, and best summarize and present the findings.

Warwick-Edinburgh Mental Well-being Scale (WEMWBS): validated for teenage school students in England and Scotland. A mixed methods assessment.

BACKGROUND: Understanding and measuring mental health and wellbeing amongst teenagers has recently become a priority. The Warwick-Edinburgh Mental Well-being Scale (WEMWBS) is validated for measuring mental wellbeing in populations aged 16 years and over in the UK. We report here a study designed to establish the validity and reliability of WEMWBS in teenagers in the UK. METHODS: WEMWBS and comparator scales, together with socio-demographic information and self-reported health, were incorporated into a self-administered questionnaire given to pupils aged 13 to 16 years in six schools in Scotland and England. Psychometric properties including internal consistency, correlations with comparator scales, test-retest stability and unidimensionality were investigated for WEMWBS. Twelve focus groups were undertaken to assess acceptability and comprehensibility of WEMWBS and were taped, transcribed and analysed thematically. RESULTS: A total of 1,650 teenagers completed the questionnaire (response rate 80.8%). Mean WEMWBS score was 48.8 (SD 6.8; median 49). Response scores covered the full range (from 14 to 70). WEMWBS demonstrated strong internal consistency and a high Cronbach's alpha of 0.87 (95% CI (0.85-0.88), n = 1517). Measures of construct validity gave values as predicted. The correlation coefficient for WEMWBS total score and psychological wellbeing domain of the Kidscreen-27 was 0.59 (95% CI [0.55; 0.62]); for the Mental Health Continuum Short Form (MHC-SF) was 0.65, 95% CI [0.62; 0.69]; and for the WHO (WHO-5) Well-being Index 0.57 (95% CI [0.53; 0.61]). The correlation coefficient for the Strengths and Difficulties Questionnaire (SDQ) was -0.44 (95% CI [-0.49; -0.40]) and for the 12-item General Health Questionnaire (GHQ12) -0.45 (95% CI [-0.49; -0.40]). Test-retest reliability was acceptable (Intraclass correlation coefficient (ICC) 0.66 (95% CI [0.59; 0.72] n = 212)). Confirmatory factor analysis demonstrated one underlying factor. WEMWBS was significantly associated with the Family Affluence Score (WEMWBS increased with increasing household socio-economic status) and had a positive association with the physical health dimension of the Kidscreen-27, but was unrelated to age, gender or location/school. Eighty students took part in focus groups. In general, although some students considered some items open to misunderstanding or misinterpretation, WEMWBS was received positively and was considered comprehensible, and acceptable. CONCLUSIONS: WEMWBS is a psychometrically strong population measure of mental wellbeing, and can be used for this purpose in teenagers aged 13 and over.

Clinical effectiveness and cost-effectiveness of pegvisomant for the treatment of acromegaly: a systematic review and economic evaluation.

BACKGROUND: Acromegaly, an orphan disease usually caused by a benign pituitary tumour, is characterised by hyper-secretion of growth hormone (GH) and insulin-like growth factor I (IGF-1). It is associated with reduced life expectancy, cardiovascular problems, a variety of insidiously progressing detrimental symptoms and metabolic malfunction. Treatments include surgery, radiotherapy and pharmacotherapy. Pegvisomant (PEG) is a genetically engineered GH analogue licensed as a third or fourth line option when other treatments have failed to normalise IGF-1 levels. METHODS: Evidence about effectiveness and cost-effectiveness of PEG was systematically reviewed. Data were extracted from published studies and used for a narrative synthesis of evidence. A decision analytical economic model was identified and modified to assess the cost-effectiveness of PEG. RESULTS: One RCT and 17 non-randomised studies were reviewed for effectiveness. PEG substantially reduced and rapidly normalised IGF-1 levels in the majority of patients, approximately doubled GH levels, and improved some of the signs and symptoms of the disease. Tumour size was unaffected at least in the short term. PEG had a generally safe adverse event profile but a few patients were withdrawn from treatment because of raised liver enzymes. An economic model was identified and adapted to estimate the lower limit for the cost-effectiveness of PEG treatment versus standard care. Over a 20 year time horizon the incremental cost-effectiveness ratio was pound81,000/QALY and pound212,000/LYG. To reduce this to pound30K/QALY would require a reduction in drug cost by about one third. CONCLUSION: PEG is highly effective for improving patients' IGF-1 level. Signs and symptoms of disease improve but evidence is lacking about long term effects on improved signs and symptoms of disease, quality of life, patient compliance and safety. Economic evaluation indicated that if current standards (UK) for determining cost-effectiveness of therapies were to be applied to PEG it would be considered not to represent good value for money.

GRADE Evidence to Decision (EtD) frameworks for adoption, adaptation, and de novo development of trustworthy recommendations: GRADE-ADOLOPMENT.

BACKGROUND: Guideline developers can: (1) adopt existing recommendations from others; (2) adapt existing recommendations to their own context; or (3) create recommendations de novo. Monetary and nonmonetary resources, credibility, maximization of uptake, as well as logical arguments should guide the choice of the approach and processes. OBJECTIVES: To describe a potentially efficient model for guideline production based on adoption, adaptation, and/or de novo development of recommendations utilizing the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Evidence to Decision (EtD) frameworks. STUDY DESIGN AND SETTING: We applied the model in a new national guideline program producing 22 practice guidelines. We searched for relevant evidence that informs the direction and strength of a recommendation. We then produced GRADE EtDs for guideline panels to develop recommendations. RESULTS: We produced a total of 80 EtD frameworks in approximately 4 months and 146 EtDs in approximately 6 months in two waves. Use of the EtD frameworks allowed panel members understand judgments of others about the criteria that bear on guideline recommendations and then make their own judgments about those criteria in a systematic approach. CONCLUSION: The "GRADE-ADOLOPMENT" approach to guideline production combines adoption, adaptation, and, as needed, de novo development of recommendations. If developers of guidelines follow EtD criteria more widely and make their work publically available, this approach should prove even more useful.

The association between air travel and deep vein thrombosis: systematic review & meta-analysis.

BACKGROUND: Air travel has been linked with the development of deep vein thrombosis (DVT) since the 1950s with a number of plausible explanations put forward for causation. No systematic review of the literature exploring this association has previously been published. METHODS: A comprehensive search was undertaken (Data bases searched were: MEDLINE, EMBASE, Cochrane Library) for studies that estimated both the incidence and the risk of DVT in air travellers relative to non-air travellers. RESULTS: In total 254 studies were identified but only six incidence studies and four risk studies met inclusion criteria justifying their use in a systematic review. Incidence of symptomatic DVT ranged from (0%) in one study to (0.28%) which was reported in pilots over ten years. The incidence of asymptomatic DVT ranged from (0%) to (10.34%). Pooled odds ratios for the two case control studies examining the risk of DVT following air travel were 1.11 (95% CI: 0.64-1.94). Pooled odds ratios for all models of travel including two studies of prolonged air travel (more than three hours) were 1.70 (95% CI: 0.89-3.22). CONCLUSION: We found no definitive evidence that prolonged (more than 3-hours) travel including air travel, increases the risk of DVT. There is evidence to suggest that flights of eight hours or more increase the risk of DVT if additional risk factors exist.

Adequacy of the endometrial samples obtained by the uterine explora device and conventional dilatation and curettage: a comparative study.

Aims. Our aim is to compare the adequacy and diagnostic yield of samples obtained by the endometrial Explora Sampler I-MX120 with endometrial specimens obtained by conventional dilatation and curettage (D&C). Methods. A total of 1270 endometrial samples were received in the histopathology laboratories at the King Khalid University Hospital, Riyadh, Saudi Arabia, between 2007 and 2010. In the outpatient clinic, the Uterine Explora Model I was used to obtain 996 samples. The remaining 274 samples were obtained by conventional D&C. Sample adequacy and the clustering of inadequate specimens according to age groups by the two different techniques were compared and statistically analyzed. Results. Out of 1270 endometrial samples, 253 (19.9%) were inadequate. The Uterine Explora was used in 88.5% of these inadequate samples (253 samples), and the remaining 11.5% were obtained by D&C. The insufficient tissue incidence was higher with the Explora (17.6%) than with the D&C (2.2%) and the difference was statistically significant (P < 0.0001). The ages of the patients, as well as the clinical indications for the procedures, were recorded. Conclusion. This retrospective study demonstrated better specimen adequacy when D&C was used compared to the higher rate of sample insufficiency obtained with the Explora.

A systematic review of recent clinical practice guidelines on the diagnosis, assessment and management of hypertension.

BACKGROUND: Despite the availability of clinical practice guidelines (CPGs), optimal hypertension control is not achieved in many parts of the world; one of the challenges is the volume of guidelines on this topic and their variable quality. To systematically review the quality, methodology, and consistency of recommendations of recently-developed national CPGs on the diagnosis, assessment and the management of hypertension. METHODOLOGY/PRINCIPAL FINDINGS: MEDLINE, EMBASE, guidelines' websites and Google were searched for CPGs written in English on the general management of hypertension in any clinical setting published between January 2006 and September 2011. Four raters independently appraised each CPG using the AGREE-II instrument and 2 reviewers independently extracted the data. Conflicts were resolved by discussion or the involvement of an additional reviewer. Eleven CPGs were identified. The overall quality ranged from 2.5 to 6 out of 7 on the AGREE-II tool. The highest scores were for "clarity of presentation" (44.4%-88.9%) and the lowest were for "rigour of development" (8.3%-30% for 9 CGPs). None of them clearly reported being newly developed or adapted. Only one reported having a patient representative in its development team. Systematic reviews were not consistently used and only 2 up-to-date Cochrane reviews were cited. Two CPGs graded some recommendations and related that to levels (but not quality) of evidence. The CPGs' recommendations on assessment and non-pharmacological management were fairly consistent. Guidelines varied in the selection of first-line treatment, adjustment of therapy and drug combinations. Important specific aspects of care (e.g. resistant hypertension) were ignored by 6/11 CPGs. The CPGs varied in methodological quality, suggesting that their implementation might not result in less variation of care or in better health-related outcomes. CONCLUSIONS/SIGNIFICANCE: More efforts are needed to promote the realistic approach of localization or local adaptation of existing high-quality CPGs to the national context.

Causes of death certification of adults: an exploratory cross-sectional study at a university hospital in Riyadh, Saudi Arabia.

BACKGROUND AND AIMS: Saudi Arabia has no precise data on causes of death. We sought to ascertain the commonest causes of death as stated in death certificates of adults and evaluate the completeness of death certificates at a teaching hospital in Riyadh. DESIGN AND SETTINGS: A cross-sectional study carried out at King Khalid University Hospital in Riyadh, Saudi Arabia, during the year 2008. METHODS: All death certificates that were issued in 2008 were reviewed and data were checked by two reviewers. Causes of death were coded according to specially-designed codes. RESULTS: The mean (SD) age of death was 63.9 (20.7) years. More than 80% arrived alive at the hospital. Among the 410 certificates, 62.2% had the first reported cause of death being classified as "inappropriate" and this tended to be slightly, but significantly more frequent among women. The first most common appropriately reported cause of death was malignancy of any type (7.3%) followed by ischemic heart diseases (4.9%). Accidents and fractures were more common in the younger age groups and among men. CONCLUSIONS: This is the first study that documents the possible gaps among healthcare professionals in Saudi Arabia in their understanding of death and its certification based on the clinical assessment of the deceased. The findings needs to be validated by similar studies from other health care sectors. It is clear, however, that proven educational, system-related and legal interventions to improve the accuracy of death certification are strongly needed if the health care priorities are to be properly identified.