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One core component of the Paediatric Autism Communication Therapy–Generalised involves supporting parents to change their interaction and communication style with their child. This behaviour change has been found to affect child outcomes. Implementation science methodologies offer a range of opportunities to investigate how interventions are delivered in practice; however, few autism intervention studies have used such designs to explore the behaviour change of parents. We interviewed 27 parents and explored their use of intervention strategies after the Paediatric Autism Communication Therapy–Generalised trial. We employed the Theoretical Domains Framework and Consolidated Framework for Implementation Research to systematically explore a range of barriers and facilitators experienced by the parents associated with parents’ characteristics, their context and features of the intervention. Our analysis revealed barriers and facilitators across three themes: Motivating Factors, which was further subdivided into Compatibility and Buy-In and Alignment of Goals and Outcomes; Opportunity and Support; Parent Characteristics. Almost all parents reported continued use of the Paediatric Autism Communication Therapy–Generalised strategies. Facilitators (e.g. parental confidence in using the strategies) and barriers (e.g. child’s behaviour) were identified. Consideration of these factors can inform identification of implementation strategies to test in future studies of Paediatric Autism Communication Therapy–Generalised and other parent-mediated early autism interventions. Lay abstract Many early autism interventions teach parents therapeutic strategies to help them adjust their communication style with their children. Research has shown that this behaviour change in parents leads to improvements in child communication. It is, therefore, important to learn what factors support or hinder parents in their use of therapeutic strategies learned in such interventions. This study set out to interview parents who had participated in a research trial of the Paediatric Autism Communication Therapy–Generalised intervention. We interviewed 27 caregivers and explored their use of the strategies up to 2 years after the end of the research trial. Qualitative frameworks were used to inform interview questions and data analysis. These frameworks focused on a range of contextual factors, including parents’ characteristics, their context and features of the intervention. Parents reported barriers and facilitators to using Paediatric Autism Communication Therapy–Generalised strategies across three themes: Motivating Factors; Opportunity and Support; Parent Characteristics. One of these themes, Motivating Factors, was further divided into the subthemes Compatibility and Buy-In and Alignment of Goals and Outcomes. Almost all parents reported continued use of the Paediatric Autism Communication Therapy–Generalised strategies. Facilitators included parental confidence in using the strategies and barriers included child’s behaviour. Consideration of these factors can inform ways to better support parents in future autism interventions.

West Nile virus (WNV) is an arbovirus transmitted by mosquitos of the genusWNV is widespread, including North America and Europe, where its range has expanded in the past decade. Rising temperatures in temperate regions are predicted to lead to an increased abundance ofThe prediction of WNV risk is challenging due to the complex interactions of vector, pathogen, host, and environment. Travelers planning to visit endemic areas should be advised regarding WNV risk and mosquito bite prevention. Evaluation of ill travelers with compatible symptoms should consider the diagnosis of WNV for those visiting in endemic areas as well as for those returning from destinations with known WNV circulation.

Chromosomal microarray (CMA) is now widely used as first-tier testing for the detection of copy number variants (CNVs) and absence of heterozygosity (AOH) in patients with multiple congenital anomalies (MCA), autism spectrum disorder (ASD), developmental delay (DD), and/or intellectual disability (ID). Chromosome analysis is commonly used to complement CMA in the detection of balanced genomic aberrations. However, the cost-effectiveness and the impact on clinical management of chromosome analysis concomitant with CMA were not well studied, and there is no consensus on how to best utilize these two tests. To assess the clinical utility and cost-effectiveness of chromosome analysis concomitant with CMA in patients with MCA, ASD, DD, and/or ID, we retrospectively analyzed 3,360 postnatal cases for which CMA and concomitant chromosome analysis were performed in the Colorado Genetic Laboratory (CGL) at the University Of Colorado School Of Medicine. Chromosome analysis alone yielded a genetic diagnosis in two patients (0.06%) and contributed additional information to CMA results in 199 (5.92%) cases. The impact of abnormal chromosome results on patient management was primarily related to counseling for reproductive and recurrence risks assessment (101 cases, 3.01%) while a few (5 cases, 0.15%) led to changes in laboratory testing and specialist referral (25 cases, 0.74%). The incremental cost-effectiveness ratio (ICER) of combined testing demonstrated the cost of each informative chromosome finding was significantly higher for patients with clinically insignificant (CI) CMA findings versus clinically significant (CS) CMA results. Our results suggest that a stepwise approach with CMA testing with reflex to chromosome analysis on cases with CS CMA findings is a more cost-effective testing algorithm for patients with MCA, ASD, and/or DD/ID.

A promising development in hormonal male contraception (HMC) is a class of bifunctional prodrugs that combine both androgenic and progestogenic activities into a single molecule. Examples of these prodrugs currently being studied are dimethandrolone undecanoate (DMAU) and 11β-methyl-19-nortestosterone-17β-dodecylcarbonate (11β-MNTDC) (1, 2). The inactive prodrugs are cleaved to release active drug over a 24-hour timeframe, providing once-a-day dosing. As potent androgens, these steroids suppress gonadotropin secretion, leading to markedly decreased serum testosterone production and circulating levels. Low testosterone levels might lead to unpleasant symptoms of hypogonadism if DMAU and 11β-MNTDC are not providing sufficient and effective androgenicity. Therefore, we examined the impact of the novel progestogenic androgens on serum testosterone levels and acceptability of varying dosages of these oral prodrugs in a secondary analysis of two Phase 1 placebo-controlled trials. Healthy male participants were randomized to take two or four oral pills of active drug or placebo per day. As DMAU and 11β-MNTDC share similar mechanisms of action and tolerability, we examined the association of dosage as well as testosterone concentrations on combined drug acceptability versus placebo. Survey respondents across the two trials (39 DMAU, 30 11β-MNTDC, 28 combined placebo group) shared similar baseline demographics. After seven days of usage, testosterone levels for those using either prodrug dropped to levels below 100 ng/dL while testosterone levels for those using the placebo (400-600 ng/dL) remained within the reference. Recipients of either DMAU or 11β-MNTDC reported greater willingness to use the active prodrug in the future (75%), compared to placebo recipients (46.4%, p=0. 007). Throughout the 28-day oral pill usage, while average testosterone levels during the period of suppression (day 7 to 28) were very low, they were significantly higher in the 200 mg group than in the 400 mg group (92.7 ng/dL vs. 49.6 ng/dL, p-value (1) Thirumalai et al. J Clin Endocrinol Metab. 2019; 104: 423-32. (2) Yuen et al. J Clin Endocrinol Metab. 2020;105. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

ObjectiveTo evaluate a new tool to aid interpretation of copy number variants (CNVs) in individuals with neurodevelopmental disabilities.MethodsCritical exon indexing (CEI) was used to identify genes with critical exons (CEGs) from clinically reported CNVs, which may contribute to neurodevelopmental disorders (NDDs). The 742 pathogenic CNVs and 1,363 variants of unknown significance (VUS) identified by chromosomal microarray analysis in 5,487 individuals with NDDs were subjected to CEI to identify CEGs. CEGs identified in a subsequent random series of VUS were evaluated for relevance to CNV interpretation.ResultsCEI identified a total of 2,492 unique CEGs in pathogenic CNVs and 953 in VUS compared with 259 CEGs in 6,965 CNVs from 873 controls. These differences are highly significant (p < 0.00001) whether compared as frequency, average, or normalized by CNV size. Twenty-one percent of VUS CEGs were not represented in Online Mendelian Inheritance in Man, highlighting limitations of existing resources for identifying potentially impactful genes within CNVs. CEGs were highly correlated with other indices and known pathways of relevance. Separately, 136 random VUS reports were reevaluated, and 76% of CEGs had not been commented on. In multiple cases, further investigation yielded additional relevant literature aiding interpretation. As one specific example, we discuss GTF2I as a CEG, which likely alters interpretation of several reported duplication VUS in the Williams-Beuren region.ConclusionsApplication of CEI to CNVs in individuals with NDDs can identify genes of potential clinical relevance, aid laboratories in effectively searching the clinical literature, and support the clinical reporting of poorly annotated VUS.

Copy number variants (CNVs) as detected by chromosomal microarray analysis (CMA) significantly contribute to the etiology of neurodevelopmental disorders, such as developmental delay (DD), intellectual disability (ID), and autism spectrum disorder (ASD). This study summarizes the results of 3.5 years of CMA testing by a CLIA-certified clinical testing laboratory 5487 patients with neurodevelopmental conditions were clinically evaluated for rare copy number variants using a 2.8-million probe custom CMA optimized for the detection of CNVs associated with neurodevelopmental disorders. We report an overall detection rate of 29.4% in our neurodevelopmental cohort, which rises to nearly 33% when cases with DD/ID and/or MCA only are considered. The detection rate for the ASD cohort is also significant, at 25%. Additionally, we find that detection rate and pathogenic yield of CMA vary significantly depending on the primary indications for testing, the age of the individuals tested, and the specialty of the ordering doctor. We also report a significant difference between the detection rate on the ultrahigh resolution optimized array in comparison to the array from which it originated. This increase in detection can significantly contribute to the efficient and effective medical management of neurodevelopmental conditions in the clinic.

From the construction of pipelines to a lack of an EU energy policy to the development of alternative energy sources, EU member states have had a difficult time judging where they stand on Russian natural gas, which has raised many issues over energy security and interdependency. Therefore, the main question of this thesis is to determine to what extent EU member states are dependent on Russia for their natural gas resources. Using the countries of the Weimar Triangle (France, Germany, and Poland) as a case study, I look at the varying relationships between these three actors and Russia as well as their distinct energy make-up. And by analyzing additional energy sources, I conclude that while member states altogether are not heavily dependent on Russian natural gas, it is necessary to consider the gas dependency of individual member states as well as that of Russia.

Interstitial deletions of chromosome band 10q22 are rare. We report on the characterization of three overlapping de novo 10q22 deletions by high-resolution array comparative genomic hybridization in three unrelated patients. Patient 1 had a 7.9 Mb deletion in 10q21.3-q22.2 and suffered from severe feeding problems, facial dysmorphisms and profound mental retardation. Patients 2 and 3 had nearly identical deletions of 3.2 and 3.6 Mb, the proximal breakpoints of which were located at an identical low-copy repeat. Both patients were mentally retarded; patient 3 also suffered from growth retardation and hypotonia. We also report on the results of breakpoint analysis by array painting in a mentally retarded patient with a balanced chromosome translocation 46,XY,t(10;13)(q22;p13)dn. The breakpoint in 10q22 was found to disrupt C10orf11, a brain-expressed gene in the common deleted interval of patients 1-3. This finding suggests that haploinsufficiency of C10orf11 contributes to the cognitive defects in 10q22 deletion patients.

Supported employment (SE) is considered an “evidence-based” practice for people with serious mental illness. We examined inpatient hospitalizations and emergency service visits among clients in a SE program based on the Individual Placement and Support (IPS) model in comparison to a propensity score matched group of clients who did not participate in IPS. A significant interaction showed that only IPS/SE clients who were also high in regular mental health services had fewer hospitalizations and emergency service visits than matched controls. The interaction effect was moderate, even when we controlled for client functioning. These findings provide support for the integration of mental health and vocational rehabilitation services, a key feature of evidence-based SE services.

While randomized clinical trials (RCTs) have helped to establish Individual Placement and Support (IPS) programs as an evidence-based practice, it is important to evaluate whether "real world" IPS programs can be implemented with fidelity and achieve outcomes comparable to programs evaluated in RCTs. The current evaluation examined retrospectively employment outcomes for go participants from an IPS-model Services for Employment and Education (SEE) program in Massachusetts over a 4.5-year period. Evaluators accessed demographic, functioning, and employment data from three sources--SEE program records/database, clinical records, and the Massachusetts Department of Mental Health Client Tracking system. Results indicate that the SEE program maintained high IPS fidelity and achieved employment outcomes comparable or superior to other SE and IPS model programs described in the literature.

A Stela of Adad-nirari III was found during the eventful season of Spring 1967 at Tell al Rimah. It stood in position inside the cella of a Late Assyrian shrine, set beside the podium, a placing that is unparalleled among the find spots of other royal stelae. It was inscribed on the face with twenty-one lines, of which nine had been deliberately erased in antiquity; the writing ran across the skirt of the king, who was sculptured upon it slightly less than life-size, but not over the frame or sides of the stone (see Plate XXXVIII). The stela is 1·30 m. high and measures 0·69 m. in width at the base; it is parabolic in shape. It is made from a single slab of hard grey, crystalline “Mosul marble”, in an excellent state of preservation. No traces of paint were visible on the surface as it was unearthed.