Effects of mavoglurant on visual attention and pupil reactivity while viewing photographs of faces in Fragile X Syndrome.

BackgroundNumerous preclinical studies have supported the theory that enhanced activation of mGluR5 signaling, due to the absence or reduction of the FMR1 protein, contributes to cognitive and behavioral deficits in patients with fragile X syndrome (FXS). However multiple phase 2 controlled trials in patients with FXS have failed to demonstrate efficacy of compounds that negatively modulate mGluR5, including two phase 2b randomized controlled trials (RCT) of mavoglurant (AFQ056, Novartis Pharma AG), when the primary measures of interest were behavioral ratings. This has cast some doubt onto the translation of the mGluR5 theory from animal models to humans with the disorder.MethodsWe evaluated social gaze behavior-a key phenotypic feature of the disorder-and sympathetic nervous system influence on pupil size using a previously-validated eye tracking paradigm as a biobehavioral probe, in 57 adolescent or adult patients with FXS at baseline and following three months of blinded treatment with one of three doses of mavoglurant or placebo, within the context of the AFQ056 RCTs.ResultsPatients with FXS treated with mavoglurant demonstrated increased total absolute looking time and number of fixations to the eye region while viewing human faces relative to baseline, and compared to those treated with placebo. In addition, patients had greater pupil reactivity to faces relative to baseline following mavoglurant treatment compared to placebo.DiscussionThe study shows that negative modulation of mGluR5 activity improves eye gaze behavior and alters sympathetically-driven reactivity to faces in patients with FXS, providing preliminary evidence of this drug's impact on behavior in humans with the disorder

Improving IQ measurement in intellectual disabilities using true deviation from population norms

BackgroundIntellectual disability (ID) is characterized by global cognitive deficits, yet the very IQ tests used to assess ID have limited range and precision in this population, especially for more impaired individuals.MethodsWe describe the development and validation of a method of raw z-score transformation (based on general population norms) that ameliorates floor effects and improves the precision of IQ measurement in ID using the Stanford Binet 5 (SB5) in fragile X syndrome (FXS; n = 106), the leading inherited cause of ID, and in individuals with idiopathic autism spectrum disorder (ASD; n = 205). We compared the distributional characteristics and Q-Q plots from the standardized scores with the deviation z-scores. Additionally, we examined the relationship between both scoring methods and multiple criterion measures.ResultsWe found evidence that substantial and meaningful variation in cognitive ability on standardized IQ tests among individuals with ID is lost when converting raw scores to standardized scaled, index and IQ scores. Use of the deviation z- score method rectifies this problem, and accounts for significant additional variance in criterion validation measures, above and beyond the usual IQ scores. Additionally, individual and group-level cognitive strengths and weaknesses are recovered using deviation scores.ConclusionTraditional methods for generating IQ scores in lower functioning individuals with ID are inaccurate and inadequate, leading to erroneously flat profiles. However assessment of cognitive abilities is substantially improved by measuring true deviation in performance from standardization sample norms. This work has important implications for standardized test development, clinical assessment, and research for which IQ is an important measure of interest in individuals with neurodevelopmental disorders and other forms of cognitive impairment

Defining Natural History: Assessment of the Ability of College Students to Aid in Characterizing Clinical Progression of Niemann-Pick Disease, Type C

Niemann-Pick Disease, type C (NPC) is a fatal, neurodegenerative, lysosomal storage disorder. It is a rare disease with broad phenotypic spectrum and variable age of onset. These issues make it difficult to develop a universally accepted clinical outcome measure to assess urgently needed therapies. To this end, clinical investigators have defined emerging, disease severity scales. The average time from initial symptom to diagnosis is approximately 4 years. Further, some patients may not travel to specialized clinical centers even after diagnosis. We were therefore interested in investigating whether appropriately trained, community-based assessment of patient records could assist in defining disease progression using clinical severity scores. In this study we evolved a secure, step wise process to show that pre-existing medical records may be correctly assessed by non-clinical practitioners trained to quantify disease progression. Sixty-four undergraduate students at the University of Notre Dame were expertly trained in clinical disease assessment and recognition of major and minor symptoms of NPC. Seven clinical records, randomly selected from a total of thirty seven used to establish a leading clinical severity scale, were correctly assessed to show expected characteristics of linear disease progression. Student assessment of two new records donated by NPC families to our study also revealed linear progression of disease, but both showed accelerated disease progression, relative to the current severity scale, especially at the later stages. Together, these data suggest that college students may be trained in assessment of patient records, and thus provide insight into the natural history of a disease

Fostering global data sharing: Highlighting the recommendations of the Research Data Alliance COVID-19 working group

© 2020 Austin CC et al. The systemic challenges of the COVID-19 pandemic require cross-disciplinary collaboration in a global and timely fashion. Such collaboration needs open research practices and the sharing of research outputs, such as data and code, thereby facilitating research and research reproducibility and timely collaboration beyond borders. The Research Data Alliance COVID-19 Working Group recently published a set of recommendations and guidelines on data sharing and related best practices for COVID-19 research. These guidelines include recommendations for researchers, policymakers, funders, publishers and infrastructure providers from the perspective of different domains (Clinical Medicine, Omics, Epidemiology, Social Sciences, Community Participation, Indigenous Peoples, Research Software, Legal and Ethical Considerations). Several overarching themes have emerged from this document such as the need to balance the creation of data adherent to FAIR principles (findable, accessible, interoperable and reusable), with the need for quick data release; the use of trustworthy research data repositories; the use of well-annotated data with meaningful metadata; and practices of documenting methods and software. The resulting document marks an unprecedented cross-disciplinary, cross-sectoral, and cross-jurisdictional effort authored by over 160 experts from around the globe. This letter summarises key points of the Recommendations and Guidelines, highlights the relevant findings, shines a spotlight on the process, and suggests how these developments can be leveraged by the wider scientific community

DNA repair: the culprit for tumor-initiating cell survival?

The existence of “tumor-initiating cells” (TICs) has been a topic of heated debate for the last few years within the field of cancer biology. Their continuous characterization in a variety of solid tumors has led to an abundance of evidence supporting their existence. TICs are believed to be responsible for resistance against conventional treatment regimes of chemotherapy and radiation, ultimately leading to metastasis and patient demise. This review summarizes DNA repair mechanism(s) and their role in the maintenance and regulation of stem cells. There is evidence supporting the hypothesis that TICs, similar to embryonic stem (ES) cells and hematopoietic stem cells (HSCs), display an increase in their ability to survive genotoxic stress and injury. Mechanistically, the ability of ES cells, HSCs and TICs to survive under stressful conditions can be attributed to an increase in the efficiency at which these cells undergo DNA repair. Furthermore, the data presented in this review summarize the results found by our lab and others demonstrating that TICs have an increase in their genomic stability, which can allow for TIC survival under conditions such as anticancer treatments, while the bulk population of tumor cells dies. We believe that these data will greatly impact the development and design of future therapies being engineered to target and eradicate this highly aggressive cancer cell population

Cognitive behavioural therapy with optional graded exercise therapy in patients with severe fatigue with myotonic dystrophy type 1:a multicentre, single-blind, randomised trial

Background: Myotonic dystrophy type 1 is the most common form of muscular dystrophy in adults and leads to severe fatigue, substantial physical functional impairment, and restricted social participation. In this study, we aimed to determine whether cognitive behavioural therapy optionally combined with graded exercise compared with standard care alone improved the health status of patients with myotonic dystrophy type 1. Methods: We did a multicentre, single-blind, randomised trial, at four neuromuscular referral centres with experience in treating patients with myotonic dystrophy type 1 located in Paris (France), Munich (Germany), Nijmegen (Netherlands), and Newcastle (UK). Eligible participants were patients aged 18 years and older with a confirmed genetic diagnosis of myotonic dystrophy type 1, who were severely fatigued (ie, a score of ≥35 on the checklist-individual strength, subscale fatigue). We randomly assigned participants (1:1) to either cognitive behavioural therapy plus standard care and optional graded exercise or standard care alone. Randomisation was done via a central web-based system, stratified by study site. Cognitive behavioural therapy focused on addressing reduced patient initiative, increasing physical activity, optimising social interaction, regulating sleep–wake patterns, coping with pain, and addressing beliefs about fatigue and myotonic dystrophy type 1. Cognitive behavioural therapy was delivered over a 10-month period in 10–14 sessions. A graded exercise module could be added to cognitive behavioural therapy in Nijmegen and Newcastle. The primary outcome was the 10-month change from baseline in scores on the DM1-Activ-c scale, a measure of capacity for activity and social participation (score range 0–100). Statistical analysis of the primary outcome included all participants for whom data were available, using mixed-effects linear regression models with baseline scores as a covariate. Safety data were presented as descriptives. This trial is registered with ClinicalTrials.gov, number NCT02118779. Findings: Between April 2, 2014, and May 29, 2015, we randomly assigned 255 patients to treatment: 128 to cognitive behavioural therapy plus standard care and 127 to standard care alone. 33 (26%) of 128 assigned to cognitive behavioural therapy also received the graded exercise module. Follow-up continued until Oct 17, 2016. The DM1-Activ-c score increased from a mean (SD) of 61·22 (17·35) points at baseline to 63·92 (17·41) at month 10 in the cognitive behavioural therapy group (adjusted mean difference 1·53, 95% CI −0·14 to 3·20), and decreased from 63·00 (17·35) to 60·79 (18·49) in the standard care group (−2·02, −4·02 to −0·01), with a mean difference between groups of 3·27 points (95% CI 0·93 to 5·62, p=0·007). 244 adverse events occurred in 65 (51%) patients in the cognitive behavioural therapy group and 155 in 63 (50%) patients in the standard care alone group, the most common of which were falls (155 events in 40 [31%] patients in the cognitive behavioural therapy group and 71 in 33 [26%] patients in the standard care alone group). 24 serious adverse events were recorded in 19 (15%) patients in the cognitive behavioural therapy group and 23 in 15 (12%) patients in the standard care alone group, the most common of which were gastrointestinal and cardiac. Interpretation: Cognitive behavioural therapy increased the capacity for activity and social participation in patients with myotonic dystrophy type 1 at 10 months. With no curative treatment and few symptomatic treatments, cognitive behavioural therapy could be considered for use in severely fatigued patients with myotonic dystrophy type 1. Funding: The European Union Seventh Framework Programme

The FMR1 Gene and Differential Susceptibility to HPA-axis and Immune Dysfunction: Examination of a Gene-Environment Interaction with Stress

There is strong evidence linking psychological stress, HPA-axis activity, and the immune system dysregulation with negative health outcomes. For example, chronic stress, HPA-axis and immune system dysfunction are all associated with greater risk of infection and diagnosis of chronic inflammatory disease, autoimmune disease, depression, and anxiety. Yet, some individuals do not develop significant health issues and instead demonstrate great resilience under these same stressful environments. The factors or mechanisms that contribute to this variability remain to be determined. Understanding these influences and how they relate to both psychological and physiological changes are especially important for current and forthcoming research on intervention, prevention and clinical application. The following dissertation contains two related studies that together are guided by a gene x environment interaction approach aimed at understanding important unanswered questions regarding the relative and collective contributions of fragile X mental retardation 1 (FMR1) genotype and psychological stress on two important physiological systems, the HPA-axis and immune system. In the first study (Chapter 2), we examined how the relationship between FMR1 genotype and immunological functioning is moderated by self-reported psychological stress. Much of the research and theory thus far has focused on FMR1 gene expression-related pathogenic mechanism (i.e. mRNA toxicity) as the cause of various negative health outcomes associated with FMR1 alleles in the premutation range. Moreover, previous work has disproportionately focused on mothers caring for a son/daughter with FXS who are known to be greatly affected by caregiving-associated chronic stress. Therefore, an important goal of this first study was to determine the extent to which the effect of self-reported stress differentially affects the association between FMR1 genotype and immune functioning by oversampling women with the premutation who are not caregivers of affected children. Another important feature of the first study was the focus on underlying biologically-based endophenotypes instead of diagnostic categories. Women with activation ratio-corrected CGG (AR-CGG) repeat lengths in the mid-premutation range (around 60-80 AR-CGG repeats) were more sensitive to the effects of psychological stress, such that women in this range with higher levels of stress display higher levels of IL-10 and lower levels of Th1-associated cytokines. In part, these findings differ from previous research demonstrating more broad suppression of cytokine production among women with FMR1 alleles in the premutation range. However, our results are consistent with previous findings of a Th1/Th2 shift in the immune system reported to be associated with stress. Specifically, higher levels of cortisol are thought to shift the balance toward more Th2-associated cytokines. This type of immunological imbalance is observed in fibromyalgia, atopic dermatitis, asthma, anxiety and depression. This may in part explain why women with the premutation are also more likely to experience some of these health issues. Our second study (Chapter 3) focuses on how psychological stress and FMR1 genotype interact and affect HPA-axis activity. This study was a natural extension of the first, namely by determining whether HPA-axis activity, which has been shown to be dysregulated in women with certain FMR1 alleles, mediates the association between FMR1 genotype and immune system dysregulation. We found that among women with AR-CGG lengths greater than 80 repeats, higher levels of self-reported stress were associated with elevated waking cortisol levels and flatter diurnal slopes. Additionally, we observed a curvilinear association between AR-CGG repeat size and waking cortisol which was moderated by stress. Women with FMR1 alleles in the 60-80 AR-CGG repeat range were more sensitive to the effect of negative life events displaying elevated waking cortisol. Our moderated-mediation analysis found no mediating effect of HPA-axis activity between stress and FMR1 genotype with immune system functioning. In sum, women with FMR1 alleles in the mid-premutation range were found to be more sensitive to the effects of stress on diurnal cortisol. These findings have implications for understanding the association between the FMR1 gene and the increased risk of developing depression, anxiety, and various inflammatory/autoimmune disorders among women with the premutation. In total, the goal of these two studies was to implement a gene-environment interaction approach in order to; (a) determine the extent to which the susceptibility of developing immune system dysregulation among certain FMR1 alleles is regulated at least in part by psychological stress and (b) determine whether diurnal HPA-axis dysregulation is a possible biological mechanism underlying this relationship. The results of these studies have the potential to impact society in a variety of ways. First, the findings from these two studies can advance our general understanding of basic biological processes underlying why and how the environment in which we live and develop gets “under the skin” affecting two important physiological systems and overall health. Second, these findings have the capacity to inform a substantial portion of the population (1 in 113-152 women are FMR1 premutation carriers), indicating that the FMR1 gene may be an important contributor to immune dysregulation in the general population. Finally, counseling and preventative research will benefit from a better understanding of when and how stress can affect individuals who might be more genetically vulnerable