Maintenance therapy with once-monthly administration of long-acting injectable risperidone in patients with schizophrenia or schizoaffective disorder: a pilot study of an extended dosing interval

BACKGROUND: Several clinical studies have established the efficacy, safety, and tolerability of long-acting risperidone administered once every 2 weeks in patients with schizophrenia or schizoaffective disorder. This report evaluates preliminary efficacy, safety, tolerability, and pharmacokinetic data for a novel (once-monthly) administration of long-acting injectable risperidone 50 mg in patients with schizophrenia or schizoaffective disorder. METHODS: Clinically stable patients participated in a 1-year, open-label, single-arm, multicenter pilot study. During the 4-week lead-in phase, patients received long-acting risperidone 50 mg injections every 2 weeks, with 2 weeks of oral risperidone supplementation. Injections of long-acting risperidone 50 mg every 4 weeks followed for up to 48 weeks, without oral supplementation. The primary endpoint was relapse; other assessments included PANSS, CGI-S, adverse event reports, and determination of risperidone and 9-hydroxyrisperidone plasma concentrations. RESULTS: Twelve patients in the intent-to-treat population (n = 67) met relapse criteria (17.9%). Relapse risk at 1 year was estimated as 22.4%. Non-statistically significant improvements in symptoms (PANSS) and clinical status (CGI-S) at endpoint were observed. The most common adverse events included schizophrenia aggravated not otherwise specified (19.5%), anxiety (16.1%), insomnia (16.1%), and headache (11.5%). There were no unexpected safety and tolerability findings. Mean plasma concentrations for risperidone and 9-hydroxyrisperidone were generally stable during the study. CONCLUSION: Once-monthly dosing of long-acting risperidone was well tolerated, associated with a relatively low relapse rate (similar to that reported with other antipsychotics), and maintained the clinically stable baseline status of most patients. Although the results suggest that some symptomatically stable patients with schizophrenia or schizoaffective disorder might be safely managed with long-acting risperidone 50 mg once monthly, these findings alone do not identify which patients will have a sufficient therapeutic benefit nor do they quantify comparative effects of standard and altered dosing. Study limitations (the open-label pilot study design, small sample size, and lack of a concurrent biweekly treatment arm) prevent broad interpretations and extrapolations of results. Controlled studies would be required to support a recommendation for alternative dosing regimens

Exome sequencing and genotyping identify a rare variant in NLRP7 gene associated with ulcerative colitis.

Background and Aims Although genome-wide association studies [GWAS] in inflammatory bowel disease [IBD] have identified a large number of common disease susceptibility alleles for both Crohn’s disease [CD] and ulcerative colitis [UC], a substantial fraction of IBD heritability remains unexplained, suggesting that rare coding genetic variants may also have a role in pathogenesis. We used high-throughput sequencing in families with multiple cases of IBD, followed by genotyping of cases and controls, to investigate whether rare protein-altering genetic variants are associated with susceptibility to IBD. Methods Whole-exome sequencing was carried out in 10 families in whom three or more individuals were affected with IBD. A stepwise filtering approach was applied to exome variants, to identify potential causal variants. Follow-up genotyping was performed in 6025 IBD cases [2948 CD; 3077 UC] and 7238 controls. Results Our exome variant analysis revealed coding variants in the NLRP7 gene that were present in affected individuals in two distinct families. Genotyping of the two variants, p.S361L and p.R801H, in IBD cases and controls showed that the p.S361L variant was significantly associated with an increased risk of ulcerative colitis [odds ratio 4.79, p = 0.0039] and IBD [odds ratio 3.17, p = 0.037]. A combined analysis of both variants showed suggestive association with an increased risk of IBD [odds ratio 2.77, p = 0.018]. Conclusions The results suggest that NLRP7 signalling and inflammasome formation may be a significant component in the pathogenesis of IBD

Smoke rings:towards a comprehensive tobacco free policy for the Olympic Games

Background The tobacco industry has long sought affiliation with major sporting events, including the Olympic Games, for marketing, advertising and promotion purposes. Since 1988, each Olympic Games has adopted a tobacco-free policy. Limited study of the effectiveness of the smoke-free policy has been undertaken to date, with none examining the tobacco industry's involvement with the Olympics or use of the Olympic brand. Methods and Findings A comparison of the contents of Olympic tobacco-free policies from 1988 to 2014 was carried out by searching the websites of the IOC and host NOCs. The specific tobacco control measures adopted for each Games were compiled and compared with measures recommended by the WHO Tobacco Free Sports Initiative and Article 13 of the Framework Convention on Tobacco Control (FCTC). This was supported by semi-structured interviews of key informants involved with the adoption of tobacco-free policies for selected games. To understand the industry's interests in the Olympics, the Legacy Tobacco Documents Library (http://legacy.library.ucsf.edu) was systematically searched between June 2013 and August 2014. Company websites, secondary sources and media reports were also searched to triangulate the above data sources. This paper finds that, while most direct associations between tobacco and the Olympics have been prohibited since 1988, a variety of indirect associations undermine the Olympic tobacco-free policy. This is due to variation in the scope of tobacco-free policies, limited jurisdiction and continued efforts by the industry to be associated with Olympic ideals. Conclusions The paper concludes that, compatible with the IOC's commitment to promoting healthy lifestyles, a comprehensive tobacco-free policy with standardized and binding measures should be adopted by the International Olympic Committee and all national Olympic committees

Original research: longitudinal evaluation of cognitively demanding daily function using performance-based functional assessment highlights heterogeneous trajectories in cognitive and functional abilities in people with Parkinson’s disease

BackgroundLongitudinal assessment of functional abilities in Parkinson’s disease (PD) is needed to determine the efficacy of cognitive interventions in providing meaningful improvements in daily life. Additionally, subtle changes in instrumental activities of daily living may precede a clinical diagnosis of dementia and could aid earlier detection of and intervention for cognitive decline.ObjectiveThe primary goal was to validate the longitudinal application of the University of California San Diego Performance-Based Skills Assessment (UPSA). An exploratory secondary goal was to determine whether UPSA may identify individuals at higher risk of cognitive decline in PD.MethodsSeventy participants with PD completed the UPSA with at least one follow-up visit. Linear mixed effects modeling was used to identify associations between baseline UPSA score and cognitive composite score (CCS) over time. Descriptive analysis of four heterogeneous cognitive and functional trajectory groups and individual case examples was performed.ResultsBaseline UPSA score predicted CCS at each timepoint for functionally impaired and unimpaired groups (p < 0.01) but did not predict the rate change in CCS over time (p = 0.83). Participants displayed heterogenous trajectories in both UPSA and CCS during the follow-up period. Most participants maintained both cognitive and functional performance (n = 54), though some displayed cognitive and functional decline (n = 4), cognitive decline with functional maintenance (n = 4), and functional decline with cognitive maintenance (n = 8).ConclusionThe UPSA is a valid measure of cognitive functional abilities over time in PD. Given the heterogeneity of functional and cognitive trajectories, this performance-based assessment did not predict cognitive decline with this relatively short follow-up. Further work is needed to understand longitudinal functional assessments in PD-associated cognitive impairment

The RNA polymerase I transcription inhibitor CX-5461 cooperates with topoisomerase 1 inhibition by enhancing the DNA damage response in homologous recombination-proficient high-grade serious ovarian cancer

Background: Intrinsic and acquired drug resistance represent fundamental barriers to the cure of high-grade serous ovarian carcinoma (HGSC), the most common histological subtype accounting for the majority of ovarian cancer deaths. Defects in homologous recombination (HR) DNA repair are key determinants of sensitivity to chemotherapy and poly-ADP ribose polymerase inhibitors. Restoration of HR is a common mechanism of acquired resistance that results in patient mortality, highlighting the need to identify new therapies targeting HR-proficient disease. We have shown promise for CX-5461, a cancer therapeutic in early phase clinical trials, in treating HR-deficient HGSC. Methods: Herein, we screen the whole protein-coding genome to identify potential targets whose depletion cooperates with CX-5461 in HR-proficient HGSC. Results: We demonstrate robust proliferation inhibition in cells depleted of DNA topoisomerase 1 (TOP1). Combining the clinically used TOP1 inhibitor topotecan with CX-5461 potentiates a G2/M cell cycle checkpoint arrest in multiple HR-proficient HGSC cell lines. The combination enhances a nucleolar DNA damage response and global replication stress without increasing DNA strand breakage, significantly reducing clonogenic survival and tumour growth in vivo. Conclusions: Our findings highlight the possibility of exploiting TOP1 inhibition to be combined with CX-5461 as a non-genotoxic approach in targeting HR-proficient HGSC.The China Scholarship Council University of Melbourne Ph.D. Scholarship supported S.Y. A National Health and Medical Research Council (NHMRC) Grant and NHMRC Senior Research Fellowship to R.B.P. supported this work. The Victorian Centre for Functional Genomics (K.J.S.) is funded by the Australian Cancer Research Foundation (ACRF), the Australian Phenomics Network (APN) through funding from the Australian Government’s National Collaborative Research Infrastructure Strategy (NCRIS) programme, the Peter MacCallum Cancer Centre Foundation and the University of Melbourne Research Collaborative Infrastructure Programm

Immune System Dysregulation During Spaceflight: Potential Countermeasures for Deep Space Exploration Missions

Recent studies have established that dysregulation of the human immune system and the reactivation of latent herpesviruses persists for the duration of a 6-month orbital spaceflight. It appears certain aspects of adaptive immunity are dysregulated during flight, yet some aspects of innate immunity are heightened. Interaction between adaptive and innate immunity also seems to be altered. Some crews experience persistent hypersensitivity reactions during flight. This phenomenon may, in synergy with extended duration and galactic radiation exposure, increase specific crew clinical risks during deep space exploration missions. The clinical challenge is based upon both the frequency of these phenomena in multiple crewmembers during low earth orbit missions and the inability to predict which specific individual crewmembers will experience these changes. Thus, a general countermeasure approach that offers the broadest possible coverage is needed. The vehicles, architecture, and mission profiles to enable such voyages are now under development. These include deployment and use of a cis-Lunar station (mid 2020s) with possible Moon surface operations, to be followed by multiple Mars flyby missions, and eventual human Mars surface exploration. Current ISS studies will continue to characterize physiological dysregulation associated with prolonged orbital spaceflight. However, sufficient information exists to begin consideration of both the need for, and nature of, specific immune countermeasures to ensure astronaut health. This article will review relevant in-place operational countermeasures onboard ISS and discuss a myriad of potential immune countermeasures for exploration missions. Discussion points include nutritional supplementation and functional foods, exercise and immunity, pharmacological options, the relationship between bone and immune countermeasures, and vaccination to mitigate herpes (and possibly other) virus risks. As the immune system has sentinel connectivity within every other physiological system, translational effects must be considered for all potential immune countermeasures. Finally, we shall discuss immune countermeasures in the context of their individualized implementation or precision medicine, based on crewmember specific immunological biases

Measuring cortical mean diffusivity to assess early microstructural cortical change in presymptomatic familial Alzheimer's disease.

BACKGROUND: There is increasing interest in improving understanding of the timing and nature of early neurodegeneration in Alzheimer's disease (AD) and developing methods to measure this in vivo. Autosomal dominant familial Alzheimer's disease (FAD) provides the opportunity for investigation of presymptomatic change. We assessed early microstructural breakdown of cortical grey matter in FAD with diffusion-weighted MRI. METHODS: Diffusion-weighted and T1-weighed MRI were acquired in 38 FAD mutation carriers (17 symptomatic, 21 presymptomatic) and 39 controls. Mean diffusivity (MD) was calculated for six cortical regions previously identified as being particularly vulnerable to FAD-related neurodegeneration. Linear regression compared MD between symptomatic and presymptomatic carriers and controls, adjusting for age and sex. Spearman coefficients assessed associations between cortical MD and cortical thickness. Spearman coefficients also assessed associations between cortical MD and estimated years to/from onset (EYO). Across mutation carriers, linear regression assessed associations between MD and EYO, adjusting for cortical thickness. RESULTS: Compared with controls, cortical MD was higher in symptomatic mutation carriers (mean ± SD CDR = 0.88 ± 0.39) for all six regions (p < 0.001). In late presymptomatic carriers (within 8.1 years of predicted symptom onset), MD was higher in the precuneus (p = 0.04) and inferior parietal cortex (p = 0.003) compared with controls. Across all presymptomatic carriers, MD in the precuneus correlated with EYO (p = 0.04). Across all mutation carriers, there was strong evidence (p < 0.001) of association between MD and cortical thickness in all regions except entorhinal cortex. After adjusting for cortical thickness, there remained an association (p < 0.05) in mutation carriers between MD and EYO in all regions except entorhinal cortex. CONCLUSIONS: Cortical MD measurement detects microstructural breakdown in presymptomatic FAD and correlates with proximity to symptom onset independently of cortical thickness. Cortical MD may thus be a feasible biomarker of early AD-related neurodegeneration, offering additional/complementary information to conventional MRI measures

Creating a Data Dictionary for Pediatric Autonomic Disorders

PURPOSE: Whether evaluating patients clinically, documenting care in the electronic health record, performing research, or communicating with administrative agencies, the use of a common set of terms and definitions is vital to ensure appropriate use of language. At a 2017 meeting of the Pediatric Section of the American Autonomic Society, it was determined that an autonomic data dictionary comprising aspects of evaluation and management of pediatric patients with autonomic disorders would be an important resource for multiple stakeholders. METHODS: Our group created the list of terms for the dictionary. Definitions were prioritized to be obtained from established sources with which to harmonize. Some definitions needed mild modification from original sources. The next tier of sources included published consensus statements, followed by Internet sources. In the absence of appropriate sources, we created a definition. RESULTS: A total of 589 terms were listed and defined in the dictionary. Terms were organized by Signs/Symptoms, Triggers, Co-morbid Disorders, Family History, Medications, Medical Devices, Physical Examination Findings, Testing, and Diagnoses. CONCLUSION: Creation of this data dictionary becomes the foundation of future clinical care and investigative research in pediatric autonomic disorders, and can be used as a building block for a subsequent adult autonomic data dictionary

Plasma steroid concentrations reflect acute disease severity and normalise during recovery in people hospitalised with COVID-19

Objective: Endocrine systems are disrupted in acute illness, and symptoms reported following coronavirus disease 2019 (COVID-19) are similar to those found with clinical hormone deficiencies. We hypothesised that people with severe acute COVID-19 and with post-COVID symptoms have glucocorticoid and sex hormone deficiencies. Design/Patients: Samples were obtained for analysis from two UK multicentre cohorts during hospitalisation with COVID-19 (International Severe Acute Respiratory Infection Consortium/World Health Organisation [WHO] Clinical Characterization Protocol for Severe Emerging Infections in the UK study), and at follow-up 5 months after hospitalisation (Post-hospitalisation COVID-19 study). Measurements: Plasma steroids were quantified by liquid chromatography–mass spectrometry. Steroid concentrations were compared against disease severity (WHO ordinal scale) and validated symptom scores. Data are presented as geometric mean (SD). Results: In the acute cohort (n = 239, 66.5% male), plasma cortisol concentration increased with disease severity (cortisol 753.3 [1.6] vs. 429.2 [1.7] nmol/L in fatal vs. least severe, p < .001). In males, testosterone concentrations decreased with severity (testosterone 1.2 [2.2] vs. 6.9 [1.9] nmol/L in fatal vs. least severe, p < .001). In the follow-up cohort (n = 198, 62.1% male, 68.9% ongoing symptoms, 165 [121–192] days postdischarge), plasma cortisol concentrations (275.6 [1.5] nmol/L) did not differ with in-hospital severity, perception of recovery, or patient-reported symptoms. Male testosterone concentrations (12.6 [1.5] nmol/L) were not related to in-hospital severity, perception of recovery or symptom scores. Conclusions: Circulating glucocorticoids in patients hospitalised with COVID-19 reflect acute illness, with a marked rise in cortisol and fall in male testosterone. These findings are not observed 5 months from discharge. The lack of association between hormone concentrations and common post-COVID symptoms suggests steroid insufficiency does not play a causal role in this condition