To better understand the impact of children’s autism spectrum disorder (ASD) severity on families, we evaluated pathways through which ASD severity affected child sleep quality, caregiver strain, and ...caregiver sleep quality. In a cross-sectional analysis through the U.S.-wide Simons Foundation Powering Autism Research for Knowledge (SPARK) cohort. Participants were caregivers of dependents with ASD aged 3–17 years (N = 3150). We found that increased severity strongly affects caregiver strain and child sleep quality. Child sleep quality was a minor mediator of increasing caregiver strain. Caregiver sleep quality depended on ASD severity only through child sleep quality and caregiver strain. Interventions aimed at improving child sleep quality or reducing caregiver strain could positively impact families of children with ASD.
Validated outcome measures with the capacity to reflect meaningful change are key to assessing potential interventions for autism spectrum disorder (ASD). We derive clinically meaningful change ...thresholds (MCTs) of the Autism Impact Measure (AIM) and identify factors associated with meaningful change. Baseline and 12-months follow-up survey of caregivers of 2,761 children with ASD aged 3–17 years from the U.S. Simons Foundation Powering Autism Research for Knowledge (SPARK) cohort were analyzed. Using caregiver-reported anchors for change, the 12-month change in estimated AIM MCT (95% confidence interval) for symptom improvement was –4.5 (–7.61, –1.37) points and 9.9 (5.12, 14.59) points for symptom deterioration. These anchor-based MCTs will facilitate future assessments of caregiver-reported change in AIM scores.
The benchmark dose (BMD) concept is increasingly utilized to analyze quantitative dose–response relationships in genetic toxicology. This methodology requires the user (i.e. the toxicologist) to a ...priori define a small increase over controls that is “acceptable” to be induced by a genotoxic test substance. The increase is called benchmark response (BMR) or critical effect size (CES), depending on the software used. To render the metrics calculated from the data of animals treated with the test substance applicable for risk assessment, the BMR or CES must represent biologically relevant changes of parameters measured in in vivo genotoxicity assays such as the Micronucleus, Comet, Transgenic rodent or Pig-a assay. Current recommendations for CES in genotoxicology are arbitrary (10% increase over mean vehicle controls) or based on limited, usually 5–6, data points (i.e. the standard deviation of the concurrent vehicle control group). We have, therefore, analyzed historical vehicle control data of standard in vivo genotoxicity test systems with statistical methods. Based on this evaluation, we illustrate limitations of the currently recommended CES values and propose a pragmatic approach that may contribute to better defining endpoint-specific CES values for BMD software like PROAST.
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer patients in the last decade, but immune-related adverse events (irAEs) pose significant clinical challenges. Despite ...advances in the management of these unique toxicities, there remains an unmet need to further characterize the patient-level drivers of irAEs in order to optimize the benefit/risk balance in patients receiving cancer immunotherapy.
An individual-patient data
meta-analysis was performed using data from 10,344 patients across 15 Roche sponsored clinical trials with atezolizumab in five different solid tumor types to assess the association between baseline risk factors and the time to onset of irAE. In this study, the overall analysis was conducted by treatment arm, indication, toxicity grade and irAE type, and the study design considered confounder adjustment to assess potential differences in risk factor profiles.
This analysis demonstrates that the safety profile of atezolizumab is generally consistent across indications in the 15 studies evaluated. In addition, our findings corroborate with prior reviews which suggest that reported rates of irAEs with PD-(L)1 inhibitors are nominally lower than CTLA-4 inhibitors. In our analysis, there were no remarkable differences in the distribution of toxicity grades between indications, but some indication-specific differences regarding the type of irAE were seen across treatment arms, where pneumonitis mainly occurred in lung cancer, and hypothyroidism and rash had a higher prevalence in advanced renal cell carcinoma compared to all other indications. Results showed consistency of risk factors across indications and by toxicity grade. The strongest and most consistent risk factors were mostly organ-specific such as elevated liver enzymes for hepatitis and thyroid stimulating hormone (TSH) for thyroid toxicities. Another strong but non-organ-specific risk factor was ethnicity, which was associated with rash, hepatitis and pneumonitis. Further understanding the impact of ethnicity on ICI associated irAEs is considered as an area for future research.
Overall, this analysis demonstrated that atezolizumab safety profile is consistent across indications, is clinically distinguishable from comparator regimens without checkpoint inhibition, and in line with literature, seems to suggest a nominally lower reported rates of irAEs vs CTLA-4 inhibitors. This analysis demonstrates several risk factors for irAEs by indication, severity and location of irAE, and by patient ethnicity. Additionally, several potential irAE risk factors that have been published to date, such as demographic factors, liver enzymes, TSH and blood cell counts, are assessed in this large-scale meta-analysis, providing a more consistent picture of their relevance. However, given the small effects size, changes to clinical management of irAEs associated with the use of Anti-PDL1 therapy are not warranted.
Trajectories of comorbidities among individuals at risk of Alzheimer's disease (AD) may differ from those aging without AD clinical syndrome. Therefore, characterizing the comorbidity burden and ...pattern associated with AD risk may facilitate earlier detection, enable timely intervention, and help slow the rate of cognitive and functional decline in AD. This case-control study was performed to compare the prevalence of comorbidities between AD cases and controls during the 5 years prior to diagnosis (or index date for controls); and to identify comorbidities with a differential time-dependent prevalence trajectory during the 5 years prior to AD diagnosis.
Incident AD cases and individually matched controls were identified in a United States claims database between January 1, 2000 and December 31, 2016. AD status and comorbidities were defined based on the presence of diagnosis codes in administrative claims records. Generalized estimating equations were used to assess evidence of changes over time and between AD and controls. A principal component analysis and hierarchical clustering was performed to identify groups of AD-related comorbidities with respect to prevalence changes over time (or trajectory), and differences between AD and controls.
Data from 186,064 individuals in the IBM MarketScan Commercial Claims and Medicare Supplementary databases were analyzed (93,032 AD cases and 93,032 non-AD controls). In total, there were 177 comorbidities with a ≥ 5% prevalence. Five main clusters of comorbidities were identified. Clusters differed between AD cases and controls in the overall magnitude of association with AD, in their diverging time trajectories, and in comorbidity prevalence. Three clusters contained comorbidities that notably increased in frequency over time in AD cases but not in controls during the 5-year period before AD diagnosis. Comorbidities in these clusters were related to the early signs and/or symptoms of AD, psychiatric and mood disorders, cerebrovascular disease, history of hazard and injuries, and metabolic, cardiovascular, and respiratory complaints.
We demonstrated a greater comorbidity burden among those who later developed AD vs. controls, and identified comorbidity clusters that could distinguish these two groups. Further investigation of comorbidity burden is warranted to facilitate early detection of individuals at risk of developing AD.
Personalised oncology, whereby patients are given therapies based on their molecular tumour profile, is rapidly becoming an essential part of optimal clinical care, at least partly facilitated by ...recent advances in next-generation sequencing-based technology using liquid- and tissue-based biopsies. Consequently, clinical trials have shifted in approach, from traditional studies evaluating cytotoxic chemotherapy in largely histology-based populations to modified, biomarker-driven studies (e.g. basket, umbrella, platform) of molecularly guided therapies and cancer immunotherapies in selected patient subsets. Such modified study designs may assess, within the same trial structure, multiple cancer types and treatments, and should incorporate a multistakeholder perspective. This is key to generating complementary, fit-for-purpose and timely evidence for molecularly guided therapies that can be used as proof-of-concept to inform further study designs, lead to approval by regulatory authorities and be used as confirmation of clinical benefit for health technology assessment bodies. In general, the future of cancer clinical trials requires a framework for the application of innovative technologies and dynamic design methodologies, in order to efficiently transform scientific discoveries into clinical utility. Next-generation, modified studies that involve the joint efforts of all key stakeholders will offer individualised strategies that ultimately contribute to globalised knowledge and collective learning. In this review, we outline the background and purpose of such modified study designs and detail key aspects from a multistakeholder perspective. We also provide methodological considerations for designing the studies and highlight how insights from already-ongoing studies may address current challenges and opportunities in the era of personalised oncology.
•Personalised oncology is rapidly becoming a key part of optimal clinical care.•Traditional clinical trials of tailored therapies are not always feasible.•Modified, multistakeholder study designs can support decision-making.•Ongoing studies may provide insights into methodological considerations.
Small molecule splicing modifiers have been previously described that target the general splicing machinery and thus have low specificity for individual genes. Several potent molecules correcting the ...splicing deficit of the SMN2 (survival of motor neuron 2) gene have been identified and these molecules are moving towards a potential therapy for spinal muscular atrophy (SMA). Here by using a combination of RNA splicing, transcription, and protein chemistry techniques, we show that these molecules directly bind to two distinct sites of the SMN2 pre-mRNA, thereby stabilizing a yet unidentified ribonucleoprotein (RNP) complex that is critical to the specificity of these small molecules for SMN2 over other genes. In addition to the therapeutic potential of these molecules for treatment of SMA, our work has wide-ranging implications in understanding how small molecules can interact with specific quaternary RNA structures.
Acute exposure to stressful experiences can rapidly increase anxiety and cause neuropsychiatric disorders. The effects of stress result in part from the release of neurotransmitters and hormones, ...which regulate gene expression in different brain regions. The fast neuroendocrine response to stress is largely mediated by norepinephrine (NE) and corticotropin releasing hormone (CRH), followed by a slower and more sustained release of corticosterone. While corticosterone is an important regulator of gene expression, it is not clear which stress-signals contribute to the rapid regulation of gene expression observed immediately after stress exposure. Here, we demonstrate in mice that 45 min after an acute swim stress challenge, large changes in gene expression occur across the transcriptome in the hippocampus, a region sensitive to the effects of stress. We identify multiple candidate genes that are rapidly and transiently altered in both males and females. Using a pharmacological approach, we show that most of these rapidly induced genes are regulated by NE through β-adrenergic receptor signaling. We find that CRH and corticosterone can also contribute to rapid changes in gene expression, although these effects appear to be restricted to fewer genes. These results newly reveal a widespread impact of NE on the transcriptome and identify novel genes associated with stress and adrenergic signaling.
•Acute stress exposure rapidly and profoundly affects the hippocampal transcriptome.•Atress-induced effects occur in both sexes, but are more pronounced in females.•Most transcriptional changes depend on norepinephrine via β2-adrenergic receptors.•The stress-induced effects also occur in other stress-related brain regions.
Solar drinking water disinfection (SODIS) is a low-cost, point-of-use water purification method that has been disseminated globally. Laboratory studies suggest that SODIS is highly efficacious in ...inactivating waterborne pathogens. Previous field studies provided limited evidence for its effectiveness in reducing diarrhoea.
We conducted a cluster-randomized controlled trial in 22 rural communities in Bolivia to evaluate the effect of SODIS in reducing diarrhoea among children under the age of 5 y. A local nongovernmental organisation conducted a standardised interactive SODIS-promotion campaign in 11 communities targeting households, communities, and primary schools. Mothers completed a daily child health diary for 1 y. Within the intervention arm 225 households (376 children) were trained to expose water-filled polyethyleneteraphtalate bottles to sunlight. Eleven communities (200 households, 349 children) served as a control. We recorded 166,971 person-days of observation during the trial representing 79.9% and 78.9% of the total possible person-days of child observation in intervention and control arms, respectively. Mean compliance with SODIS was 32.1%. The reported incidence rate of gastrointestinal illness in children in the intervention arm was 3.6 compared to 4.3 episodes/year at risk in the control arm. The relative rate of diarrhoea adjusted for intracluster correlation was 0.81 (95% confidence interval 0.59-1.12). The median length of diarrhoea was 3 d in both groups.
Despite an extensive SODIS promotion campaign we found only moderate compliance with the intervention and no strong evidence for a substantive reduction in diarrhoea among children. These results suggest that there is a need for better evidence of how the well-established laboratory efficacy of this home-based water treatment method translates into field effectiveness under various cultural settings and intervention intensities. Further global promotion of SODIS for general use should be undertaken with care until such evidence is available.
www.ClinicalTrials.govNCT00731497 Please see later in the article for Editors' Summary.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Synucleinopathies including Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are characterized by the accumulation of abnormal α-synuclein in intraneuronal inclusions, named Lewy bodies. ...Mutations in GBA1, the gene encoding the lysosomal hydrolase glucocerebrosidase, have been identified as the most common genetic risk factor for PD and DLB. However, despite extensive research, the mechanism by which glucocerebrosidase dysfunction increases the risk for PD or DLB still remains elusive.
In our study we expand the toolbox for PD-DLB post-mortem studies by introducing new quantitative biochemical assays for glucocerebrosidase and α-synuclein. Applying causal modelling, we determine how these parameters are interrelated and ultimately impact disease manifestation.
We developed quantitative immuno-based assays for glucocerebrosidase and α-synuclein (total and phosphorylated at Serine 129) protein levels, as well as a liquid chromatography–mass spectrometry method for the detection of the glucocerebrosidase lipid substrate glucosylsphingosine. These assays were applied on tissue samples from frontal cortex, putamen and substantia nigra of PD (n = 15) and DLB (n = 15) patients and age-matched non-demented controls (n = 15).
Our results confirm elevated p-129 over total α-synuclein levels in the insoluble fraction of PD and DLB post-mortem brain tissue and we found significantly increased α-synuclein levels in the soluble fractions in PD and DLB. Furthermore, we identified an inverse correlation between reduced glucocerebrosidase enzyme activity and protein levels with increased glucosylsphingosine levels. In the substantia nigra, a brain region particularly vulnerable in Parkinson's disease, we found a significant correlation between glucocerebrosidase protein reduction and increased p129/total α-synuclein ratios.
We assessed the direction and strength of the interrelation between all measured parameters by confirmatory path analysis. Interestingly, we found that glucocerebrosidase dysfunction impacts the PD-DLB status by increasing α-synuclein ratios in the substantia nigra, which was partly mediated by increasing glucosylsphingosine levels.
In conclusion, we show that the introduced immuno-based assays enable the quantitative assessment of glucocerebrosidase and α-synuclein parameters in post-mortem brain. In the substantia nigra, reduced glucocerebrosidase levels contribute to the increase in α-synuclein levels and to PD-DLB disease manifestation partly by increasing its glycolipid substrate glucosylsphingosine. This interrelation between glucocerebrosidase, glucosylsphingosine and α-synuclein parameters supports the hypothesis that glucocerebrosidase acts as a modulator of PD-DLB.
•Path analysis - a new tool to understand the GBA/ a-syn axis•Ser129 phosphorylated a-syn levels are increased in LBD•In the SN reduced glucocerebrosidase protein correlates with increased α-synuclein•Glucocerebrosidase contributes to LBD partly by increasing glucosylsphingosine
PDF
