Perspectives of Adolescents and Young Adults With Sickle Cell Disease and Clinicians on Improving Transition Readiness With a Video Game Intervention.

We aimed to learn the experiences of clinicians and adolescents and young adults with sickle cell disease (AYA-SCD) with managing their disease at home and making medical decisions as they transition from pediatric to adult care, and their perceptions of a video game intervention to positively impact these skills. We conducted individual, semistructured interviews with patients (AYA-SCD ages 15 to 26 years) and clinicians who provide care to AYA-SCD at an urban, quaternary-care hospital. Interviews elicited patients' and clinicians' experiences with AYA-SCD, barriers and facilitators to successful home management, and their perspectives on shared decision-making and a video game intervention. To identify themes, we conducted an inductive analysis until data saturation was reached. Participants (16 patients and 21 clinicians) identified 4 main themes: (1) self-efficacy as a critical skill for a successful transition from pediatric to adult care, (2) the importance of patient engagement in making medical decisions, (3) multilevel determinants of optimal self-efficacy and patient engagement, and (4) support for a video game intervention which, by targeting potential determinants of AYA-SCD achieving optimal self-efficacy and engagement in decision-making, may improve these important skills.

Psychiatric medication prescriptions increasing for college students above and beyond the COVID-19 pandemic.

Psychiatric medication prescriptions for college students have been rising since 2007, with approximately 17% of college students prescribed medication for a mental health issue. This increase mirrors overall increases in both mental health diagnoses and treatment of university students. As psychiatric medication prescriptions for college students were increasing prior to pandemic, the goal of this study was to compare these prescriptions over the years, while accounting for the added stressor of the COVID-19 pandemic. This study utilized cross-sectional, retrospective data from a cohort of college students receiving care from the university's health service. We examined prescriptions for mental healthcare from 2015 to 2021. There was a significant increase in the percentage of psychiatric medication prescriptions in 2020 (baseline 15.8%; threshold 3.5%) and 2021 (baseline 41.3%; threshold 26.3%) compared to the historical baseline average for the whole sample and as well as for female students (2020 baseline 21.3% and threshold 4.6%; 2021 baseline 55.1% and threshold 33.7%). Within these years, we found higher trends for prescriptions in April-May as well as September-December. Overall, we found that psychiatric medication prescriptions have continued to rise through the years, with a large increase occurring during the pandemic. In addition, we found that these increases reflect the academic year, which is important for university health centers to consider when they are planning to staff clinics and plan the best way to treat college students with mental health difficulties in the future.

Corruption of DNA end-joining in mammalian chromosomes by progerin expression.

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic condition characterized by features of accelerated aging and a life expectancy of about 14 years. HGPS is commonly caused by a point mutation in the LMNA gene which codes for lamin A, an essential component of the nuclear lamina. The HGPS mutation alters splicing of the LMNA transcript, leading to a truncated, farnesylated form of lamin A termed "progerin." Progerin is also produced in small amounts in healthy individuals by alternative splicing of RNA and has been implicated in normal aging. HGPS is associated with an accumulation of genomic DNA double-strand breaks (DSBs), suggesting alteration of DNA repair. DSB repair normally occurs by either homologous recombination (HR), an accurate, templated form of repair, or by nonhomologous end-joining (NHEJ), a non-templated rejoining of DNA ends that can be error-prone; however a good portion of NHEJ events occurs precisely with no alteration to joined sequences. Previously, we reported that over-expression of progerin correlated with increased NHEJ relative to HR. We now report on progerin's impact on the nature of DNA end-joining. We used a model system involving a DNA end-joining reporter substrate integrated into the genome of cultured thymidine kinase-deficient mouse fibroblasts. Some cells were engineered to express progerin. Two closely spaced DSBs were induced in the integrated substrate through expression of endonuclease I-SceI, and DSB repair events were recovered through selection for thymidine kinase function. DNA sequencing revealed that progerin expression correlated with a significant shift away from precise end-joining between the two I-SceI sites and toward imprecise end-joining. Additional experiments revealed that progerin did not reduce HR fidelity. Our work suggests that progerin suppresses interactions between complementary sequences at DNA termini, thereby shifting DSB repair toward low-fidelity DNA end-joining and perhaps contributing to accelerated and normal aging through compromised genome stability.

Circulating Ceramides- Are Origins Important for Sphingolipid Biomarkers and Treatments?

Biomarkers are important tools for describing the adequacy or inadequacy of biological processes (to allow for the early and accurate diagnosis) and monitoring the biological effects of intervention strategies (to identify and develop optimal dose and treatment strategies). A number of lipid biomarkers are implicated in metabolic disease and the circulating levels of these biomarkers are used in clinical settings to predict and monitor disease severity. There is convincing evidence that specific circulating ceramide species can be used as biological predictors and markers of cardiovascular disease, atherosclerosis and type 2 diabetes mellitus. Here, we review the existing literature that investigated sphingolipids as biomarkers for metabolic disease prediction. What are the advantages and disadvantages? Are circulating ceramides predominantly produced in the liver? Will hepatic sphingolipid inhibitors be able to completely prevent and treat metabolic disease? As sphingolipids are being employed as biomarkers and potential metabolic disease treatments, we explore what is currently known and what still needs to be discovered.

IL-6 family cytokines as potential therapeutic strategies to treat metabolic diseases.

Metabolic disease is highly prevalent. Here we discuss the therapeutic utility of using gp130 receptor ligands as a therapeutic strategy to treat metabolic disease.

Training Public Sector Clinicians in Competency-Based Clinical Supervision: Methods, Curriculum, and Lessons Learned.

This article describes an initiative to train public sector clinicians in competency-based clinical supervision. It was delivered as an 18-session course taught online to clinicians employed in departments of behavioral health in nine Southern California counties. The curriculum was co-constructed by a team of clinical supervision scholars and leaders who then served as instructors. Each two-hour meeting addressed a specific topic for which a training video had been prepared, usually featuring a member of the training team who had expertise in that topic. The second part of each meeting focused on a class member's supervision case presentation. Those presentations revealed 35 themes; the four most frequently occurring were: developing supervisees' clinical competencies, addressing countertransference and parallel process, balancing clinical and administrative supervisory roles, and addressing record keeping/paperwork. Participants' pre-to-post supervisory self-efficacy changes demonstrated a moderate effect size (Cohen's d = .46) for the training, with the greatest pre- to post-training changes being in the use of technology, multicultural competencies (awareness of oppression, bias, and stereotyping in clinical work and in clinical supervision), and contracting. They reported that the strengths of the course included an inclusive learning environment and opportunities to reflect on and apply new knowledge and skills, though they also reported struggling with the assignments and the course platform software. Lessons learned reflected the use of technology in this online program, the importance of obtaining buy-in from agency decision makers and being prepared to address challenges related to the use of direct observation in supervision, gatekeeping, and enacting the simultaneous roles of administrative and clinical supervisor.

The role of ceramides in metabolic disorders: when size and localization matters.

Ceramide accumulation is a hallmark in the manifestation of numerous obesity-related diseases, such as type 2 diabetes mellitus and atherosclerosis. Until the early 2000s, ceramides were viewed as a homogenous class of sphingolipids. However, it has now become clear that ceramides exert fundamentally different effects depending on the specific fatty acyl chain lengths, which are integrated into ceramides by a group of enzymes known as dihydroceramide synthases. In addition, alterations in ceramide synthesis, trafficking and metabolism in specific cellular compartments exert distinct consequences on metabolic homeostasis. Here, we examine the emerging concept of how the intracellular localization of ceramides with distinct acyl chain lengths can regulate glucose metabolism, thus emphasizing their potential as targets in the development of novel and specific therapies for obesity and obesity-associated diseases.

CerS6-Derived Sphingolipids Interact with Mff and Promote Mitochondrial Fragmentation in Obesity.

Ectopic lipid deposition and altered mitochondrial dynamics contribute to the development of obesity and insulin resistance. However, the mechanistic link between these processes remained unclear. Here we demonstrate that the C16:0 sphingolipid synthesizing ceramide synthases, CerS5 and CerS6, affect distinct sphingolipid pools and that abrogation of CerS6 but not of CerS5 protects from obesity and insulin resistance. We identify proteins that specifically interact with C16:0 sphingolipids derived from CerS5 or CerS6. Here, only CerS6-derived C16:0 sphingolipids bind the mitochondrial fission factor (Mff). CerS6 and Mff deficiency protect from fatty acid-induced mitochondrial fragmentation in vitro, and the two proteins genetically interact in vivo in obesity-induced mitochondrial fragmentation and development of insulin resistance. Our experiments reveal an unprecedented specificity of sphingolipid signaling depending on specific synthesizing enzymes, provide a mechanistic link between hepatic lipid deposition and mitochondrial fragmentation in obesity, and define the CerS6-derived sphingolipid/Mff interaction as a therapeutic target for metabolic diseases.

Quantitative evaluation of an integrated nurse model of care providing hepatitis C treatment to people attending homeless services in Melbourne, Australia.

BACKGROUND: The prevalence of hepatitis C virus (HCV) has been reported to be high among people experiencing homelessness. People who are homeless often have multiple needs that may take precedence over HCV testing and treatment. We quantitatively evaluated the outcomes of a service providing HCV treatment to people attending homeless services. METHODS: Clients attending homeless services were referred to a nurse specialising in HCV-related care. The nurse provided HCV testing, education and case-management while prescriptions were provided by an affiliated doctor. Logistic regression was used to explore factors associated with treatment commencement. RESULTS: Fifty-two clients referred (78%) underwent testing, thirty-nine were HCV-RNA positive among whom 18 (46%) reported sleeping rough and 29 (74%) reported injecting drug use; 66% had injected less than three months ago. Twenty-four (62%) clients commenced treatment, of whom thirteen (54%) had a sustained virological response test; all were cured. Treatment commencement was lower among people who reported sleeping rough (aOR 0.15, 95%CI 0.029-0.73). There was no difference in treatment commencement based on injecting drugs (aOR 1.06, 95%CI 0.21-5.2). CONCLUSION: Most clients' commenced treatment and the majority were successfully cured using a dedicated nursing service. Clients who reported sleeping rough may still face personal and/or system level barriers to HCV treatment.

CerS1-Derived C18:0 Ceramide in Skeletal Muscle Promotes Obesity-Induced Insulin Resistance.

Skeletal muscle accumulates ceramides in obesity, which contribute to the development of obesity-associated insulin resistance. However, it remained unclear which distinct ceramide species in this organ contributes to instatement of systemic insulin resistance. Here, ceramide profiling of high-fat diet (HFD)-fed animals revealed increased skeletal muscle C18:0 ceramide content, concomitant with increased expression of ceramide synthase (CerS)1. Mice lacking CerS1, either globally or specifically in skeletal muscle (CerS1ΔSkM), exhibit reduced muscle C18:0 ceramide content and significant improvements in systemic glucose homeostasis. CerS1ΔSkM mice exhibit improved insulin-stimulated suppression of hepatic glucose production, and lack of CerS1 in skeletal muscle improves systemic glucose homeostasis via increased release of Fgf21 from skeletal muscle. In contrast, muscle-specific deficiency of C16:0 ceramide-producing CerS5 and CerS6 failed to protect mice from obesity-induced insulin resistance. Collectively, these results reveal the tissue-specific function of distinct ceramide species during the development of obesity-associated insulin resistance.

Topiramate versus carbamazepine monotherapy for epilepsy: an individual participant data review.

BACKGROUND: Epilepsy is a common neurological condition in which abnormal electrical discharges from the brain cause recurrent unprovoked seizures. It is believed that with effective drug treatment, up to 70% of individuals with active epilepsy have the potential to become seizure-free and go into long-term remission shortly after starting drug therapy, the majority of which may be able to achieve remission with a single antiepileptic drug (AED).The correct choice of first-line antiepileptic therapy for individuals with newly diagnosed seizures is of great importance. It is important that the choice of AED for an individual is based on the highest-quality evidence available regarding the potential benefits and harms of various treatments. It is also important to compare the efficacy and tolerability of AEDs appropriate to given seizure types.Topiramate and carbamazepine are commonly used AEDs. Performing a synthesis of the evidence from existing trials will increase the precision of results of outcomes relating to efficacy and tolerability, and may help inform a choice between the two drugs. OBJECTIVES: To assess the effects of topiramate monotherapy versus carbamazepine monotherapy for epilepsy in people with partial-onset seizures (simple or complex partial and secondarily generalised) or generalised onset tonic-clonic seizures (with or without other generalised seizure types). SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register (14 April 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (14 April 2016) and MEDLINE (Ovid, 1946 to 14 April 2016). We imposed no language restrictions. We also contacted pharmaceutical companies and trial investigators. SELECTION CRITERIA: Randomised controlled trials in children or adults with partial-onset seizures or generalised-onset tonic-clonic seizures with or without other generalised seizure types with a comparison of monotherapy with either topiramate or carbamazepine. DATA COLLECTION AND ANALYSIS: This was an individual participant data (IPD) review. Our primary outcome was 'time to withdrawal of allocated treatment', and our secondary outcomes were 'time to first seizure post randomisation', 'time to 6-month remission, 'time to 12-month remission' and incidence of adverse events. We used Cox proportional hazards regression models to obtain trial-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs), and used the generic inverse variance method to obtain the overall pooled HRs and 95% CIs. MAIN RESULTS: IPD were available for 1151 of 1239 eligible individuals from two of three eligible studies (93% of the potential data). A small proportion of individuals recruited into these trials had 'unclassified seizures;' for analysis purposes, these individuals are grouped with those with generalised onset seizures. For remission outcomes, a HR < 1 indicated an advantage for carbamazepine, and for first seizure and withdrawal outcomes, a HR < 1 indicated an advantage for topiramate.The main overall results, given as pooled HR adjusted for seizure type (95% CI) were: for time to withdrawal of allocated treatment 1.16 (0.98 to 1.38); time to first seizure 1.11 (0.96 to 1.29); and time to 6-month remission 0.88 (0.76 to 1.01). There were no statistically significant differences between the drugs. A statistically significant advantage for carbamazepine was shown for time to 12-month remission: 0.84 (0.71 to 1.00).The results of this review are applicable mainly to individuals with partial-onset seizures; 85% of included individuals experienced seizures of this type at baseline. For individuals with partial-onset seizures, a statistically significant advantage for carbamazepine was shown for time to withdrawal of allocated treatment (HR 1.20, 95% CI 1.00 to 1.45) and time to 12-month remission (HR 0.84, 95% CI 0.71 to 1.00). No statistically significant differences were apparent between the drugs for other outcomes and for the limited number of individuals with generalised-onset tonic-clonic seizures with or without other generalised seizure types or unclassified seizures.The most commonly reported adverse events with both drugs were drowsiness or fatigue, 'pins and needles' (tingling sensation), headache, gastrointestinal disturbance and anxiety or depression The rate of adverse events was similar across the two drugs.We judged the methodological quality of the included trials generally to be good; however, there was some evidence that the open-label design of the larger of the two trials may have influenced the withdrawal rate from the trial. Hence, we judged the evidence for the primary outcome of treatment withdrawal to be moderate for individuals with partial-onset seizures and low for individuals with generalised-onset seizures. For efficacy outcomes (first seizure, remission), we judged the evidence from this review to be high for individuals with partial-onset seizures and moderate for individuals with generalised-onset or unclassified seizures. AUTHORS' CONCLUSIONS: For individuals with partial-onset seizures, there is evidence that carbamazepine is less likely to be withdrawn and that 12-month remission will be achieved earlier than with topiramate. No differences were found between the drugs in terms of the outcomes measured in the review for individuals with generalised tonic-clonic seizures with or without other seizure types or unclassified epilepsy; however, we encourage caution in the interpretation of these results due to the small numbers of participants with these seizure types.We recommend that future trials should be designed to the highest quality possible and take into consideration masking, choice of population, classification of seizure type, duration of follow-up, choice of outcomes and analysis, and presentation of results.

Carbamazepine versus phenobarbitone monotherapy for epilepsy: an individual participant data review.

BACKGROUND: This is an updated version of the original Cochrane Review, first published in Issue 1, 2003 and updated in 2015. This review is one in a series of Cochrane Reviews investigating pair-wise monotherapy comparisons.Epilepsy is a common neurological condition in which abnormal electrical discharges from the brain cause recurrent unprovoked seizures. It is believed that with effective drug treatment, up to 70% of individuals with active epilepsy have the potential to become seizure-free and go into long-term remission shortly after starting drug therapy with a single antiepileptic drug in monotherapy.Worldwide, carbamazepine and phenobarbitone are commonly used broad-spectrum antiepileptic drugs, suitable for most epileptic seizure types. Carbamazepine is a current first-line treatment for partial onset seizures, and is used in the USA and Europe. Phenobarbitone is no longer considered a first-line treatment because of concerns over associated adverse events, particularly documented behavioural adverse events in children treated with the drug. However, phenobarbitone is still commonly used in low- and middle-income countries because of its low cost. No consistent differences in efficacy have been found between carbamazepine and phenobarbitone in individual trials; however, the confidence intervals generated by these studies are wide, and therefore, synthesising the data of the individual trials may show differences in efficacy. OBJECTIVES: To review the time to withdrawal, remission, and first seizure of carbamazepine compared with phenobarbitone when used as monotherapy in people with partial onset seizures (simple or complex partial and secondarily generalised) or generalised onset tonic-clonic seizures (with or without other generalised seizure types). SEARCH METHODS: For the latest update, we searched the following databases on 18 August 2016: the Cochrane Epilepsy Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO), MEDLINE (Ovid, from 1946), the US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov), and the World Health Organization International Clinical Trials Registry Platform (ICTRP). Previously we also searched SCOPUS (from 1823) as an alternative to Embase, but this is no longer necessary, because randomised controlled trials (RCTs) and quasi-RCTs in Embase are now included in CENTRAL. We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field. SELECTION CRITERIA: RCTs in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of carbamazepine monotherapy versus phenobarbitone monotherapy. DATA COLLECTION AND ANALYSIS: This was an individual participant data (IPD) review. Our primary outcome was 'time to withdrawal of allocated treatment', and our secondary outcomes were 'time to achieve 12-month remission', 'time to achieve six-month remission', 'time to first seizure post-randomisation', and 'adverse events'. We used Cox proportional hazards regression models to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs), with the generic inverse variance method used to obtain the overall pooled HR and 95% CI. MAIN RESULTS: IPD were available for 836 participants out of 1455 eligible individuals from six out of 13 trials; 57% of the potential data. For remission outcomes, HR > 1 indicated an advantage for phenobarbitone, and for first seizure and withdrawal outcomes, HR > 1 indicated an advantage for carbamazepine.The main overall results (pooled HR adjusted for seizure type, 95% CI) were HR 1.50 for time to withdrawal of allocated treatment (95% CI 1.15 to 1.95; P = 0.003); HR 0.93 for time to achieve 12-month remission (95% CI 0.72 to 1.20; P = 0.57); HR 0.99 for time to achieve six-month remission (95% CI 0.80 to 1.23; P = 0.95); and HR 0.87 for time to first seizure (95% CI 0.72 to 1.06; P = 0.18). Results suggest an advantage for carbamazepine over phenobarbitone in terms of time to treatment withdrawal and no statistically significant evidence between the drugs for the other outcomes. We found evidence of a statistically significant interaction between treatment effect and seizure type for time to first seizure recurrence (Chi² test for subgroup differences P = 0.03), where phenobarbitone was favoured for partial onset seizures (HR 0.76, 95% CI 0.60 to 0.96; P = 0.02) and carbamazepine was favoured for generalised onset seizures (HR 1.23, 95% CI 0.88 to 1.77; P = 0.27). We found no evidence of an interaction between treatment effect and seizure type for the other outcomes. However, methodological quality of the included studies was variable, with 10 out of the 13 included studies (4 out of 6 studies contributing IPD) judged at high risk of bias for at least one methodological aspect, leading to variable individual study results, and therefore, heterogeneity in the analyses of this review. We conducted sensitivity analyses to examine the impact of poor methodological aspects, where possible. AUTHORS' CONCLUSIONS: Overall, we found evidence suggestive of an advantage for carbamazepine in terms of drug effectiveness compared with phenobarbitone (retention of the drug in terms of seizure control and adverse events) and evidence suggestive of an association between treatment effect and seizure type for time to first seizure recurrence (phenobarbitone favoured for partial seizures and carbamazepine favoured for generalised seizures). However, this evidence was judged to be of low quality due to poor methodological quality and the potential impact on individual study results (and therefore variability (heterogeneity) present in the analysis within this review), we encourage caution when interpreting the results of this review and do not advocate that the results of this review alone should be used in choosing between carbamazepine and phenobarbitone. We recommend that future trials should be designed to the highest quality possible with considerations for allocation concealment and masking, choice of population, choice of outcomes and analysis, and presentation of results.

Lamotrigine versus carbamazepine monotherapy for epilepsy: an individual participant data review.

BACKGROUND: This is an updated version of the original Cochrane review published in Issue 1, 2006 of the Cochrane Database of Systematic Reviews.Epilepsy is a common neurological condition in which abnormal electrical discharges from the brain cause recurrent unprovoked seizures. It is believed that with effective drug treatment up to 70% of individuals with active epilepsy have the potential to become seizure-free and to go into long-term remission shortly after starting drug therapy with a single antiepileptic drug (AED) in monotherapy.The correct choice of first-line antiepileptic therapy for individuals with newly diagnosed seizures is of great importance. It is important that the choice of AEDs for an individual is made using the highest quality evidence regarding the potential benefits and harms of the various treatments. It is also important that the effectiveness and tolerability of AEDs appropriate to given seizure types are compared to one another.Carbamazepine or lamotrigine are first-line recommended treatments for new onset partial seizures and as a first- or second-line treatment for generalised tonic-clonic seizures. Performing a synthesis of the evidence from existing trials will increase the precision of the results for outcomes relating to efficacy and tolerability and may assist in informing a choice between the two drugs. OBJECTIVES: To review the time to withdrawal, remission and first seizure with lamotrigine compared to carbamazepine when used as monotherapy in people with partial onset seizures (simple or complex partial and secondarily generalised) or generalised onset tonic-clonic seizures (with or without other generalised seizure types). SEARCH METHODS: The first searches for this review were run in 1997. For the most recent update we searched the Cochrane Epilepsy Group Specialized Register (17 October 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 17 October 2016) and MEDLINE (Ovid, 1946 to 17 October 2016). We imposed no language restrictions. We also contacted pharmaceutical companies and trial investigators. SELECTION CRITERIA: Randomised controlled trials in children or adults with partial onset seizures or generalised onset tonic-clonic seizures comparing monotherapy with either carbamazepine or lamotrigine. DATA COLLECTION AND ANALYSIS: This was an individual participant data (IPD) review. Our primary outcome was time to withdrawal of allocated treatment and our secondary outcomes were time to first seizure post-randomisation, time to six-month, 12-month and 24-month remission, and incidence of adverse events. We used Cox proportional hazards regression models to obtain trial-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs), using the generic inverse variance method to obtain the overall pooled HR and 95% CI. MAIN RESULTS: We included 13 studies in this review. Individual participant data were available for 2572 participants out of 3394 eligible individuals from nine out of 13 trials: 78% of the potential data. For remission outcomes, a HR < 1 indicated an advantage for carbamazepine and for first seizure and withdrawal outcomes a HR < 1 indicated an advantage for lamotrigine.The main overall results (pooled HR adjusted for seizure type) were: time to withdrawal of allocated treatment (HR 0.72, 95% CI 0.63 to 0.82), time to first seizure (HR 1.22, 95% CI 1.09 to 1.37) and time to six-month remission (HR 0.84, 95% CI 0.74 to 0.94), showing a significant advantage for lamotrigine compared to carbamazepine for withdrawal but a significant advantage for carbamazepine compared to lamotrigine for first seizure and six-month remission. We found no difference between the drugs for time to 12-month remission (HR 0.91, 95% CI 0.77 to 1.07) or time to 24-month remission (HR 1.00, 95% CI 0.80 to 1.25), however only two trials followed up participants for more than one year so the evidence is limited.The results of this review are applicable mainly to individuals with partial onset seizures; 88% of included individuals experienced seizures of this type at baseline. Up to 50% of the limited number of individuals classified as experiencing generalised onset seizures at baseline may have had their seizure type misclassified, therefore we recommend caution when interpreting the results of this review for individuals with generalised onset seizures.The most commonly reported adverse events for both of the drugs across all of the included trials were dizziness, fatigue, gastrointestinal disturbances, headache and skin problems. The rate of adverse events was similar across the two drugs.The methodological quality of the included trials was generally good, however there is some evidence that the design choice of masked or open-label treatment may have influenced the withdrawal rates of the trials. Hence, we judged the quality of the evidence for the primary outcome of treatment withdrawal to be moderate for individuals with partial onset seizures and low for individuals with generalised onset seizures. For efficacy outcomes (first seizure, remission), we judged the quality of evidence to be high for individuals with partial onset seizures and moderate for individuals with generalised onset seizures. AUTHORS' CONCLUSIONS: Lamotrigine was significantly less likely to be withdrawn than carbamazepine but the results for time to first seizure suggested that carbamazepine may be superior in terms of seizure control. A choice between these first-line treatments must be made with careful consideration. We recommend that future trials should be designed to the highest quality possible with consideration of masking, choice of population, classification of seizure type, duration of follow-up, choice of outcomes and analysis, and presentation of results.

Individual participant data meta-analyses compared with meta-analyses based on aggregate data.

BACKGROUND: Meta-analyses based on individual participant data (IPD-MAs) allow more powerful and uniformly consistent analyses as well as better characterisation of subgroups and outcomes, compared to those which are based on aggregate data (AD-MAs) extracted from published trial reports. However, IPD-MAs are a larger undertaking requiring greater resources than AD-MAs. Researchers have compared results from IPD-MA against results obtained from AD-MA and reported conflicting findings. We present a methodology review to summarise this empirical evidence . OBJECTIVES: To review systematically empirical comparisons of meta-analyses of randomised trials based on IPD with those based on AD extracted from published reports, to evaluate the level of agreement between IPD-MA and AD-MA and whether agreement is affected by differences in type of effect measure, trials and participants included within the IPD-MA and AD-MA, and whether analyses were undertaken to explore the main effect of treatment or a treatment effect modifier. SEARCH METHODS: An electronic search of the Cochrane Library (includes Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness, CENTRAL, Cochrane Methodology Register, HTA database, NHS Economic Evaluations Database), MEDLINE, and Embase was undertaken up to 7 January 2016. Potentially relevant articles that were known to any of the review authors and reference lists of retrieved articles were also checked. SELECTION CRITERIA: Studies reporting an empirical comparison of the results of meta-analyses of randomised trials using IPD with those using AD. Studies were included if sufficient numerical data, comparing IPD-MA and AD-MA, were available in their reports. DATA COLLECTION AND ANALYSIS: Two review authors screened the title and abstract of identified studies with full-text publications retrieved for those identified as eligible or potentially eligible. A 'quality' assessment was done and data were extracted independently by two review authors with disagreements resolved by involving a third author. Data were summarised descriptively for comparisons where an estimate of effect measure and corresponding precision have been provided both for IPD-MA and for AD-MA in the study report. Comparisons have been classified according to whether identical effect measures, identical trials and patients had been used in the IPD-MA and the AD-MA, and whether the analyses were undertaken to explore the main effect of treatment, or to explore a potential treatment effect modifier.Effect measures were transformed to a standardised scale (z scores) and scatter plots generated to allow visual comparisons. For each comparison, we compared the statistical significance (at the 5% two-sided level) of an IPD-MA compared to the corresponding AD-MA and calculated the number of discrepancies. We examined discrepancies by type of analysis (main effect or modifier) and according to whether identical trials, patients and effect measures had been used by the IPD-MA and AD-MA. We calculated the average of differences between IPD-MA and AD-MA (z scores, ratio effect estimates and standard errors (of ratio effects)) and 95% limits of agreement. MAIN RESULTS: From the 9330 reports found by our searches, 39 studies were eligible for this review with effect estimate and measure of precision extracted for 190 comparisons of IPD-MA and AD-MA. We classified the quality of studies as 'no important flaws' (29 (74%) studies) or 'possibly important flaws' (10 (26%) studies).A median of 4 (interquartile range (IQR): 2 to 6) comparisons were made per study, with 6 (IQR 4 to 11) trials and 1225 (542 to 2641) participants in IPD-MAs and 7 (4 to 11) and 1225 (705 to 2541) for the AD-MAs. One hundred and forty-four (76%) comparisons were made on the main treatment effect meta-analysis and 46 (24%) made using results from analyses to explore treatment effect modifiers.There is agreement in statistical significance between the IPD-MA and AD-MA for 152 (80%) comparisons, 23 of which disagreed in direction of effect. There is disagreement in statistical significance for 38 (20%) comparisons with an excess proportion of IPD-MA detecting a statistically significant result that was not confirmed with AD-MA (28 (15%)), compared with 10 (5%) comparisons with a statistically significant AD-MA that was not confirmed by IPD-MA. This pattern of disagreement is consistent for the 144 main effect analyses but not for the 46 comparisons of treatment effect modifier analyses. Conclusions from some IPD-MA and AD-MA differed even when based on identical trials, participants (but not necessarily identical follow-up) and treatment effect measures. The average difference between IPD-MA and AD-MA in z scores, ratio effect estimates and standard errors is small but limits of agreement are wide and include important differences in both directions. Discrepancies between IPD-MA and AD-MA do not appear to increase as the differences between trials and participants increase. AUTHORS' CONCLUSIONS: IPD offers the potential to explore additional, more thorough, and potentially more appropriate analyses compared to those possible with AD. But in many cases, similar results and conclusions can be drawn from IPD-MA and AD-MA. Therefore, before embarking on a resource-intensive IPD-MA, an AD-MA should initially be explored and researchers should carefully consider the potential added benefits of IPD.

Transcranial magnetic stimulation for the treatment of epilepsy.

BACKGROUND: Epilepsy is a highly prevalent neurological condition characterized by repeated unprovoked seizures with various etiologies. Although antiepileptic medications produce clinical improvement in most individuals, nearly a third of individuals have drug-resistant epilepsy that carries significant morbidity and mortality. There remains a need for non-invasive and more effective therapies for this population. Transcranial magnetic stimulation (TMS) uses electromagnetic coils to excite or inhibit neurons, with repetitive pulses at low-frequency producing an inhibitory effect that could conceivably reduce cortical excitability associated with epilepsy. OBJECTIVES: To assess the evidence for the use of TMS in individuals with drug-resistant epilepsy compared with other available treatments in reducing seizure frequency, improving quality of life, reducing epileptiform discharges, antiepileptic medication use, and side-effects. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO), MEDLINE (Ovid 1946 to 10 March 2016), ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (ICTRP) up to March 2016. We also searched SCOPUS (1823 to June 2014) as a substitute for Embase (but it is no longer necessary to search SCOPUS, because randomized controlled trials (RCTs) and quasi-RCTs in EMBASE are now included in CENTRAL). SELECTION CRITERIA: Eligible studies were RCTs that were double-blinded, single-blinded or unblinded, and placebo, no treatment, or active controlled, which used repetitive transcranial magnetic stimulation (rTMS) without restriction of frequency, duration, intensity, or setup (focal or vertex treatment) on patients with drug-resistant epilepsy. The search revealed 274 records from the databases, that after selection provided seven full-text relevant studies for inclusion. Of the seven studies included, five were completed studies with published data and included randomized, blinded trials. The total number of participants in the seven trials was 230. DATA COLLECTION AND ANALYSIS: We extracted information from each trial including methodological data; participant demographics including baseline seizure frequency, type of epileptic drugs taken; intervention details and intervention groups for comparison; potential biases; and outcomes and time points, primarily change in seizure frequency or responder rates, as well as quality of life and epileptiform discharges, adverse effects, and changes in medication use. MAIN RESULTS: Two of the seven studies analyzed showed a statistically significant reduction in seizure rate from baseline (72% and 78.9% reduction of seizures per week from the baseline rate, respectively). The other five studies showed no statistically significant difference in seizure frequency following rTMS treatment compared with controls. We were not able to combine the results of the trials in analysis due to differences in the designs of the studies. Four studies evaluated our secondary endpoint of mean number of epileptic discharges, and three of the four showed a statistically significant reduction in discharges. Quality of life was not assessed in any of the studies. Adverse effects were uncommon among the studies and typically involved headache, dizziness, and tinnitus. No significant changes in medication use were found in the trials. AUTHORS' CONCLUSIONS: Overall, we judged the quality of evidence for the primary outcomes of this review to be low. There is evidence that rTMS is safe and not associated with any adverse events, but given the variability in technique and outcome reporting that prevented meta-analysis, the evidence for efficacy of rTMS for seizure reduction is still lacking despite reasonable evidence that it is effective at reducing epileptiform discharges.

The Use and Reporting of the Cross-Over Study Design in Clinical Trials and Systematic Reviews: A Systematic Assessment.

BACKGROUND: Systematic reviews of treatment interventions in stable or chronic conditions often require the synthesis of clinical trials with a cross-over design. Previous work has indicated that methodology for analysing cross-over data is inadequate in trial reports and in systematic reviews assessing trials with this design. OBJECTIVE: We assessed systematic review methodology for synthesising cross-over trials among Cochrane Cystic Fibrosis and Genetic Disorders Group reviews published to July 2015, and assessed the quality of reporting among the cross-over trials included in these reviews. METHODOLOGY: We performed data extraction of methodology and reporting in reviews, trials identified and trials included within reviews. PRINCIPAL FINDINGS: We reviewed a total of 142 Cochrane systematic reviews including 53 reviews which synthesised evidence from 218 cross-over trials. Thirty-three (63%) Cochrane reviews described a clear and appropriate method for the inclusion of cross-over data, and of these 19 (56%) used the same method to analyse results. 145 cross-over trials were described narratively or treated as parallel trials in reviews but in 30 (21%) of these trials data existed in the trial reports to account for the cross-over design. At the trial level, the analysis and presentation of results were often inappropriate or unclear, with only 69 (32%) trials presenting results that could be included in meta-analysis. CONCLUSIONS: Despite development of accessible, technical guidance and training for Cochrane systematic reviewers, statistical analysis and reporting of cross-over data is inadequate at both the systematic review and the trial level. Plain language and practical guidance for the inclusion of cross-over data in meta-analysis would benefit systematic reviewers, who come from a wide range of health specialties. Minimum reporting standards for cross-over trials are needed.

Treatments for the prevention of Sudden Unexpected Death in Epilepsy (SUDEP).

BACKGROUND: Sudden Unexpected Death in Epilepsy (SUDEP) is defined as sudden, unexpected, witnessed or unwitnessed, non-traumatic or non-drowning death of people with epilepsy, with or without evidence of a seizure, excluding documented status epilepticus and in whom postmortem examination does not reveal a structural or toxicological cause for death. SUDEP has a reported incidence of 1 to 2 per 1000 patient years and represents the most common epilepsy-related cause of death. The presence and frequency of generalised tonic-clonic seizures (GTCS), male sex, early age of seizure onset, duration of epilepsy, and polytherapy are all predictors of risk of SUDEP. The exact pathophysiology of SUDEP is currently unknown, although GTCS-induced cardiac, respiratory, and brainstem dysfunction appears likely. Appropriately chosen antiepileptic drug treatment can render around 70% of patients free of all seizures. However, around one-third will remain drug refractory despite polytherapy. Continuing seizures place patients at risk of SUDEP, depression, and reduced quality of life. Preventative strategies for SUDEP include reducing the occurrence of GTCS by timely referral for presurgical evaluation in people with lesional epilepsy and advice on lifestyle measures; detecting cardiorespiratory distress through clinical observation and seizure, respiratory, and heart rate monitoring devices; preventing airway obstruction through nocturnal supervision and safety pillows; reducing central hypoventilation through physical stimulation and enhancing serotonergic mechanisms of respiratory regulation using selective serotonin reuptake inhibitors (SSRIs); reducing adenosine and endogenous opioid-induced brain and brainstem depression. OBJECTIVES: To assess the effectiveness of interventions in preventing SUDEP in people with epilepsy by synthesising evidence from randomised controlled trials of interventions and cohort and case-control non-randomised studies. SEARCH METHODS: We searched the following databases: Cochrane Epilepsy Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL, Issue 11, 2015) via the Cochrane Register of Studies Online (CRSO); MEDLINE (Ovid, 1946 onwards); SCOPUS (1823 onwards); PsycINFO (EBSCOhost, 1887 onwards); CINAHL Plus (EBSCOhost, 1937 onwards); ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We used no language restrictions. The date of the last search was 12 November 2015. We checked the reference lists of retrieved studies for additional reports of relevant studies and contacted lead study authors for any relevant unpublished material. We identified duplicate studies by screening reports according to title, authors' names, location, and medical institute, omitting any duplicated studies. We identified any grey literature studies published in the last five years by searching: Zetoc database; ISI Proceedings; International Bureau for Epilepsy (IBE) congress proceedings database; International League Against Epilepsy (ILAE) congress proceedings database; abstract books of symposia and congresses, meeting abstracts, and research reports. SELECTION CRITERIA: We aimed to include randomised controlled trials (RCTs), quasi-RCTs, and cluster-RCTs; prospective non-randomised cohort controlled and uncontrolled studies; and case-control studies of adults and children with epilepsy receiving an intervention for the prevention of SUDEP. Types of interventions included: early versus delayed pre-surgical evaluation for lesional epilepsy; educational programmes; seizure-monitoring devices; safety pillows; nocturnal supervision; selective serotonin reuptake inhibitors (SSRIs); opiate antagonists; and adenosine antagonists. DATA COLLECTION AND ANALYSIS: We aimed to collect data on study design factors and participant demographics for included studies. The primary outcome of interest was the number of deaths from SUDEP. Secondary outcomes included: number of other deaths (unrelated to SUDEP); change in mean depression and anxiety scores (as defined within the study); clinically important change in quality of life, that is any change in quality of life score (average and endpoint) according to validated quality of life scales; and number of hospital attendances for seizures. MAIN RESULTS: We identified 582 records from the databases and search strategies. We found 10 further records by searching other resources (handsearching). We removed 211 duplicate records and screened 381 records (title and abstract) for inclusion in the review. We excluded 364 records based on the title and abstract and assessed 17 full-text articles. We excluded 15 studies: eight studies did not assess interventions to prevent SUDEP; five studies measured sensitivity of devices to detect GTCS but did not directly measure SUDEP; and two studies assessed risk factors for SUDEP but not interventions for preventing SUDEP. One listed study is awaiting classification.We included one case-control study at serious risk of bias within a qualitative analysis in this review. This study of 154 cases of SUDEP and 616 controls ascertained a protective effect for the presence of nocturnal supervision (unadjusted odds ratio (OR) 0.34, 95% confidence interval (CI) 0.22 to 0.53) and when a supervising person shared the same bedroom or when special precautions, for example a listening device, were used (unadjusted OR 0.41, 95% CI 0.20 to 0.82). This effect was independent of seizure control. Non-SUDEP deaths; changes to anxiety, depression, and quality of life; and number of hospital attendances were not reported. AUTHORS' CONCLUSIONS: We found very low-quality evidence of a preventative effect for nocturnal supervision against SUDEP. Further research is required to identify the effectiveness of other current interventions, for example seizure detection devices, safety pillows, SSRIs, early surgical evaluation, educational programmes, and opiate and adenosine antagonists in preventing SUDEP in people with epilepsy.

Motivators of and Barriers to Engagement in Healthy Eating Behaviors among non-Hispanic Black Adults.

OBJECTIVES: The objective of this study was to determine if non-Hispanic Black adults' levels of endorsement of motivators and barriers related to healthy eating are significantly associated with their level of engagement in healthy eating and their perceived importance of healthy eating and if these investigated variables differ by gender, income, and/or age. METHOD: An assessment battery was completed by a cross-sectional sample of 207 non-Hispanic Black adults in Bronx, NY (54.1 % female; age: M = 38, SD = 14.12). Participants were recruited by culturally diverse data collectors at community-based locations within Bronx. RESULTS: Building healthy eating into a routine was a significant motivator of healthy eating (p < 0.001), and having low self-control over eating behaviors was a significant barrier to healthy eating (p < 0.05). Importance ratings of healthy eating were positively associated with motivators to engaging in healthy eating (routine: p < 0.001; availability of healthy foods: p < 0.001; addressing medical issues: p < 0.001; convenience of eating healthy foods: p < 0.01). There were age and income differences in several motivators and barriers. IMPLICATIONS: Intervention programs to increase healthy eating among adults similar to those in this study may benefit from including a focus on increasing self-control of eating behaviors and incorporating healthy eating into one's routine.

Immediate antiepileptic drug treatment, versus placebo, deferred, or no treatment for first unprovoked seizure.

BACKGROUND: There is considerable disagreement about the risk of recurrence following a first unprovoked epileptic seizure. A decision about whether to start antiepileptic drug treatment following a first seizure should be informed by information on the size of any reduction in risk of future seizures, the impact on long-term seizure remission, and the risk of adverse effects. OBJECTIVES: To review the probability of seizure recurrence, seizure remission, mortality, and adverse effects of antiepileptic drug (AED) treatment given immediately after the first seizure compared to controls, in children and adults. SEARCH METHODS: We searched the following databases: Cochrane Epilepsy Group Specialized Register (accessed 13 October 2015), Cochrane Central Register of Controlled Trials (The Cochrane Library September 2015, issue 9, accessed 13 October 2015), PUBMED (accessed 22 April 2015), MEDLINE (Ovid, 1946 to 13 October 2015), EMBASE (accessed 22 April 2015), ClinicalTrials.gov (accessed 15 October 2015), and the WHO International Clinical Trials Registry Platform (ICTRP, accessed 13 October 2015). There were no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs that could be blinded or unblinded. People of any age with a first unprovoked seizure of any type. Included studies compared participants receiving immediate antiepileptic treatment versus those receiving deferred treatment, those assigned to placebo, and those untreated. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the studies identified by the search strategy for inclusion in the review and extracted data. The quality of the evidence was classified in four categories according to the GRADE approach. Dichotomous outcomes were expressed as Risk Ratios (RR) with 95% confidence intervals (CI). Time-to-event outcomes were expressed as Hazard Ratios (HR) with 95% CI. Only one trial used a double-blind design, and the two largest studies were unblinded. Most of the recurrences were generalized tonic-clonic seizures, a major type of seizures that is easily recognised, which should reduce the risk of outcome reporting bias. MAIN RESULTS: After exclusion of uninformative papers, only six studies (nine reports) were selected for inclusion. For the two largest studies data were available for individual participant meta-analysis. Compared to controls, participants randomised to immediate treatment had a lower probability of relapse at one year (RR 0.49, 95% CI 0.42 to 0.58, high quality evidence), at five years (RR 0.78; 95% CI 0.68 to 0.89; high quality evidence) and a higher probability of an immediate five-year remission (RR 1.25; 95% CI 1.02 to 1.54, high quality evidence). However there was no difference between immediate treatment and control in terms of five year remission at any time (RR 1.02, 95% CI 0.87 to 1.21, high quality evidence). Antiepileptic drugs did not affect overall mortality after a first seizure (RR 1.16; 95% CI 0.69 to 1.95, high quality evidence). Compared to deferred treatment (RR 1.49, 95% CI 1.23 to 1.79, moderate quality evidence), treatment of the first seizure was associated with a significantly higher risk of adverse events. Moderate to low quality imprecise evidence was available for the association of treatment of the first seizure compared to no treatment or placebo (RR 14.50, 95% CI 1.93 to 108.76) and(RR 4.91, 95% CI 1.10 to 21.93) respectively) AUTHORS' CONCLUSIONS: Treatment of the first unprovoked seizure reduces the risk of a subsequent seizure but does not affect the proportion of patients in remission in the long-term. Antiepileptic drugs are associated with adverse events, and there is no evidence that they reduce mortality. In light of this review, the decision to start antiepileptic drug treatment following a first unprovoked seizure should be individualized and based on patient preference, clinical, legal, and socio-cultural factors.