Cancer risks following diagnostic and therapeutic radiation exposure in children

The growing use of interventional and fluoroscopic imaging in children represents a tremendous benefit for the diagnosis and treatment of benign conditions. Along with the increasing use and complexity of these procedures comes concern about the cancer risk associated with ionizing radiation exposure to children. Children are considerably more sensitive to the carcinogenic effects of ionizing radiation than adults, and children have a longer life expectancy in which to express risk. Numerous epidemiologic cohort studies of childhood exposure to radiation for treatment of benign diseases have demonstrated radiation-related risks of cancer of the thyroid, breast, brain and skin, as well as leukemia. Many fewer studies have evaluated cancer risk following diagnostic radiation exposure in children. Although radiation dose for a single procedure might be low, pediatric patients often receive repeated examinations over time to evaluate their conditions, which could result in relatively high cumulative doses. Several cohort studies of girls and young women subjected to multiple diagnostic radiation exposures have been informative about increased mortality from breast cancer with increasing radiation dose, and case-control studies of childhood leukemia and postnatal diagnostic radiation exposure have suggested increased risks with an increasing number of examinations. Only two long-term follow-up studies of cancer following cardiac catheterization in childhood have been conducted, and neither reported an overall increased risk of cancer. Most cancers can be induced by radiation, and a linear dose-response has been noted for most solid cancers. Risks of radiation-related cancer are greatest for those exposed early in life, and these risks appear to persist throughout life

Development of lifetime comorbidity in the world health organization world mental health surveys

CONTEXT: Although numerous studies have examined the role of latent variables in the structure of comorbidity among mental disorders, none has examined their role in the development of comorbidity. OBJECTIVE: To study the role of latent variables in the development of comorbidity among 18 lifetime DSM-IV disorders in the World Health Organization World Mental Health Surveys. DESIGN: Nationally or regionally representative community surveys. SETTING: Fourteen countries. PARTICIPANTS: A total of 21 229 survey respondents. MAIN OUTCOME MEASURES: First onset of 18 lifetime DSM-IV anxiety, mood, behavior, and substance disorders assessed retrospectively in the World Health Organization Composite International Diagnostic Interview. RESULTS: Separate internalizing (anxiety and mood disorders) and externalizing (behavior and substance disorders) factors were found in exploratory factor analysis of lifetime disorders. Consistently significant positive time-lagged associations were found in survival analyses for virtually all temporally primary lifetime disorders predicting subsequent onset of other disorders. Within-domain (ie, internalizing or externalizing) associations were generally stronger than between-domain associations. Most time-lagged associations were explained by a model that assumed the existence of mediating latent internalizing and externalizing variables. Specific phobia and obsessive-compulsive disorder (internalizing) and hyperactivity and oppositional defiant disorders (externalizing) were the most important predictors. A small number of residual associations remained significant after controlling the latent variables. CONCLUSIONS: The good fit of the latent variable model suggests that common causal pathways account for most of the comorbidity among the disorders considered herein. These common pathways should be the focus of future research on the development of comorbidity, although several important pairwise associations that cannot be accounted for by latent variables also exist that warrant further focused study

Upper Palaeolithic genomes reveal deep roots of modern Eurasians.

We extend the scope of European palaeogenomics by sequencing the genomes of Late Upper Palaeolithic (13,300 years old, 1.4-fold coverage) and Mesolithic (9,700 years old, 15.4-fold) males from western Georgia in the Caucasus and a Late Upper Palaeolithic (13,700 years old, 9.5-fold) male from Switzerland. While we detect Late Palaeolithic-Mesolithic genomic continuity in both regions, we find that Caucasus hunter-gatherers (CHG) belong to a distinct ancient clade that split from western hunter-gatherers ∼45 kya, shortly after the expansion of anatomically modern humans into Europe and from the ancestors of Neolithic farmers ∼25 kya, around the Last Glacial Maximum. CHG genomes significantly contributed to the Yamnaya steppe herders who migrated into Europe ∼3,000 BC, supporting a formative Caucasus influence on this important Early Bronze age culture. CHG left their imprint on modern populations from the Caucasus and also central and south Asia possibly marking the arrival of Indo-Aryan languages.This research was supported by the European Research Council (ERC) Starting Grant to R.P. (ERC-2010-StG 263441). D.B., M.H and AM. were also supported by the ERC (295729-CodeX, 310763-GeneFlow and 647787-LocalAdaptation respectively). The National Geographic Global Exploration Fund funded fieldwork in Satsurblia Cave l from April 2013 to February 2014 (grant- GEFNE78–13). V.S. was supported by a scholarship from the Gates Cambridge Trust and M.G.L. by a BBSRC DTP studentship. C.G. was supported by the Irish Research Council for Humanities and Social Sciences (IRCHSS) ERC Support Programme and the Marie-Curie Intra-European Fellowships (FP7-IEF-328024). R.M. was funded by the BEAN project of the Marie Curie ITN (289966) and L.C. by the Irish Research Council (GOIPG/2013/1219). R.L.M. was funded by the ALS Association of America (2284) and Fondation Thierry Latran (ALSIBD). M.C. was supported by Swiss NSF grant 31003A_156853. We acknowledge Shota Rusataveli Georgian National Science Foundation as well as the DJEI/DES/SFI/HEA Irish Centre for High-End Computing (ICHEC) for the provision of computational facilities and Science Foundation Ireland (12/ERC/B2227) for provision of sequencing facilities. We thank Valeria Mattiangeli and Matthew D. Teasdale for their assistance.This is the final version of the article. It was first available from NPG via http://dx.doi.org/10.1038/ncomms991

Disruption of Saccadic Adaptation with Repetitive Transcranial Magnetic Stimulation of the Posterior Cerebellum in Humans

Saccadic eye movements are driven by motor commands that are continuously modified so that errors created by eye muscle fatigue, injury, or—in humans—wearing spectacles can be corrected. It is possible to rapidly adapt saccades in the laboratory by introducing a discrepancy between the intended and actual saccadic target. Neurophysiological and lesion studies in the non-human primate as well as neuroimaging and patient studies in humans have demonstrated that the oculomotor vermis (lobules VI and VII of the posterior cerebellum) is critical for saccadic adaptation. We studied the effect of transiently disrupting the function of posterior cerebellum with repetitive transcranial magnetic stimulation (rTMS) on the ability of healthy human subjects to adapt saccadic eye movements. rTMS significantly impaired the adaptation of the amplitude of saccades, without modulating saccadic amplitude or variability in baseline conditions. Moreover, increasing the intensity of rTMS produced a larger impairment in the ability to adapt saccadic size. These results provide direct evidence for the role of the posterior cerebellum in man and further evidence that TMS can modulate cerebellar function

Association of blood lactate with type 2 diabetes: the Atherosclerosis Risk in Communities Carotid MRI Study

Background Accumulating evidence implicates insufficient oxidative capacity in the development of type 2 diabetes. This notion has not been well tested in large, population-based studies

Cortical and cerebellar activation induced by reflexive and voluntary saccades

Reflexive saccades are driven by visual stimulation whereas voluntary saccades require volitional control. Behavioral and lesional studies suggest that there are two separate mechanisms involved in the generation of these two types of saccades. This study investigated differences in cerebral and cerebellar activation between reflexive and self-paced voluntary saccadic eye movements using functional magnetic resonance imaging. In two experiments (whole brain and cerebellum) using the same paradigm, differences in brain activations induced by reflexive and self-paced voluntary saccades were assessed. Direct comparison of the activation patterns showed that the frontal eye fields, parietal eye field, the motion-sensitive area (MT/V5), the precuneus (V6), and the angular and the cingulate gyri were more activated in reflexive saccades than in voluntary saccades. No significant difference in activation was found in the cerebellum. Our results suggest that the alleged separate mechanisms for saccadic control of reflexive and self-paced voluntary are mainly observed in cerebral rather than cerebellar areas

Treatment of irritable bowel syndrome with diarrhoea using titrated ondansetron (TRITON): study protocol for a randomised controlled trial

Background: Irritable bowel syndrome with diarrhoea (IBS-D) affects up to 4% of the general population. Symptoms include frequent, loose, or watery stools with associated urgency, resulting in marked reduction of quality of life and loss of work productivity. Ondansetron, a 5HT3 receptor antagonist, has had an excellent safety record for over 20 years as an antiemetic, yet is not widely used in the treatment of IBS-D. It has, however, been shown to slow colonic transit and in a small randomised, placebo-controlled, cross-over pilot study, benefited patients with IBS-D. Methods: This trial is a phase III, parallel group, randomised, double-blind, multi-centre, placebo-controlled trial, with embedded mechanistic studies. Participants (n = 400) meeting Rome IV criteria for IBS-D will be recruited from outpatient and primary care clinics and by social media to receive either ondansetron (dose titrated up to 24 mg daily) or placebo for 12 weeks. Throughout the trial, participants will record their worst abdominal pain, worst urgency, stool frequency, and stool consistency on a daily basis. The primary endpoint is the proportion of “responders” in each group, using Food and Drug Administration (FDA) recommendations. Secondary endpoints include pain intensity, stool consistency, frequency, and urgency. Mood and quality of life will also be assessed. Mechanistic assessments will include whole gut transit, faecal tryptase and faecal bile acid concentrations at baseline and between weeks 8 and 11. A subgroup of participants will also undergo assessment of sensitivity (n = 80) using the barostat, and/or high-resolution colonic manometry (n = 40) to assess motor patterns in the left colon and the impact of ondansetron. Discussion: The TRITON trial aims to assess the effect of ondansetron across multiple centres. By defining ondansetron’s mechanisms of action we hope to better identify patients with IBS-D who are likely to respond

The descriptive epidemiology of DSM-IV Adult ADHD in the World Health Organization World Mental Health Surveys

We previously reported on the cross-national epidemiology of ADHD from the first 10 countries in the WHO World Mental Health (WMH) Surveys. The current report expands those previous findings to the 20 nationally or regionally representative WMH surveys that have now collected data on adult ADHD. The Composite International Diagnostic Interview (CIDI) was administered to 26,744 respondents in these surveys in high-, upper-middle-, and low-/lower-middle-income countries (68.5% mean response rate). Current DSM-IV/CIDI adult ADHD prevalence averaged 2.8% across surveys and was higher in high (3.6%)- and upper-middle (3.0%)- than low-/lower-middle (1.4%)-income countries. Conditional prevalence of current ADHD averaged 57.0% among childhood cases and 41.1% among childhood subthreshold cases. Adult ADHD was significantly related to being male, previously married, and low education. Adult ADHD was highly comorbid with DSM-IV/CIDI anxiety, mood, behavior, and substance disorders and significantly associated with role impairments (days out of role, impaired cognition, and social interactions) when controlling for comorbidities. Treatment seeking was low in all countries and targeted largely to comorbid conditions rather than to ADHD. These results show that adult ADHD is prevalent, seriously impairing, and highly comorbid but vastly under-recognized and undertreated across countries and cultures

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline