Cost-Effectiveness of Nusinersen and Universal Newborn Screening for Spinal Muscular Atrophy.

OBJECTIVE: To evaluate the cost-effectiveness of nusinersen with and without universal newborn screening for infantile-onset spinal muscular atrophy (SMA). STUDY DESIGN: A Markov model using data from clinical trials with US epidemiologic and cost data was developed. The primary interventions studied were nusinersen treatment in a screening setting, nusinersen treatment in a nonscreening setting, and standard care. Analysis was conducted from a societal perspective. RESULTS: Compared with no screening and no treatment, the incremental cost-effectiveness ratio (ICER) for nusinersen with screening was $330 558 per event-free life year (LY) saved, whereas the ICER for nusinersen treatment without screening was $508 481 per event-free LY saved. For nusinersen with screening to be cost-effective at a willingness-to-pay (WTP) threshold of $50 000 per event-free LY saved, the price would need to be $23 361 per dose, less than one-fifth its current price of $125 000. Preliminary data from the NURTURE trial indicated an 85.7% improvement in expected LYs saved compared with our base results. In probabilistic sensitivity analysis, nusinersen and screening was a preferred strategy 93% of the time at a $500 000 WTP threshold. CONCLUSION: Universal newborn screening for SMA provides improved economic value for payers and patients when nusinersen is available.

Group metacognitive therapy for adolescents with anxiety and depressive disorders: A pilot study.

OBJECTIVE(S): The metacognitive model suggests that beliefs about cognition maintain repetitive negative thinking (RNT), a transdiagnostic process that underlies commonly comorbid, emotional disorders. To date, there has been the limited application of metacognitive therapy (MCT) to adolescents. This study aimed to evaluate a six-session group transdiagnostic MCT program for adolescents with anxiety and/or depressive disorders. METHOD: Participants (N = 10; 3 male, 7 female; average age 15.2 years) completed measures of metacognition and RNT at assessment, baseline period, during treatment, and at 1- and 3-month follow-ups. RESULTS: Nine participants attended all six treatment sessions and one discontinued after four sessions. At posttreatment and follow-ups, the majority of participants no longer met diagnostic criteria for anxiety or depressive disorders and evidenced a clinically significant or reliable change in metacognitions and RNT. CONCLUSIONS: Results suggest that group MCT is promising in terms of acceptability and effectiveness for adolescents with anxiety and/or depressive disorders.

Structure and validity of the Clinical Perfectionism Questionnaire in female adolescents.

BACKGROUND: Perfectionism is a transdiagnostic risk factor across psychopathology. The Clinical Perfectionism Questionnaire (CPQ) was developed to assess change in order to provide clinical utility, but currently the psychometric properties of the CPQ with adolescents is unknown. AIMS: To assess the factor structure and construct validity of the CPQ in female adolescents. METHOD: The CPQ was administered to 267 females aged 14-19 years of age. Confirmatory factor analysis (CFA) was used to examine the validity of the two-factor model and a second-order factor model. Pearson correlations were used to evaluate the relationships between the CPQ and a wide range of measures of perfectionism, psychopathology and personality traits. RESULTS: The study demonstrated internal consistency, construct validity and incremental validity of the CPQ in a sample of female adolescents. The CFA in the present study confirmed the two-factor model of the CPQ with Factor 1 relating to perfectionistic strivings and Factor 2 representing perfectionistic concerns. The second-order two factor model indicated no deterioration in fit. CONCLUSIONS: The two-factor model of the CPQ fits with the theoretical definition of clinical perfectionism where the over-dependence of self-worth on achievement and concern over mistakes are key elements. The CPQ is suitable for use with female adolescents in future research that seeks to better understand the role of perfectionism in the range of mental illnesses that impact youth.

A Psychometric Examination of the Pathological Obsessive Compulsive Personality Scale (POPS): Initial Study in an Undergraduate Sample.

Obsessive-compulsive personality disorder (OCPD) has been subject to numerous definition and classification changes, which has contributed to difficulties in reliable measurement of the disorder. Consequently, OCPD measures have yielded poor validity and inconsistent prevalence estimates. Reliable and valid measures of OCPD are needed. The aim of the current study was to examine the factor structure and psychometric properties of the Pathological Obsessive Compulsive Personality Scale (POPS). Participants (N = 571 undergraduates) completed a series of self-report measures online, including the POPS. Confirmatory factor analysis was used to compare the fit of unidimensional, five factor, and bifactor models of the POPS. Convergent and divergent validity were assessed in relation to other personality dimensions. A bifactor model provided the best fit to the data, indicating that the total POPS scale and four subscales can be scored to obtain reliable indicators of OCPD. The POPS was most strongly associated with a disorder-specific measure of OCPD, however there were also positive associations with theoretically disparate constructs, thus further research is needed to clarify validity of the scale.

Modified Mindfulness-Based Cognitive Therapy for Depressive Symptoms in Parkinson's Disease: a Pilot Trial.

BACKGROUND: Mindfulness-based cognitive therapy (MBCT) has evidence of efficacy in a range of populations, but few studies to date have reported on MBCT for treatment of anxious and depressive symptoms in Parkinson's disease (PD). AIMS: The aim of this study was to examine the efficacy of modified MBCT in reducing symptoms of anxiety and depression and improving quality of life in PD. METHOD: Thirty-six individuals with PD were randomly assigned to either modified MBCT or a waitlist control. Changes in symptoms of anxiety, depression and quality of life were compared at group level using generalized linear mixed models and at individual level using reliable change analysis. RESULTS: At post-treatment, there was a significant reduction in depressive symptoms for people undertaking modified MBCT at both group and individual levels compared with controls. There was no significant effect on anxiety or quality of life at the group level, although significantly more people had reliable improvement in anxiety after modified MBCT than after waitlist. Significantly more waitlist participants had reliable deterioration in symptoms of anxiety and depression than those completing modified MBCT. Most participants stayed engaged in modified MBCT, with only three drop-outs. DISCUSSION: This proof-of-concept study demonstrates the potential efficacy of modified MBCT as a treatment for depressive symptoms in Parkinson's disease and suggests further research is warranted.

Consensus-based perspectives of pediatric inpatient eating disorder services.

OBJECTIVE: There are few evidence-based guidelines for inpatient pediatric eating disorders. The aim was to gain perspectives from those providing and receiving inpatient pediatric eating disorder care on the essential components treatment. METHOD: A modified Delphi technique was used to develop consensus-based opinions. Participants (N = 74) were recruited for three panels: clinicians (n = 24), carers (n = 31), and patients (n = 19), who endorsed three rounds of statements online. RESULTS: A total of 167 statements were rated, 79 were accepted and reached a consensus level of at least 75% across all panels, and 87 were rejected. All agreed that families should be involved in treatment, and thatpsychological therapy be offered in specialist inpatient units. Areas of disagreement included that patients expressed a desire for autonomy in sessions being available without carers, and that weight gain should be gradual and admissions longer, in contrast to carers and clinicians. Carers endorsed that legal frameworks should be used to retain patients if required, and that inpatients are supervised at all times, in contrast to patients and clinicians. Clinicians endorsed that food access should be restricted outside meal times, in contrast to patients and carers. DISCUSSION: The findings indicate areas of consensus in admission criteria, and that families should be involved in treatment, family involvement in treatment, while there was disagreement across groups on topics including weight goals and nutrition management. Perspectives from patients, carers, and clinicians may be useful to consider during future revisions of best practice guidelines.

A randomized controlled trial of unguided internet cognitive-behavioral treatment for perfectionism in individuals who engage in regular exercise.

OBJECTIVE: Clinical perfectionism has been found to be a risk and maintaining factor in eating disorders (EDs), compulsive exercise, and athlete burnout. This study investigated whether an unguided internet cognitive-behavioral treatment (ICBT) for perfectionism would reduce ED pathology, compulsive exercise, and burnout in individuals who engage in regular exercise. METHOD: Participants were randomly allocated to intervention (n = 38) or waitlist control (n =29). A generalized linear mixed model (GLMM) analysis was conducted pre and post treatment. A follow-up analysis was conducted with the intervention group at 3 and 6 months. RESULTS: The intervention group experienced a significant reduction in perfectionism (FMPS-CM: F[1,117] = 17.53, p = < .001, Cohen's d = .82), ED symptomology (EDE-Q: F[1,55] = 7.27, p = .009,Cohen's d = .53) and compulsive exercise (CET: F[1,116] = 10.33, p < .001,Cohen's d = .63). The changes attained post-treatment were maintained within the intervention group at 3-month (FMPS-CM (t[1,100] = 3.67, p < . 001, Cohen's d = .85) (EDE-Q (t[1,50] = 2.20, p = .03, Cohen's d = 1.26) and 6-month follow-up (FMPS (t[1,100] = 2.74, p = 007, Cohen's d = .70) (EDE-Q (t[1,50] = 2.18, p = .03, Cohen's d = 1.26). DISCUSSION: The results indicate unguided ICBT for perfectionism can have a significant impact on perfectionism, compulsive exercise, and ED symptomatology.

A Pilot Investigation of Cognitive Behavioural Therapy for Clinical Perfectionism in Obsessive Compulsive Disorder.

BACKGROUND: Perfectionism is strongly associated with obsessive compulsive disorder (OCD). Cognitive behavioural therapy for perfectionism (CBT-P) has been found to result in reductions in a range of symptoms in individuals with anxiety disorders, depression and eating disorders. AIM: To pilot-test the efficacy of group CBT for perfectionism in participants with OCD and elevated perfectionism. METHOD: Participants were randomized to receive immediate 8-week group CBT-P (n = 4) or an 8-week waitlist followed by CBT-P (n = 7). RESULTS: Reliable reductions and a large effect size indicated that CBT-P was associated with improvements in perfectionism and OCD severity at post-test. However, these changes were not clinically significant and drop-out was high, resulting in a small final sample. CONCLUSIONS: CBT-P may be effective in reducing perfectionism and disorder-specific OCD symptoms. However, the high drop-out rate and lack of clinically significant findings suggest that further research needs to be conducted to determine the efficacy of CBT for perfectionism in OCD.

The Relationship between Obsessive Compulsive Personality and Obsessive Compulsive Disorder Treatment Outcomes: Predictive Utility and Clinically Significant Change.

BACKGROUND: The evidence regarding whether co-morbid obsessive compulsive personality disorder (OCPD) is associated with treatment outcomes in obsessive compulsive disorder (OCD) is mixed, with some research indicating that OCPD is associated with poorer response, and some showing that it is associated with improved response. AIMS: We sought to explore the role of OCPD diagnosis and the personality domain of conscientiousness on treatment outcomes for exposure and response prevention for OCD. METHOD: The impact of co-morbid OCPD and conscientiousness on treatment outcomes was examined in a clinical sample of 46 participants with OCD. RESULTS: OCPD diagnosis and scores on conscientiousness were not associated with poorer post-treatment OCD severity, as indexed by Yale-Brown Obsessive Compulsive Scale (YBOCS) scores, although the relative sample size of OCPD was small and thus generalizability is limited. CONCLUSION: This study found no evidence that OCPD or conscientiousness were associated with treatment outcomes for OCD. Further research with larger clinical samples is required.

Eating disorder examination: Factor structure and norms in a clinical female pediatric eating disorder sample.

OBJECTIVE: The factor structure of the eating disorder examination (EDE) has never been tested in a clinical pediatric sample, and no normative data exist. METHOD: The factor structure of an adapted EDE was examined in a clinical sample of 665 females aged 9-17 years with anorexia nervosa spectrum (70%), bulimia nervosa spectrum (12%), purging disorder (3%), and unspecified feeding and eating disorders (15%). RESULTS: The original four-factor model was a good fit in a confirmatory factor analysis as well a higher order model with three dimensions of restraint, eating concern, and combined weight concern/shape concern. Normative data are reported for clinicians to identify the percentiles in which their patients' score. DISCUSSION: The findings support dimensions of restraint, eating concern, weight concern, and shape concern in a clinical pediatric sample. This supports the factorial validity of the EDE, and the norms may assist clinicians to evaluate symptoms in females under 18 years.

A Preliminary Investigation into Worry about Mental Health: Development of the Mental Health Anxiety Inventory.

BACKGROUND: Worry about physical health is broadly referred to as health anxiety and can range from mild concern to severe or persistent anxiety such as that found in DSM-IV hypochondriasis. While much is known about anxiety regarding physical health, little is known about anxiety regarding mental health. However, recent conceptualizations of health anxiety propose that individuals can experience severe and problematic worry about mental health in similar ways to how people experience extreme worry about physical health. AIMS: Given the paucity of research in this area, the aim of the current study was to explore anxiety regarding mental health through validation of the Mental Health Anxiety Inventory (MHAI), a modified version of the Short Health Anxiety Inventory. METHOD: The MHAI, and measures of state anxiety (Depression, Anxiety and Stress Scales-21), trait worry (Penn State Worry Questionnaire), and health anxiety (Short Health Anxiety Inventory) were administered to 104 adult volunteers from the general community. RESULTS: The MHAI demonstrated high internal consistency, acceptable test-retest reliability, and good construct validity when correlated with other measures of anxiety. Results also indicated that participants worried about their mental health and physical health equally, and that almost 9% of participants reported levels of mental health anxiety that were potentially problematic. CONCLUSION: Preliminary results suggest that a small proportion of adults in the community may experience high levels of mental health anxiety requiring treatment, and that the MHAI, if validated further, could be a useful tool for assessing this form of anxiety.

What parents want to know about the storage and use of residual newborn bloodspots.

Many state newborn screening programs retain residual newborn screening bloodspots for a variety of purposes including quality assurance, biomedical research, and forensic applications. This project was designed to determine the information that prospective parents want to know about this practice. Eleven focus groups were conducted in four states. Pregnant women and their partners and parents of young children (N = 128) were recruited from the general public. Focus group participants viewed two educational movies on newborn screening and DBS retention and use. Transcripts were analyzed with qualitative methods and the results were synthesized to identify key information items. We identified 14 categories of information from the focus groups that were synthesized into seven items prospective parents want to know about residual DBS. The items included details about storage, potential uses, risks and burdens, safeguards, anonymity, return of results, and parental choice. For those state programs that retain residual dried bloodspots, inclusion of the seven things parents want to know about residual dried bloodspots in educational materials may improve parental understanding, trust, and acceptance of the retention and use of stored bloodspots.

Can corrective information reduce negative appraisals of intrusive thoughts in a community sample?

BACKGROUND: Improving mental health literacy in the general population is important as it is associated with early detection and treatment-seeking for mental health problems. Target areas for mental health literacy programs should be guided by research that tests the impact of improving knowledge of psychological constructs associated with the development of mental health problems. AIMS: This study investigated the impact of providing corrective information about the nature of intrusive thoughts on their subsequent appraisal in a community sample. METHOD: In an online, experimental design, 148 community participants completed measures of obsessive-compulsive symptoms and appraisals (Obsessive Compulsive Inventory-Revised [OCI-R]; Intrusions Inventory [III]). Individuals were instructed to read either a brief informational text about the nature of intrusive thoughts or a control text. All participants then completed post-test measurements of appraisals. Intervention effectiveness was analysed using hierarchical multiple regression. RESULTS: Individuals in the intervention group reported significantly lower levels of maladaptive appraisals than those in the control group (α = .05). CONCLUSIONS: The results of this study support the efficacy of provision of brief written information in reducing negative appraisals of intrusive thoughts in a community sample. It suggests a possible role for education about intrusive thoughts as a prevention strategy for obsessive-compulsive disorder.

Improving Exposure Therapy: Rationale and Design of an International Consortium.

The Exposure Therapy Consortium (ETC) was established to advance the science and practice of exposure therapy. To encourage participation from researchers and clinicians, this article describes the organizational structure and activities of the ETC. Initial research working group experiences and a proof-of-principle study underscore the potential of team science and larger-scale collaborative research in this area. Clinical working groups have begun to identify opportunities to enhance access to helpful resources for implementing exposure therapy effectively. This article discusses directions for expanding the consortium's activities and its impact on a global scale.

Public attitudes regarding a pilot study of newborn screening for spinal muscular atrophy.

A population-based pilot study of newborns screening for a rare genetic condition, spinal muscular atrophy (SMA), is being conducted with funding from the National Institutes of Health. The first component of the study is to assess the ethical, legal, and social implications of population-based pilot studies with a focus on public engagement and parental decision-making for the proposed opt-out approach in this research. We conducted focus groups with members of the general public to ascertain attitudes about the pilot study and acceptability of an opt-out approach in two states, Colorado and Utah, where the pilot screening is being proposed (N = 70). We developed an informational video for the project and showed it to the groups prior to the discussion in order to inform participants about population-based research, newborn screening (NBS), permission/consent models, and SMA. Results indicated support for the conduct of pilot studies that is consistent with the current standard of practice for similar population-based programs. There was support for an opt-out approach for parental decision-making; however there was limited parental knowledge about population-based research, NBS and SMA. In general, our participants considered this pilot study to be low risk and of potential benefit to infants and families. The majority of participants were supportive of an opt-out approach with information delivered through various avenues

Neuronal expression of ndst3 in early zebrafish development is responsive to Wnt signaling manipulation.

Heparan sulfate proteoglycans (HSPGs) are constituents of the cell surface and extracellular matrix and are vital for various activities within the cell. The N-deacetylase/N-sulfotransferase (heparin glucosaminyl) family of enzymes, or NDST, modifies heparan sulfate (HS) by catalyzing both the N-deacetylation and the N-sulfation of N-acetylglucosamine residues. In zebrafish, a single ndst3 gene is an orthologue of both mammalian NDST3 and NDST4 genes. The role of ndst3 in zebrafish development has not been investigated and such study may provide insight into the role(s) of both mammalian orthologues. Here, we characterized expression of ndst3 during early development in zebrafish and found it to be predominately neuronal. We found that expression of ndst3 is sensitive to Wnt signaling manipulation, with stimulation of the Wnt pathway resulting in robust expansion of ndst3 expression domains. Finally, using CRISPR/Cas9 genome editing, we mutagenized the ndst3 gene and isolated an allele, ndst3nu20, resulting in a frameshift and premature protein truncation. We discovered Ndst3 is not essential for zebrafish survival as ndst3nu20 homozygous mutants are viable and fertile.

Runx1 is a tumor suppressor gene in the mouse gastrointestinal tract.

The Runx1 transcription factor plays an important role in tissue homeostasis through its effects on stem/progenitor cell populations and differentiation. The effect of Runx1 on epithelial differentiation of the secretory cell lineage of the colon was recently demonstrated. This study aimed to examine the role of Runx1 in tumor development in epithelial cells of the gastrointestinal tract. Conditional knockout mice that lacked Runx1 expression in epithelial cells of the GI tract were generated. These mice were crossed onto the Apc(Min) background, killed and their intestinal tumor phenotypes were compared with Apc(Min) Runx1 wild-type control mice. Apc-wild-type Runx1-mutant mice were also examined for tumor development. Colons from Runx1 knockout and wild-type mice were used for genome-wide mRNA expression analyses followed by gene-specific quantitative RT-PCR of whole colon and colon epithelium to identify Runx1 target genes. Runx1 deficiency in intestinal epithelial cells significantly enhanced tumorigenesis in Apc(Min) mice. Notably, epithelial Runx1 deficiency in Apc-wild-type mice was sufficient to cause tumor development. Absence of Runx1 was associated with global changes in the expression of genes involved in inflammation and intestinal metabolism, and with gene sets indicative of a metastatic phenotype and poor prognosis. Gene-specific analysis of Runx1-deficient colon epithelium revealed increased expression of genes linked to an expansion of the stem/progenitor cell population. These results identify Runx1 as a novel tumor suppressor gene for gastrointestinal tumors and support a role for Runx1 in maintaining the balance between the intestinal stem/progenitor cell population and epithelial differentiation of the GI tract.

Concerns of newborn blood screening advisory committee members regarding storage and use of residual newborn screening blood spots.

OBJECTIVES: We assessed attitudes and opinions of members of newborn blood screening (NBS) advisory committees regarding the storage and secondary research use of residual specimens from NBS. METHODS: We conducted focus groups in 2008 and 2009 with NBS advisory committees (4 focus groups; n = 39 participants) in the Mountain States region (i.e., AZ, CO, MT, NM, NV, TX, UT, and WY). RESULTS: Participants identified several challenges to implementing policies for storage of and research on residual newborn blood specimens. Themes that emerged from the data were public health relevancy; improvement of parental knowledge; impact of enhanced parental involvement; concerns over ownership, privacy, and confidentiality; identification of secondary research uses; and role of advisory committees. CONCLUSIONS: Participants indicated that secondary uses of residual specimens entailed opportunities for improvements in NBS programs but also carried significant risks for their programs. Addressing concerns from stakeholders will be necessary for state-level adoption of national recommendations.

Exploring the use of a Comic for Education about Expanded Carrier Screening among a Diverse Group of Mothers.

Purpose: Expanded carrier screening (ECS) during prenatal care is an important test for identifying prospective parents' risk of inherited genetic diseases. However, barriers remain for effectively educating patients about ECS. Graphic medicine (i.e. comics) has grown as a mechanism for patient education. The purpose of this study was to explore attitudes and opinions of a comic to educate about ECS during prental care. Methods: Focus groups were conducted with pregnant women or women who recently gave birth (6 groups, n=54). The participants were all female, 44.4% Latino/Hispanic, 16.7% Bi-Racial/Other, and 43.3% reporting some college education or high school degree. Results: Most participants reported high enjoyment with the comic due to their relatability to the characters, simplicity of the story, description of medical outcomes in everyday terms and the exploration of multiple outcomes possible with ECS. In addition, participants reported that during pregnancy their reading habits increase as well as emotional reactions to the content and some participants stated they avoided reading information that may cause stress or anxiety. Conclusion: More research is needed to assess what features of the comic promote understanding and how that influences decisions and pre-test patient education for ECS. The use of graphic narratives may enable individuals to better understand medical information in general.

The upper respiratory tract microbiome of indigenous Orang Asli in north-eastern Peninsular Malaysia.

Much microbiome research has focused on populations that are predominantly of European descent, and from narrow demographics that do not capture the socio-economic and lifestyle differences which impact human health. Here we examined the airway microbiomes of the Orang Asli, the indigenous peoples of Malaysia. A total of 130 participants were recruited from two sites in the north-eastern state of Terengganu in Peninsular Malaysia. Using 16S rRNA sequencing, the nasal microbiome was significantly more diverse in those aged 5-17 years compared to 50+ years (p = 0.023) and clustered by age (PERMANOVA analysis of the Bray-Curtis distance, p = 0.001). Hierarchical clustering of Bray-Curtis dissimilarity scores revealed six microbiome clusters. The largest cluster (n = 28; 35.4%) had a marked abundance of Corynebacterium. In the oral microbiomes Streptococcus, Neisseria and Haemophilus were dominant. Using conventional microbiology, high levels of Staphylococcus aureus carriage were observed, particularly in the 18-65 age group (n = 17/36; 47.2% 95% CI: 30.9-63.5). The highest carriage of pneumococci was in the <5 and 5 to 17 year olds, with 57.1% (4/7) and 49.2% (30/61), respectively. Sixteen pneumococcal serotypes were identified, the most common being the nonvaccine-type 23A (14.6%) and the vaccine-type 6B (9.8%). The prevalence of pneumococcal serotypes covered by pneumococcal conjugate vaccines support introduction into a Malaysian national immunisation schedule. In addition, the dominance of Corynebacterium in the airway microbiomes is intriguing given their role as a potentially protective commensal with respect to acute infection and respiratory health.