Towards Preclinical Validation of Arbaclofen (R-baclofen) Treatment for 16p11.2 Deletion Syndrome.

A microdeletion on human chromosome 16p11.2 is one of the most common copy number variants associated with autism spectrum disorder and other neurodevelopmental disabilities. Arbaclofen, a GABA(B) receptor agonist, is a component of racemic baclofen, which is FDA-approved for treating spasticity, and has been shown to alleviate behavioral phenotypes, including recognition memory deficits, in animal models of 16p11.2 deletion. Given the lack of reproducibility sometimes observed in mouse behavioral studies, we brought together a consortium of four laboratories to study the effects of arbaclofen on behavior in three different mouse lines with deletions in the mouse region syntenic to human 16p11.2 to test the robustness of these findings. Arbaclofen rescued cognitive deficits seen in two 16p11.2 deletion mouse lines in traditional recognition memory paradigms. Using an unsupervised machine-learning approach to analyze behavior, one lab found that arbaclofen also rescued differences in exploratory behavior in the open field in 16p11.2 deletion mice. Arbaclofen was not sedating and had modest off-target behavioral effects at the doses tested. Our studies show that arbaclofen consistently rescues behavioral phenotypes in 16p11.2 deletion mice, providing support for clinical trials of arbaclofen in humans with this deletion.

Staff Experience in the NHS: A National Study-An Experience-Based Design Approach.

Introduction: A positive patient experience is a key component of good quality of care. Post-pandemic healthcare systems face the challenge of addressing burnout among healthcare staff, who are directly involved in the delivery of healthcare, which has implications for the patient experience. There is an established association between staff and patient experience; exploring the experience of staff may give insights into factors that negatively impact the patient experience. Experience-based design (EBD) is a quality improvement approach that uses the experience of service users to derive improvements. The purpose of this study is to design, validate, and test an EBD tool that may be used to capture the staff experience. Methods: A focus group of clinical and nonclinical staff (identified through the NHS Elect networks) and the development team coproduced an EBD survey based on nine "touch-points" of a typical working day. Once the survey questionnaire was tested and agreed with it was distributed to 1300 members of NHS networks. Results: A total of 377 NHS staff responded to the questionnaire. Analysis revealed effective teamwork had a positive psychological impact on staff. However, increased workload, missed meal breaks, and an increased administrative/IT burden were associated with the greatest negative responses by clinical and nonclinical staff. Conclusion: Overall, factors impacting staff well-being are multifaceted and varied between trusts. However, leaders in healthcare can use EBD to identify targeted improvements for the day-to-day experiences of staff.

Analysis of the Experience-Based Design Feedback Data on a National Scale.

The United Kingdom Office of National Statistics population estimates that 10 million people are aged 65 years and older, of which some would be considered frail. This is conceptualized as a complex progressive loss of physiological and social function. In order to establish and evaluate appropriate services, feedback tools designed for this patient group have begun to take greater importance, which the Acute Frailty Network has been developing using experience-based design. These tools focus on the experience of frail patients in the settings of accident and emergency and the acute medical unit. An analysis of data from 12 hospitals was used to look at the common emotions and comments expressed at the key touchpoints. A total of 609 respondents were used in the analysis, revealing that patients expressed mostly positive experiences. The areas with the most negative emotions and comments were in the domains "being admitted," "first assessment," and "preparing to leave hospital." We would recommend that future quality improvement projects focus in improving the communication standards around the admission and discharge process.

Comprehensive Analysis of the 16p11.2 Deletion and Null Cntnap2 Mouse Models of Autism Spectrum Disorder.

Autism spectrum disorder comprises several neurodevelopmental conditions presenting symptoms in social communication and restricted, repetitive behaviors. A major roadblock for drug development for autism is the lack of robust behavioral signatures predictive of clinical efficacy. To address this issue, we further characterized, in a uniform and rigorous way, mouse models of autism that are of interest because of their construct validity and wide availability to the scientific community. We implemented a broad behavioral battery that included but was not restricted to core autism domains, with the goal of identifying robust, reliable phenotypes amenable for further testing. Here we describe comprehensive findings from two known mouse models of autism, obtained at different developmental stages, using a systematic behavioral test battery combining standard tests as well as novel, quantitative, computer-vision based systems. The first mouse model recapitulates a deletion in human chromosome 16p11.2, found in 1% of individuals with autism. The second mouse model harbors homozygous null mutations in Cntnap2, associated with autism and Pitt-Hopkins-like syndrome. Consistent with previous results, 16p11.2 heterozygous null mice, also known as Del(7Slx1b-Sept1)4Aam weighed less than wild type littermates displayed hyperactivity and no social deficits. Cntnap2 homozygous null mice were also hyperactive, froze less during testing, showed a mild gait phenotype and deficits in the three-chamber social preference test, although less robust than previously published. In the open field test with exposure to urine of an estrous female, however, the Cntnap2 null mice showed reduced vocalizations. In addition, Cntnap2 null mice performed slightly better in a cognitive procedural learning test. Although finding and replicating robust behavioral phenotypes in animal models is a challenging task, such functional readouts remain important in the development of therapeutics and we anticipate both our positive and negative findings will be utilized as a resource for the broader scientific community.