Intractable epilepsy in patients treated for childhood acute lymphocytic leukemia

AbstractPurposeIn the 1970s and 80s, standard treatment for childhood acute lymphocytic leukemia (ALL) included both intrathecal methotrexate and whole-brain irradiation. During acute treatment, seizures were not uncommon. The development of intractable epilepsy years after treatment, however, has not been well described in the literature. We describe five patients who were treated for acute lymphocytic leukemia as children, who later developed intractable epilepsy.ResultsAll of the patients were diagnosed with leukemia before age seven. Treatment included both whole-brain irradiation and intrathecal chemotherapy. All five received intrathecal methotrexate; in addition, two also received intrathecal cytosine arabinoside. The first seizure occurred at a mean of 7.5 years after diagnosis. Four patients have multiple seizure types, and all patients have been on multiple antiepileptic drugs. All five patients are cognitively impaired.ConclusionsSuccessful treatment for childhood leukemia may be followed by signs of late cerebral injury including intractable epilepsy. We propose that neurotoxicity resulting from exposure to intrathecal methotrexate and cranial irradiation may have contributed to the intractable epilepsy seen in our five patients

A Comparison of Rectal Diazepam Gel and Placebo for Acute Repetitive Seizures

ABSTRACT Background Acute repetitive seizures are readily recognizable episodes involving increased seizure frequency. Urgent treatment is often required. Rectal diazepam gel is a promising therapy. Methods We conducted a randomized, doubleblind, parallel-group, placebo-controlled study of home-based treatment for acute repetitive seizures. Patients were randomly assigned to receive either rectal diazepam gel, at doses ranging from 0.2 to 0.5 mg per kilogram of body weight on the basis of age, or placebo. Children received one dose at the onset of acute repetitive seizures and a second dose four hours later. Adults received three doses — one dose at onset, and two more doses 4 and 12 hours after onset. Treatment was administered by a care giver, such as a parent, who had received special training. The number of seizures after the first dose was counted for 12 hours in children and for 24 hours in adults. Results Of 125 study patients (64 assigned to diazepam and 61 to placebo) with a history of acute repetitive seizures, 91 (47 children and 44 adults) were treated for an exacerbation of seizures during the study period. Diazepam treatment was superior to placebo with regard to the outcome variables related to efficacy: reduced seizure frequency (P\u3c0.001) and improved global assessment of treatment outcome by the care giver (frequency and severity of seizures and drug toxicity) (P\u3c0.001). Post hoc analysis showed diazepam to be superior to placebo in reducing seizure frequency in both children (P\u3c0.001) and adults (P=0.02), but only in children was it superior with regard to improvement in global outcome (P\u3c0.001). The time to the first recurrence of seizures after initial treatment was longer for the patients receiving diazepam (P\u3c0.001). Thirty-five patients reported at least one adverse effect of treatment; somnolence was the most frequent. Respiratory depression was not reported. Conclusions Rectal diazepam gel, administered at home by trained care givers, is an effective and welltolerated treatment for acute repetitive seizures. (N Engl J Med 1998;338:1869-75.

Vignette 23: Indigenous Management Systems Can Promote More Sustainable Salmon Fisheries in the Salish Sea

Indigenous peoples of the Northern Pacific Rim have harvested salmon for more than 10,000 years, and Pacific salmon (Oncorhynchus spp.) form the foundation of social-ecological systems encompassing communities from California to Kamchatka and Northern Japan. Through continuous placed-based interdependence with salmon, Indigenous societies formed deliberate and well-honed systems of salmon management. These systems promoted the sustained productivity of salmon fisheries. In Canada and the United States, Indigenous sovereignty and resource stewardship were forcibly disrupted by colonial government authority. Despite the destructive impacts of colonization, Indigenous culture and knowledge are resurgent in Canada and the United States. Indigenous fishing technologies and management systems are being documented and reinvigorated. Systems of Indigenous salmon management can support long- term opportunities for equitable and sustainable harvest of salmon across western North America

Molecular genetics of nicotine dependence and abstinence: whole genome association using 520,000 SNPs

BACKGROUND: Classical genetic studies indicate that nicotine dependence is a substantially heritable complex disorder. Genetic vulnerabilities to nicotine dependence largely overlap with genetic vulnerabilities to dependence on other addictive substances. Successful abstinence from nicotine displays substantial heritable components as well. Some of the heritability for the ability to quit smoking appears to overlap with the genetics of nicotine dependence and some does not. We now report genome wide association studies of nicotine dependent individuals who were successful in abstaining from cigarette smoking, nicotine dependent individuals who were not successful in abstaining and ethnically-matched control subjects free from substantial lifetime use of any addictive substance. RESULTS: These data, and their comparison with data that we have previously obtained from comparisons of four other substance dependent vs control samples support two main ideas: 1) Single nucleotide polymorphisms (SNPs) whose allele frequencies distinguish nicotine-dependent from control individuals identify a set of genes that overlaps significantly with the set of genes that contain markers whose allelic frequencies distinguish the four other substance dependent vs control groups (p < 0.018). 2) SNPs whose allelic frequencies distinguish successful vs unsuccessful abstainers cluster in small genomic regions in ways that are highly unlikely to be due to chance (Monte Carlo p < 0.00001). CONCLUSION: These clustered SNPs nominate candidate genes for successful abstinence from smoking that are implicated in interesting functions: cell adhesion, enzymes, transcriptional regulators, neurotransmitters and receptors and regulation of DNA, RNA and proteins. As these observations are replicated, they will provide an increasingly-strong basis for understanding mechanisms of successful abstinence, for identifying individuals more or less likely to succeed in smoking cessation efforts and for tailoring therapies so that genotypes can help match smokers with the treatments that are most likely to benefit them

A systematic review evaluating the psychometric properties of measures of social inclusion

Introduction: Improving social inclusion opportunities for population health has been identified as a priority area for international policy. There is a need to comprehensively examine and evaluate the quality of psychometric properties of measures of social inclusion that are used to guide social policy and outcomes. Objective: To conduct a systematic review of the literature on all current measures of social inclusion for any population group, to evaluate the quality of the psychometric properties of identified measures, and to evaluate if they capture the construct of social inclusion. Methods: A systematic search was performed using five electronic databases: CINAHL, PsycINFO, Embase, ERIC and Pubmed and grey literature were sourced to identify measures of social inclusion. The psychometric properties of the social inclusion measures were evaluated against the COSMIN taxonomy of measurement properties using pre-set psychometric criteria. Results: Of the 109 measures identified, twenty-five measures, involving twenty-five studies and one manual met the inclusion criteria. The overall quality of the reviewed measures was variable, with the Social and Community Opportunities Profile-Short, Social Connectedness Scale and the Social Inclusion Scale demonstrating the strongest evidence for sound psychometric quality. The most common domain included in the measures was connectedness (21), followed by participation (19); the domain of citizenship was covered by the least number of measures (10). No single instrument measured all aspects within the three domains of social inclusion. Of the measures with sound psychometric evidence, the Social and Community Opportunities Profile-Short captured the construct of social inclusion best. Conclusions: The overall quality of the psychometric properties demonstrate that the current suite of available instruments for the measurement of social inclusion are promising but need further refinement. There is a need for a universal working definition of social inclusion as an overarching construct for ongoing research in the area of the psychometric properties of social inclusion instruments

Genetic diversity fuels gene discovery for tobacco and alcohol use

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury(1-4). These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries(5). Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.Peer reviewe

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society