Melatonin in Youth: N-of-1 trials in a stimulant-treated ADHD Population (MYNAP): study protocol for a randomized controlled trial

Attention-deficit/hyperactivity disorder (ADHD) is a common neurological disorder affecting 5\ua0% of children worldwide. A prevalent problem for children with ADHD is initial insomnia. The gold standard treatment to manage ADHD symptoms is stimulant medications, which may exacerbate the severity of existing initial insomnia. Currently, no gold standard treatment option exists for initial insomnia for these children. Melatonin, a hormone and a popular natural health product, is commonly provided to children by parents and recommended by healthcare providers, but high quality pediatric evidence is lacking.This trial is a multicenter randomized triple-blind, placebo-controlled, parallel-group, randomized, controlled trial (RCT), in which each participant is offered an N-of-1 trial. An N-of-1 trial is a multiple-crossover, randomized, controlled trial conducted in a single individual. For the N-of-1 trial, each participant will undergo three pairs of treatment/placebo periods; each period is 1\ua0week in length. Half the participants will have melatonin in the first period, the other half will start with placebo, and this will make up the parallel-group RCT. The primary outcome will be mean difference in sleep onset latency as measured by sleep diaries. A comparison of treatment effects yielded by the RCT data versus the aggregated N-of-1 trial data will also be assessed.This trial will provide rigorous evidence for the effectiveness of melatonin in children with ADHD on stimulants who experience initial insomnia. Further, this study will provide the first prospectively planned head-to-head comparison of RCT data with pooled data from a series of N-of-1 trials. Aggregated N-of-1 trials may be a powerful tool to produce high quality clinical trial evidence.ClinicalTrials.gov, NCT02333149 . Registered on 16 December 2014. Australian New Zealand Clinical Trials Registry, ACTRN12614000542695 . Registered on 21 May 2014

Association of Noncirrhotic Portal Hypertension in HIV-Infected Persons and Antiretroviral Therapy with Didanosine: A Nested Case-Control Study

Background. Noncirrhotic portal hypertension (NCPH) is a newly described life-threatening liver disease of unknown cause in human immunodeficiency virus (HIV)-infected persons. Postulated pathogenesis includes prolonged exposure to antiretroviral therapy, particularly didanosine. Methods. We performed a nested case-control study including 15 patients with NCPH and 75 matched control subjects of the Swiss HIV Cohort Study to investigate risk factors for the development of NCPH. Matching criteria were similar duration of HIV infection, absence of viral hepatitis, and follow-up to at least the date of NCPH diagnosis in the respective case. Results. All 15 case patients had endoscopically documented esophageal varices and absence of liver cirrhosis on biopsies; 4 died because of hepatic complications. At NCPH diagnosis, case patients and control subjects were similar concerning sex; race; Centers for Disease Control and Prevention stage; HIV-RNA level; CD4 cell count nadir; and lipids and lipodystrophy. Differences were found in age (conditional logistic regression odds ratio [OR] for 10 years older, 2.9; 95% confidence interval [CI], 1.4-6.1); homosexuality (OR, 4.5; 95% CI, 1.2-17); current CD4 cell count <200 cells/µL (OR, 34.3; 95% CI, 4.3-277); diabetes mellitus (OR, 8.8; 95% CI, 1.6-49); alanine aminotransferase level higher than normal (OR, 13.0; 95% CI, 2.7-63); alkaline phosphatase higher than normal (OR, 18.3; 95% CI, 4.0-85); and platelets lower than normal (OR, 20.5; 95% CI, 2.4-178). Cumulative exposure to antiretroviral therapy (OR per year, 1.3; 95% CI, 1.0-1.6), nucleoside reverse-transcriptase inhibitor (OR, 1.3; 95% CI, 1.1-1.7), didanosine (OR, 3.4; 95% CI, 1.5-8.1), ritonavir (OR, 1.4; 95% CI, 1.0-1.9), and nelfinavir (OR, 1.4; 95% CI, 1.0-1.9) were longer in case patients. Exposure to nonnucleoside reverse-transcriptase inhibitor and other protease inhibitors were not different between groups. In bivariable models, only the association of NCPH with didanosine exposure was robust; other covariables were not independent risk factors. Conclusions. We found a strong association between prolonged exposure to didanosine and the development of NCP

Detection of primary melanoma in individuals at extreme high risk: a prospective 5-year follow-up study

IMPORTANCE: The clinical phenotype and certain predisposing genetic mutations that confer increased melanoma risk are established; however, no consensus exists regarding optimal screening for such individuals. Early identification remains the most important intervention in reducing melanoma mortality. OBJECTIVE: To evaluate the impact of full-body examinations every 6 months supported by dermoscopy and total-body photography (TBP) on all patients and sequential digital dermoscopy imaging (SDDI), when indicated, on detecting primary melanoma in an extreme-risk population. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational study from February 2006 to February 2011, with patients recruited from Sydney Melanoma Diagnostic Centre and Melanoma Institute Australia who had a history of invasive melanoma and dysplastic nevus syndrome, history of invasive melanoma and at least 3 first-degree or second-degree relatives with prior melanoma, history of at least 2 primary invasive melanomas, or a CDKN2A or CDK4 gene mutation. EXPOSURES: Six-month full-body examination compared with TBP. For equivocal lesions, SDDI short term (approximately 3 months) or long term (≥6 months), following established criteria, was performed. Atypical lesions were excised. MAIN OUTCOMES AND MEASURES: New primary melanoma numbers, characteristics, and cumulative incidence in each patient subgroup; effect of diagnostic aids on new melanoma identification. RESULTS: In 311 patients with a median (interquartile range [IQR]) follow-up of 3.5 (2.4-4.2) years, 75 primary melanomas were detected, 14 at baseline visit. Median (IQR) Breslow thickness of postbaseline incident melanomas was in situ (in situ to 0.60 mm). Thirty-eight percent were detected using TBP and 39% with SDDI. Five melanomas were greater than 1 mm Breslow thickness, 3 of which were histologically desmoplastic; the other 2 had nodular components. The benign to malignant excision ratio was 1.6:1 for all lesions excised and 4.4:1 for melanocytic lesions. Cumulative risk of developing a novel primary melanoma was 12.7% by year 2, with new primary melanoma incidence during the final 3 years of follow-up half of that observed during the first 2 years (incidence density ratio, 0.43 [95% CI, 0.25-0.74]; P = .002). CONCLUSIONS AND RELEVANCE: Monitoring patients at extreme risk with TBP and SDDI assisted with early diagnosis of primary melanoma. Hypervigilance for difficult-to-detect thick melanoma subtypes is crucial. Copyright 2014 American Medical Association. All rights reserved

Blood pressure lowering with alcohol-mediated renal denervation using the Peregrine infusion Catheter is independent of injection site location

Objectives The current analysis utilized core laboratory angiographic data from a prospective, single-arm, open-label, multi-center feasibility study to ascertain whether the location of alcohol infusion within main renal arteries during renal denervation (RDN) had an impact on the BP-lowering effect at 6 months. Background The influence of the location of alcohol infusion during RDN, within the main renal artery (proximal, middle, or distal), on the magnitude of the blood pressure (BP) lowering is unstudied. Methods The Peregrine Catheter was used to perform alcohol-mediated RDN with an infusion of 0.6 mL of alcohol per artery as the neurolytic agent in 90 main arteries and four accessory arteries of 45 patients with hypertension. Results No relationship between the site of alcohol infusion and change from baseline in both office systolic and 24-hour systolic ambulatory BP (ABP) at 6 months was observed. When analyzed at the artery level, the least squares (LS) mean changes ± SEM from baseline to 6 months post-procedure in 24-hour systolic ABP when analyzed by renal arterial location were −11.9 ± 2.4 mmHg (distal), −10 ± 1.6 mmHg (middle), and −10.6 ± 1.3 mmHg (proximal) (all p < 0.0001 for change from baseline within groups). The results were similar for office systolic BP. There was no difference between treated locations (proximal is reference). Conclusion In this post-hoc analysis, the location of alcohol infusion within the main renal artery using the Peregrine system, with alcohol as the neurolytic agent for chemical RDN, did not affect the magnitude of BP changes at 6 months

High Prevalence of Anorectal Chlamydial Infection in HIV-Infected Men Who Have Sex with Men in Switzerland

Human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) were enrolled in an anorectal Chlamydia trachomatis screening study. Anorectal Chlamydia DNA was detected in 16 (10.9%) of 147 men, mainly among asymptomatic patients and patients having >20 sexual partners. These results support routine anorectal Chlamydia screening in HIV-infected MSM who report unprotected anal intercours

Erythropoietin Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy

Experimental studies targeting traumatic brain injury (TBI) have reported that erythropoietin (EPO) is an endogenous neuroprotectant in multiple models. In addition to its neuroprotective effects, it has also been shown to enhance reparative processes including angiogenesis and neurogenesis. Based on compelling pre-clinical data, EPO was tested by the Operation Brain Trauma Therapy (OBTT) consortium to evaluate therapeutic potential in multiple TBI models along with biomarker assessments. Based on the pre-clinical TBI literature, two doses of EPO (5000 and 10,000 IU/kg) were tested given at 15 min after moderate fluid percussion brain injury (FPI), controlled cortical impact (CCI), or penetrating ballistic-like brain injury (PBBI) with subsequent behavioral, histopathological, and biomarker outcome assessments. There was a significant benefit on beam walk with the 5000 IU dose in CCI, but no benefit on any other motor task across models in OBTT. Also, no benefit of EPO treatment across the three TBI models was noted using the Morris water maze to assess cognitive deficits. Lesion volume analysis showed no treatment effects after either FPI or CCI; however, with the 5000 IU/kg dose of EPO, a paradoxical increase in lesion volume and percent hemispheric tissue loss was seen after PBBI. Biomarker assessments included measurements of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) in blood at 4 or 24 h after injury. No treatment effects were seen on biomarker levels after FPI, whereas treatment at either dose exacerbated the increase in GFAP at 24 h in PBBI but attenuated 24-4 h delta UCH-L1 levels at high dose in CCI. Our data indicate a surprising lack of efficacy of EPO across three established TBI models in terms of behavioral, histopathological, and biomarker assessments. Although we cannot rule out the possibility that other doses or more prolonged treatment could show different effects, the lack of efficacy of EPO reduced enthusiasm for its further investigation in OBTT

Targeted delivery of a vaccine protein to Langerhans cells in the human skin via the C-type lectin receptor Langerin

Human skin is a preferred vaccination site as it harbors multiple dendritic cell (DC) subsets, which display distinct C-type lectin receptors (CLR) that recognize pathogens. Antigens can be delivered to CLR by antibodies or ligands to boost antigen-specific immune responses. This concept has been established in mouse models but detailed insights into the functional consequences of antigen delivery to human skin DC in situ are sparse. In this study, we cloned and produced an anti-human Langerin antibody conjugated to the EBV nuclear antigen 1 (EBNA1). We confirmed specific binding of anti-Langerin-EBNA1 to Langerhans cells (LC). This novel LC-based vaccine was then compared to an existing anti-DEC-205-EBNA1 fusion protein by loading LC in epidermal cell suspensions before coculturing them with autologous T cells. After restimulation with EBNA1-peptides, we detected elevated levels of IFN-γ- and TNF-α-positive CD4+ T cells with both vaccines. When we injected the fusion proteins intradermally into human skin explants, emigrated skin DC targeted via DEC-205-induced cytokine production by T cells, whereas the Langerin-based vaccine failed to do so. In summary, we demonstrate that antibody-targeting approaches via the skin are promising vaccination strategies, however, further optimizations of vaccines are required to induce potent immune responses

Specification of Neuronal Identities by Feedforward Combinatorial Coding

Neuronal specification is often seen as a multistep process: earlier regulators confer broad neuronal identity and are followed by combinatorial codes specifying neuronal properties unique to specific subtypes. However, it is still unclear whether early regulators are re-deployed in subtype-specific combinatorial codes, and whether early patterning events act to restrict the developmental potential of postmitotic cells. Here, we use the differential peptidergic fate of two lineage-related peptidergic neurons in the Drosophila ventral nerve cord to show how, in a feedforward mechanism, earlier determinants become critical players in later combinatorial codes. Amongst the progeny of neuroblast 5–6 are two peptidergic neurons: one expresses FMRFamide and the other one expresses Nplp1 and the dopamine receptor DopR. We show the HLH gene collier functions at three different levels to progressively restrict neuronal identity in the 5–6 lineage. At the final step, collier is the critical combinatorial factor that differentiates two partially overlapping combinatorial codes that define FMRFamide versus Nplp1/DopR identity. Misexpression experiments reveal that both codes can activate neuropeptide gene expression in vast numbers of neurons. Despite their partially overlapping composition, we find that the codes are remarkably specific, with each code activating only the proper neuropeptide gene. These results indicate that a limited number of regulators may constitute a potent combinatorial code that dictates unique neuronal cell fate, and that such codes show a surprising disregard for many global instructive cues