Functional abilities, respiratory and cardiac function in a large cohort of adults with Duchenne muscular dystrophy treated with glucocorticoids.

BACKGROUND AND PURPOSE: The transition to adult services, and subsequent glucocorticoid management, is critical in adults with Duchenne muscular dystrophy. This study aims (1) to describe treatment, functional abilities, respiratory and cardiac status during transition to adulthood and adult stages; and (2) to explore the association between glucocorticoid treatment after loss of ambulation (LOA) and late-stage clinical outcomes. METHODS: This was a retrospective single-centre study on individuals with Duchenne muscular dystrophy (≥16 years old) between 1986 and 2022. Logistic regression, Cox proportional hazards models and survival analyses were conducted utilizing data from clinical records. RESULTS: In all, 112 individuals were included. Mean age was 23.4 ± 5.2 years and mean follow-up was 18.5 ± 5.5 years. At last assessment, 47.2% were on glucocorticoids; the mean dose of prednisone was 0.38 ± 0.13 mg/kg/day and of deflazacort 0.43 ± 0.16 mg/kg/day. At age 16 years, motor function limitations included using a manual wheelchair (89.7%), standing (87.9%), transferring from a wheelchair (86.2%) and turning in bed (53.4%); 77.5% had a peak cough flow <270 L/min, 53.3% a forced vital capacity percentage of predicted <50% and 40.3% a left ventricular ejection fraction <50%. Glucocorticoids after LOA reduced the risk and delayed the time to difficulties balancing in the wheelchair, loss of hand to mouth function, forced vital capacity percentage of predicted <30% and forced vital capacity <1 L and were associated with lower frequency of left ventricular ejection fraction <50%, without differences between prednisone and deflazacort. Glucocorticoid dose did not differ by functional, respiratory or cardiac status. CONCLUSION: Glucocorticoids after LOA preserve late-stage functional abilities, respiratory and cardiac function. It is suggested using functional abilities, respiratory and cardiac status at transition stages for adult services planning.

Cardiac care of children with dystrophinopathy and females carrying DMD-gene variations.

OBJECTIVE: We provide succinct, evidence-based and/or consensus-based best practice guidance for the cardiac care of children living with Duchenne muscular dystrophy (DMD) as well as recommendations for screening and management of female carriers of mutations in the DMD-gene. METHODS: Initiated by an expert working group of UK-based cardiologists, neuromuscular clinicians and DMD-patient representatives, draft guidelines were created based on published evidence, current practice and expert opinion. After wider consultation with UK-cardiologists, consensus was reached on these best-practice recommendations for cardiac care in DMD. RESULTS: The resulting recommendations are presented in the form of a succinct care pathway flow chart with brief justification. The guidance signposts evidence on which they are based and acknowledges where there have been differences in opinion. Guidelines for cardiac care of patients with more advanced cardiac dystrophinopathy at any age have also been considered, based on the previous published work of Quinlivan et al and are presented here in a similar format. The recommendations have been endorsed by the British Cardiovascular Society. CONCLUSION: These guidelines provide succinct, reasoned recommendations for all those managing paediatric patients with early or advanced stages of cardiomyopathy as well as females with cardiac dystrophinopathy. The hope is that this will result in more uniform delivery of high standards of care for children with cardiac dystrophinopathy, so improving heart health into adulthood through timely earlier interventions across the UK.

Experiencing Event Management During the Coronavirus Pandemic: A Public Sector Perspective.

Events have played a significant role in the way in which the Coronavirus pandemic has been experienced and known around the world. Little is known though about how the pandemic has impacted on supporting, managing and governing events in municipal (i.e., local) authorities as key stakeholders, nor how events have featured in the opening-up of localities. This paper reports on empirical research with senior events officers for local authorities in the UK on these key knowledge gaps. Specifically, it examines events officers' unfolding experiences of the pandemic. The paper points to unpreparedness for a crisis of this scale and magnitude, and the roles of innovation, adaptation and co-production in the emergent response. It highlights the transformative nature of the pandemic through reconsiderations of the purpose of public sector involvement in events and, from a policy perspective, how relatively smaller-scale, more agile and lower-risk arts events and performances can figure in local recovery. Finally, while the effects on, and response of, the body corporate (the local authority) to crises is an obvious focus, it is important to recognise those of the individuals who manage the response and drive change.

Improving translatability of preclinical studies for neuromuscular disorders: lessons from the TREAT-NMD Advisory Committee for Therapeutics (TACT).

Clinical trials for rare neuromuscular diseases imply, among other investments, a high emotional burden for the whole disease community. Translation of data from preclinical studies to justify any clinical trial must be carefully pondered in order to minimize the risk of clinical trial withdrawal or failure. A rigorous distinction between proof-of-concept and preclinical efficacy studies using animal models is key to support the rationale of a clinical trial involving patients. This Review evaluates the experience accumulated by the TREAT-NMD Advisory Committee for Therapeutics, which provides detailed constructive feedback on clinical proposals for neuromuscular diseases submitted by researchers in both academia and industry, and emphasizes that a timely critical review of preclinical efficacy data from animal models, including biomarkers for specific diseases, combined with adherence to existing guidelines and standard protocols, can significantly help to de-risk clinical programs and prevent disappointments and costly engagement.

Exhaled nitric oxide levels to guide treatment for adults with asthma.

BACKGROUND: Asthma guidelines aim to guide health practitioners to optimise treatment for patients so as to minimise symptoms, improve or maintain good lung function, and prevent acute exacerbations or flare-ups. The principle of asthma guidelines is based on a step-up or step-down regimen of asthma medications to maximise good health outcomes using minimum medications. Asthma maintenance therapies reduce airway inflammation that is usually eosinophilic. Tailoring asthma medications in accordance with airway eosinophilic levels may improve asthma outcomes such as indices of control or reduce exacerbations or both. Fractional exhaled nitric oxide (FeNO) is a marker of eosinophilic inflammation, and as it is easy to measure, has an advantage over other measurements of eosinophilic inflammation (for example sputum eosinophils). OBJECTIVES: To evaluate the efficacy of tailoring asthma interventions based on exhaled nitric oxide (FeNO), in comparison to not using FeNO, that is management based on clinical symptoms (with or without spirometry/peak flow) or asthma guidelines or both, for asthma-related outcomes in adults. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and reference lists of articles. The last searches were undertaken in June 2016. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing adjustment of asthma medications based on exhaled nitric oxide levels compared to not using FeNO, that is management based on clinical symptoms (with or without spirometry/peak flow) or asthma guidelines or both. DATA COLLECTION AND ANALYSIS: We reviewed results of searches against predetermined criteria for inclusion. We independently selected relevant studies in duplicate. Two review authors independently assessed trial quality and extracted data. We contacted study authors for further information, receiving responses from four. MAIN RESULTS: We included seven adult studies; these studies differed in a variety of ways including definition of asthma exacerbations, FeNO cutoff levels used (15 to 35 ppb), the way in which FeNO was used to adjust therapy, and duration of study (4 to 12 months). Of 1700 randomised participants, 1546 completed the trials. The mean ages of the participants ranged from 28 to 54 years old. The inclusion criteria for the participants in each study varied, but all had a diagnosis of asthma and required asthma medications. In the meta-analysis, there was a significant difference in the primary outcome of asthma exacerbations between the groups, favouring the FeNO group. The number of people having one or more asthma exacerbations was significantly lower in the FeNO group compared to the control group (odds ratio (OR) 0.60, 95% confidence interval (CI) 0.43 to 0.84). The number needed to treat to benefit (NNTB) over 52 weeks was 12 (95% CI 8 to 32). Those in the FeNO group were also significantly more likely to have a lower exacerbation rate than the controls (rate ratio 0.59, 95% CI 0.45 to 0.77). However, we did not find a difference between the groups for exacerbations requiring hospitalisation (OR 0.14, 95% CI 0.01 to 2.67) or rescue oral corticosteroids (OR 0.86, 95% CI 0.50 to 1.48). There was also no significant difference between groups for any of the secondary outcomes (FEV1, FeNO levels, symptoms scores, or inhaled corticosteroid doses at final visit).We considered three included studies that had inadequate blinding to have a high risk of bias. However, when these studies were excluded from the meta-analysis, the difference between the groups for the primary outcomes (exacerbations) remained statistically significant. The GRADE quality of the evidence ranged from moderate (for the outcome 'exacerbations') to very low (for the outcome 'inhaled corticosteroid dose at final visit') based on the lack of blinding and statistical heterogeneity. Six of the seven studies were industry supported, but the company had no role in the study design or data analyses. AUTHORS' CONCLUSIONS: With new studies included since the last version of this review, which included adults and children, this updated meta-analysis in adults with asthma showed that tailoring asthma medications based on FeNO levels (compared with primarily on clinical symptoms) decreased the frequency of asthma exacerbations but did not impact on day-to-day clinical symptoms, end-of-study FeNO levels, or inhaled corticosteroid dose. Thus, the universal use of FeNO to help guide therapy in adults with asthma cannot be advocated. As the main benefit shown in the studies in this review was a reduction in asthma exacerbations, the intervention may be most useful in adults who have frequent exacerbations. Further RCTs encompassing different asthma severity, ethnic groups in less affluent settings, and taking into account different FeNO cutoffs are required.

Improving the informed consent process in international collaborative rare disease research: effective consent for effective research.

The increased international sharing of data in research consortia and the introduction of new technologies for sequencing challenge the informed consent (IC) process, adding complexities that require coordination between research centres worldwide. Rare disease consortia present special challenges since available data and samples may be very limited. Thus, it is especially relevant to ensure the best use of available resources but at the same time protect patients' right to integrity. To achieve this aim, there is an ethical duty to plan in advance the best possible consent procedure in order to address possible ethical and legal hurdles that could hamper research in the future. Therefore, it is especially important to identify key core elements (CEs) to be addressed in the IC documents for international collaborative research in two different situations: (1) new research collections (biobanks and registries) for which information documents can be created according to current guidelines and (2) established collections obtained without IC or with a previous consent that does not cover all CEs. We propose here a strategy to deal with consent in these situations. The principles have been applied and are in current practice within the RD-Connect consortia - a global research infrastructure funded by the European Commission Seventh Framework program but forward looking in terms of issues addressed. However, the principles established, the lessons learned and the implications for future research are of direct relevance to all internationally collaborative rare-disease projects.

Inhaled corticosteroids for subacute cough in children.

BACKGROUND: Cough is the most common symptom presenting to primary healthcare services. Cough in children is associated with significant morbidity for both children and their parents. While inhaled corticosteroids (ICS) can potentially reduce cough associated with airway inflammation and airway hyper-reactivity, use of ICS in children is not without potential adverse effects. Therefore, it would be beneficial to clinical practice to evaluate the evidence for the efficacy of ICS in reducing the severity of cough in children with subacute cough (defined as cough duration of two to four weeks) systematically. OBJECTIVES: To evaluate the efficacy of ICS in reducing the severity of cough in children with subacute cough. SEARCH METHODS: The Cochrane Register of Controlled Trials (CENTRAL), the Cochrane Airways Group Specialised Register, MEDLINE, EMBASE, review articles and reference lists of relevant articles were searched. The latest searches were performed in November 2011. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing ICS with a control group in children with subacute cough were considered for inclusion. DATA COLLECTION AND ANALYSIS: Search results were reviewed against pre-determined criteria for inclusion. Two sets of review authors independently selected, extracted and assessed the data for inclusion. Study authors were contacted for further information where required. Data were analysed as 'intention to treat'. MAIN RESULTS: The search identified 1178 potentially relevant titles; however, there were no published studies that were specifically designed to answer this question. Two studies met criteria for inclusion in the review and 98 children were included in the meta-analysis. There was no significant difference between groups in the proportion of children 'not cured' at follow-up (primary outcome measure), with a pooled odds ratio (OR) of 0.61 (95% confidence interval (CI) 0.24 to 1.55). However, the included studies were limited in their ability to answer the review question by the fact that all participants were infants, post acute bronchiolitis illness, and cough duration at the start of study medication was ill-defined. AUTHORS' CONCLUSIONS: There is currently no evidence to support the use of ICS for treatment of subacute cough in children. However, this systematic review is limited by the small number of studies available for analysis and the size, quality and design of these studies. Further well-designed RCTs are required to support or refute the efficacy of treatment with ICS in children with subacute cough.

Impact of Chlamydia trachomatis in the reproductive setting: British Fertility Society Guidelines for practice.

Chlamydia trachomatis infection of the genital tract is the most common sexually transmitted infection and has a world-wide distribution. The consequences of infection have an adverse effect on the reproductive health of women and are a common cause of infertility. Recent evidence also suggests an adverse effect on male reproduction. There is a need to standardise the approach in managing the impact of C. trachomatis infection on reproductive health. We have surveyed current UK practice towards screening and management of Chlamydia infections in the fertility setting. We found that at least 90% of clinicians surveyed offered screening. The literature on this topic was examined and revealed a paucity of solid evidence for estimating the risks of long-term reproductive sequelae following lower genital tract infection with C. trachomatis. The mechanism for the damage that occurs after Chlamydial infections is uncertain. However, instrumentation of the uterus in women with C. trachomatis infection is associated with a high risk of pelvic inflammatory disease, which can be prevented by appropriate antibiotic treatment and may prevent infected women from being at increased risk of the adverse sequelae, such as ectopic pregnancy and tubal factor infertility. Recommendations for practice have been proposed and the need for further studies is identified.

Tailored interventions based on exhaled nitric oxide versus clinical symptoms for asthma in children and adults.

BACKGROUND: The measurement of severity and control of asthma in both children and adults can be based on subjective or objective measures. It has been advocated that fractional exhaled nitric oxide (FeNO) can be used to monitor airway inflammation as it correlates with some markers of asthma. Interventions for asthma therapies have been traditionally based on symptoms and/or spirometry. OBJECTIVES: To evaluate the efficacy of tailoring asthma interventions based on exhaled nitric oxide in comparison to clinical symptoms (with or without spirometry/peak flow) for asthma related outcomes in children and adults. SEARCH STRATEGY: We searched the Cochrane Airways Group Specialised Register of Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and reference lists of articles. The last search was completed in February 2009. SELECTION CRITERIA: All randomised controlled comparisons of adjustment of asthma therapy based on exhaled nitric oxide compared to traditional methods (primarily clinical symptoms and spirometry/peak flow). DATA COLLECTION AND ANALYSIS: Results of searches were reviewed against pre-determined criteria for inclusion. Relevant studies were independently selected in duplicate. Two authors independently assessed trial quality and extracted data. Authors were contacted for further information with response from one. MAIN RESULTS: Two studies have been added for this update, which now includes six (2 adults and 4 children/adolescent) studies; these studies differed in a variety of ways including definition of asthma exacerbations, FeNO cut off levels, the way in which FeNO was used to adjust therapy and duration of study. Of 1053 participants randomised, 1010 completed the trials. In the meta-analysis, there was no significant difference between groups for the primary outcome of asthma exacerbations or for other outcomes (clinical symptoms, FeNO level and spirometry). In post-hoc analysis, a significant reduction in mean final daily dose inhaled corticosteroid per adult was found in the group where treatment was based on FeNO in comparison to clinical symptoms, (mean difference -450 mcg; 95% CI -677 to -223 mcg budesonide equivalent/day). However, the total amount of inhaled corticosteroid used in one of the adult studies was 11% greater in the FeNO arm. In contrast, in the paediatric studies, there was a significant increase in inhaled corticosteroid dose in the FeNO strategy arm (mean difference of 140 mcg; 95% CI 29 to 251, mcg budesonide equivalent/day). AUTHORS' CONCLUSIONS: Tailoring the dose of inhaled corticosteroids based on exhaled nitric oxide in comparison to clinical symptoms was carried out in different ways in the six studies and found only modest benefit at best and potentially higher doses of inhaled corticosteroids in children. The role of utilising exhaled nitric oxide to tailor the dose of inhaled corticosteroids cannot be routinely recommended for clinical practice at this stage and remains uncertain.

The 'WHO Safe Communities' model for the prevention of injury in whole populations.

BACKGROUND: The World Health Organization (WHO) 'safe communities' approach to injury prevention has been embraced around the world as a model for co-ordinating community efforts to enhance safety and reduce injury. Approximately 150 communities throughout the world have formal 'Safe Communities' designation. It is of public health interest to determine to what degree the model is successful, and whether it reduces injury rates. This Cochrane Review is an update of a previous published version. OBJECTIVES: To determine the effectiveness of the WHO Safe Communities model to prevent injury in whole populations. SEARCH STRATEGY: Our search included CENTRAL, MEDLINE and EMBASE, PsycINFO, ISI Web of Science: Social Sciences Citation Index (SSCI) and ZETOC. We handsearched selected journals and contacted key people from each WHO Safe Community. The last search was December 2008. SELECTION CRITERIA: Two authors independently screened studies for inclusion. Included studies were those conducted within a WHO Safe Community that reported changes in population injury rates within the community compared to a control community. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data. Meta-analysis was not appropriate due to the heterogeneity of the included studies. MAIN RESULTS: We included evaluations for 21 communities from five countries in two geographical regions in the world: Austria, Sweden and Norway, and Australia and New Zealand. Although positive results were reported for some communities, there was no consistent relationship between being a WHO designated Safe Community and subsequent changes in observed injury rates. AUTHORS' CONCLUSIONS: There is marked inconsistency in the results of the studies included in this systematic review. While the frequency of injury in some study communities did reduce following their designation as a WHO Safe Community, there remains insufficient evidence from which to draw definitive conclusions regarding the effectiveness of the model.The lack of consistency in results may be due to the heterogeneity of the approaches to implementing the model, varying efficacy of activities and strategies, varying intensity of implementation and methodological limitations in evaluations. While all communities included in the review fulfilled the WHO Safe Community criteria, these criteria were too general to prescribe a standardised programme of activity or evaluation methodology.Adequate documentation describing how various Safe Communities implemented the model was limited, making it unclear which factors affected success. Where a reduction in injury rates was not reported, lack of information makes it difficult to distinguish whether this was due to problems with the model or with the way in which it was implemented.

Caring in residential aged-care. Qualitative findings from an e-cohort sub-study.

AIM: The aim of this e-cohort sub-study was to explore and describe nurses' understandings of 'caring' in residential aged-care. BACKGROUND: The quality of the work environment is an important issue for recruitment, retention and workforce planning. Knowledge about the people in and the place that is the residential aged-care facility may assist with the problems surrounding the recruitment and retention of nurses in the workforce. DESIGN: Qualitative electronic cohort sub-study. METHODS: This paper presents the qualitative research findings from an electronic cohort sub-study of 58 registered and enrolled nurses working in the residential aged-care sector in 2007. Data were collected through an open ended question and a qualitative content analysis was used to generate the core categories. RESULTS: The concept of caring was grounded in and constrained by, the everyday reality of the nurses in the study. Organisational imperatives for the completion of documentation necessary for accreditation and funding combined with under-staffing restricted the time available for caring practices. Some nurses represented residential care faculties as devoid of care, others as a place where the resident was central to their work and care. The staff perceived of themselves as an ageing workforce in need of rejuvenation and resourcing. CONCLUSION: The concept of caring is manifest in nurses' language as they describe their workplace, the residents, themselves and the structures that impact on what they do. Good caring manifests itself when the residents are central to the business of the aged care facility. However, nurses in this study describe a range of restrictive factors impeding caring practices and diminishing workforce morale and motivation to create environments that can truly be called a 'home-away-from-home' and one that all people would find acceptable. RELEVANCE TO CLINICAL PRACTICE: These findings have implications for aged-care sector recruitment, retention and workforce planning within residential aged-care facilities.

Validation of CARE-Q in residential aged-care: rating of importance of caring behaviours from an e-cohort sub-study.

AIM AND OBJECTIVE: To validate the Caring Assessment Report Evaluation Q-sort questionnaire in the residential aged-care setting. Based on this determination, to conclude with what degree of confidence the questionnaire can be used to determine the ranking of the importance of caring behaviours amongst aged-care nurses and residents in residential aged-care. BACKGROUND: Perceptions of caring may be context specific. Caring in residential aged-care may stand in contrast to the sense of caring understood and practiced in other settings. DESIGN: Self-administered survey. METHODS: Residents from three not-for-profit aged-care facilities, across both high-care (nursing-home) and low-care (hostel care) were surveyed relying on the Caring Assessment Report Evaluation Q-sort questionnaire. A sub-sample of registered and enrolled nurses working in residential aged-care and registered with the Nurses & Midwives e-cohort study completed the same survey. RESULTS: Although the Caring Assessment Report Evaluation Q-sort questionnaire showed good internal consistency for the sample of nurses, the results for the residents were more erratic. Both groups displayed large ranges for the inter-item correlations. The results of the Mann-Whitney U-test indicated that the nurses rated the Comforts, Anticipates and Trusting relationship as significantly more important than the residents. Both groups rated the Explains and facilitates subscale as least important. All subscales, however, received median scores greater than, or equal to, six (seven-point, Likert scale) indicating that all were considered important overall. CONCLUSION: Based on poor Cronbach's alpha coefficients, negative inter-item correlations and qualitative observations, without further development within the residential aged-care facility the free response format version of the Caring Assessment Report Evaluation Q-sort may not be an appropriate measure to use with residential aged-care residents. More research needs to be conducted into how residents and nurses are interpreting the items in the Caring Assessment Report Evaluation Q-sort. RELEVANCE TO CLINICAL PRACTICE: There will always remain a need for nurses to enact behaviours that are meaningful to residents (and patients generally).

Live birth following preimplantation genetic screening for trisomy 21. Should aneuploidy screening be offered to all older patients undergoing IVF?

A 42-year-old female patient with history of secondary infertility was referred to our assisted conception unit for in vitro fertilization (IVF). Before her referral, she had two cycles of IVF at another centre; the first was unsuccessful and, after conceiving at the second attempt, the pregnancy was terminated at 14 weeks' gestation following a positive nuchal translucency scan and a diagnosis of trisomy 21 (Down syndrome) by a chorionic villous biopsy performed in the first trimester. The screening tests for trisomy 21 were offered to the patient in view of her advanced age. Subsequent karyotyping revealed that both partners had a normal chromosomal complement. Following genetic counselling, the couple were offered IVF treatment along with preimplantation genetic screening for trisomy 21. Four of the five embryos were suitable for biopsy, and one blastomere from each embryo was analyzed using fluorescent in situ hybridization for chromosome 21. The analysis revealed that two embryos had trisomy 21, one had monosomy 21, and only one embryo was diploid for chromosome 21. The single diploid embryo was transferred to the uterus on day 3, and resulted in an uneventful pregnancy and delivery of a healthy live-born male.

The J-Tip Needle-Free Injection System in controlled ovarian hyperstimulation in in vitro fertilization: a pilot study.

OBJECTIVE: To evaluate the use of a novel needle-free system (J-Tip) in the administration of gonadotropins for controlled ovarian hyperstimulation (COH) in IVF. DESIGN: An open-label, single-center, pilot study. SETTING: Assisted conception unit of a university hospital. PATIENT(S): Twenty patients undergoing COH over a 3-month period. INTERVENTION(S): COH was carried out using a fixed dose of rFSH administered via the J-Tip System in a GnRH antagonist cycle. MAIN OUTCOME MEASURE(S): The primary endpoint was the mean number of oocytes collected per patient, and secondary endpoints were incidence of technically correct injections, clinical pregnancy, and cancellation rates. Patient diaries were kept throughout the study. RESULT(S): Sixteen patients completed the trial, four of whom became pregnant, with a high overall satisfaction rate. CONCLUSION(S): This is the first report of the use of the novel J-Tip Needle-Free Injection System for administration of gonadotropins in IVF with successful ovarian stimulation and achievement of pregnancies. This report indicates that this technique is associated with minimal pain and high patient acceptability. Large-scale multicenter studies are required to examine the reproducibility of these results and the J-Tip's cost-effectiveness as well as to compare the J-tip System with conventional needle-wise administration for COH before its introduction into routine IVF practice.

Longitudinal predictors of changes to illicit drug use among young Australian women.

AIM: Much information regarding predictors of illicit drug initiation and cessation is drawn from cross-sectional data. This paper aims to determine the longitudinal changes in factors associated with initiation and cessation of illicit drugs by young Australian women over a 3-year period. PARTICIPANTS: The sample was the cohort of young women moving from their mid- to late 20s, completing the Australian Longitudinal Study on Women's Health (ALSWH) survey in 2000 and 2003, who were either 'new' users or 'quitters' at the 2003 survey. MEASUREMENTS: Crude and multivariate associations between changes in predictor variables and the probability of illicit drug initiation or cessation were evaluated. Variables significant in univariate analyses were used to create multivariable logistic regression models which predicted initiation and cessation of illicit drugs. FINDINGS: All categories of smokers, except ex-smokers and those who adopted and quit smoking between surveys, were less likely to cease the use of illicit drugs. Women who became pregnant were more likely to cease illicit drug use. Women who continued to drink at levels described as long-/short-term risk and women who suffered continuing emotional abuse were less likely to cease use of illicit drugs. CONCLUSIONS: Longitudinal studies that examine factors associated with illicit drug initiation are best conducted in a cohort aged in their late teens to early 20s. Following the current cohort into their late 30s may further explain predictors of illicit drug cessation.

Live birth following the first mutation specific pre-implantation genetic diagnosis for haemophilia A.

Haemophilia A is an X-linked, recessive, inherited bleeding disorder which affects 1 in 5000 males born worldwide. It is caused by mutations in the FactorVIII (F8) gene on chromosome Xq28. We describe for the first time two mutation specific, single cell protocols for pre-implantation genetic diagnosis (PGD) of haemophilia. A that enable the selection of both male and female unaffected embryos. This approach offers an alternative to sexing, frequently used for X-linked disorders, that results in the discarding of all male embryos including the 50% that would have been normal. Two families with a history of severe haemophilia. A requested carrier diagnosis and subsequently proceeded to PGD. The mutation in family 1 is a single nucleotide substitution c.5953C > T, R1966X in exon 18 and in family 2, c.5122C > T, R1689C in exon 14 of the F8 gene. Amplification efficiency was compared between distilled water and SDS/proteinase K cell lysis (98.0%, 96/98 and 80%, 112/140 respectively) using 238 single lymphocytes. Blastomeres from spare IVF cleavage-stage embryos donated for research showed amplification efficiencies of 83.3% (45/54) for the R1966X and 92.9% (13/14) for the R1689C mutations. The rate of allele dropout (ADO) on heterozygous lymphocytes was 1.1% (1/93) for R1966X and 5.94% (6/101) for R1689C mutations. A single PGD treatment cycle for family 1 resulted in two embryos for transfer but these failed to implant. However, with family 2, two embryos were transferred to the uterus on day 4 resulting in a successful singleton pregnancy and subsequent live birth of a normal non-carrier female.