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Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by an expanded CAG repeat in huntingtin (HTT). Given an important role for HTT in development and significant neurodegeneration at the time of clinical manifestation in HD, early treatment of allele-specific drugs represents a promising strategy. The feasibility of an allele-specific antisense oligonucleotide (ASO) targeting single-nucleotide polymorphisms (SNPs) has been demonstrated in models of HD. Here, we constructed a map of haplotype-specific insertion-deletion variations (indels) to develop alternative mutant-HTT-specific strategies. We mapped indels annotated in the 1000 Genomes Project data on common HTT haplotypes, revealing candidate indels for mutant-specific HTT targeting. Subsequent sequencing of an HD family confirmed candidate sites and revealed additional allele-specific indels. Interestingly, the most common normal HTT haplotype carries indels of big allele length differences at many sites, further uncovering promising haplotype-specific targets. When patient-derived cells carrying the most common HTT diplotype were treated with ASOs targeting the mutant alleles of candidate indels (rs772629195 or rs72239206), complete mutant specificity was observed. In summary, our map of haplotype-specific indels permits the identification of allele-specific targets in HD subjects, potentially contributing to the development of safe HTT-lowering therapeutics that are suitable for early treatment in HD.

Dominant gain-of-function mechanisms in Huntington’s disease (HD) suggest that selective silencing of mutant HTT produces robust therapeutic benefits. Here, capitalizing on exonic protospacer adjacent motif–altering (PAM-altering) SNP (PAS), we developed an allele-specific CRISPR/Cas9 strategy to permanently inactivate mutant HTT through nonsense-mediated decay (NMD). Comprehensive sequence/haplotype analysis identified SNP-generated NGG PAM sites on exons of common HTT haplotypes in HD subjects, revealing a clinically relevant PAS-based mutant-specific CRISPR/Cas9 strategy. Alternative allele of rs363099 (29th exon) eliminates the NGG PAM site on the most frequent normal HTT haplotype in HD, permitting mutant-specific CRISPR/Cas9 therapeutics in a predicted ~20% of HD subjects with European ancestry. Our rs363099-based CRISPR/Cas9 showed perfect allele specificity and good targeting efficiencies in patient-derived cells. Dramatically reduced mutant HTT mRNA and complete loss of mutant protein suggest that our allele-specific CRISPR/Cas9 strategy inactivates mutant HTT through NMD. In addition, GUIDE-Seq analysis and subsequent validation experiments support high levels of on-target gene specificity. Our data demonstrate a significant target population, complete mutant specificity, decent targeting efficiency in patient-derived cells, and minimal off-target effects on protein-coding genes, proving the concept of PAS-based allele-specific NMD-CRISPR/Cas9 and supporting its therapeutic potential in HD.

Joanna H Cox,1 Ananda Nahar,2 Cristiano Termine,3 Massimo Agosti,4,5 Umberto Balottin,6,7 Stefano Seri,8 Andrea E Cavanna8–101Sandwell and West Birmingham NHS Foundation Trust, Birmingham, UK; 2University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; 3Child Neuropsychiatry Unit, Department of Medicine and Surgery, University of Insubria, Varese, Italy; 4Neonatology Unit, Department of Maternal and Child Health, Del Ponte Hospital, Varese, Italy; 5Paediatric Unit, Department of Medicine and Surgery, University of Insubria, Varese, Italy; 6Child Neuropsychiatry Unit, IRCCS Mondino Foundation, Pavia, Italy; 7Child Neuropsychiatry Unit, Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy; 8School of Life and Health Sciences, Aston Brain Centre, Aston University, Birmingham, UK; 9Department of Neuropsychiatry, Birmingham and Solihull Mental Health NHS Foundation Trust (BSMHFT) and University of Birmingham, Birmingham, UK; 10Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology and University College London, London, UKAbstract: Tourette syndrome (TS) is a complex neurodevelopmental disorder characterized by multiple motor and vocal tics, which commonly presents with multiple behavioral problems, including co-morbid attention-deficit and hyperactivity disorder and obsessive-compulsive disorder. Both tics and co-morbid conditions have been shown to potentially affect patients’ health-related quality of life. While TS typically presents in childhood, its manifestations peak in severity during adolescence, a critical period in which affected individuals are exposed to potential stigma from peers. Physical and behavioral manifestations can also contribute to stigma, which subsequently leads to poorer health outcomes, discrimination, and a reduced willingness to seek help. The available evidence suggests that young patients with TS can experience reduced social acceptance from peers and difficulties establishing relationships. There is also evidence that some health care professionals share the unhelpful belief that young patients with TS should be disciplined in order to correct their disruptive behavior, based on the erroneous assumption that tics can be consciously controlled. Studies focussed on self-perception in patients with TS have yielded inconsistent results, with some studies showing problems in the domains of self-concept and self-esteem. Feelings of isolation, loneliness, and experiences of bullying have been reported more consistently. Interventions are required to reduce misconceptions about the condition and thus reduce stigma through targeted education and behavioral interventions. A multi-faceted approach that focuses on educating children, adults, and educators about TS would be beneficial to help alleviate stigma. This can be combined with self-advocacy and tailored psychological therapies for young patients with TS. The present paper reviews the current literature on stigma and self-perception in adolescents with TS in order to inform clinical decisions about management strategies and possible interventions to improve health-related quality of life.Keywords: tourette syndrome, tics, stigma, self-perception, adolescents

Joanna H Cox,1 Stefano Seri,2,3 Andrea E Cavanna,2,4,5 1Heart of England NHS Foundation Trust, 2School of Life and Health Sciences, Aston Brain Centre, Aston University, 3Children’s Epilepsy Surgery Programme, The Birmingham Children’s Hospital NHS Foundation Trust, 4Department of Neuropsychiatry, Birmingham and Solihull Mental Health NHS Foundation Trust, Birmingham, 5Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology and UCL, London, UK Abstract: Tourette syndrome is a childhood-onset chronic tic disorder characterized by multiple motor and vocal tics and often accompanied by specific behavioral symptoms ranging from obsessionality to impulsivity. A considerable proportion of patients report significant impairment in health-related quality of life caused by the severity of their tics and behavioral symptoms and require medical intervention. The most commonly used medications are antidopaminergic agents, which have been consistently shown to be effective for tic control, but are also associated with poor tolerability because of their adverse effects. The newer antipsychotic medication aripiprazole is characterized by a unique mechanism of action (D2 partial agonism), and over the last decade has increasingly been used for the treatment of tics. We conducted a systematic literature review to assess the available evidence on the efficacy and safety of aripiprazole in pediatric patients with Tourette syndrome and other chronic tic disorders (age range: 4–18 years). Our search identified two randomized controlled trials (involving 60 and 61 participants) and ten open-label studies (involving between six and 81 participants). The majority of these studies used two validated clinician-rated instruments (Yale Global Tic Severity Scale and Clinical Global Impression scale) as primary outcome measures. The combined results from randomized controlled trials and open-label studies showed that aripiprazole is an effective, safe, and well-tolerated medication for the treatment of tics. Aripiprazole-related adverse effects (nausea, sedation, and weight gain) were less frequent compared to other antidopaminergic medications used for tic management and, when present, were mostly transient and mild. The reviewed studies were conducted on small samples and had relatively short follow-up periods, thus highlighting a need for further trials to assess the long-term use of aripiprazole in pediatric patients with Tourette syndrome and other chronic tic disorders with measurement of its efficacy using both clinician-rated and self-report scales. Keywords: Tourette syndrome, tics, aripiprazole, efficacy, tolerability

Andrea E Cavanna,1–3 Stefano Seri3,4 1Department of Neuropsychiatry, Birmingham and Solihull Mental Health NHS Foundation Trust and University of Birmingham, Birmingham, 2Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, 3School of Life and Health Sciences, Aston Brain Centre, Wellcome Trust Laboratory for MEG Studies, Aston University, 4Children’s Epilepsy Surgery Programme, The Birmingham Children’s Hospital NHS Foundation Trust, Birmingham, UK Abstract: Misophonia is characterized by a negative reaction to a sound with a specific pattern and meaning to a given individual. In this paper, we review the clinical features of this relatively common yet underinvestigated condition, with focus on co-occurring neurodevelopmental disorders. Currently available data on the putative pathophysiology of the condition can inform our understanding and guide the diagnostic process and treatment approach. Tinnitus retraining therapy and cognitive behavior therapy have been proposed as the most effective treatment strategies for reducing symptoms; however, current treatment algorithms should be validated in large population studies. At the present stage, competing paradigms see misophonia as a physiological state potentially inducible in any subject, an idiopathic condition (which can present with comorbid psychiatric disorders), or a symptomatic manifestation of an underlying psychiatric disorder. Agreement on the use of standardized diagnostic criteria would be an important step forward in terms of both clinical practice and scientific inquiry. Areas for future research include phenomenology, epidemiology, modulating factors, neurophysiological underpinnings, and treatment trials. Keywords: misophonia, selective sound sensitivity syndrome, hyperacusis, neurodevelopmental disorders, Tourette syndrome, obsessive-compulsive spectrum

Joanna H Cox1 Stefano Seri2,3 Andrea E Cavanna1,2,4,51College of Medical and Dental Sciences, University of Birmingham, 2School of Life and Health Sciences, Aston Brain Centre, Aston University, 3Children’s Epilepsy Surgery Programme, The Birmingham Children’s Hospital NHS Foundation Trust, 4Department of Neuropsychiatry, Birmingham and Solihull Mental Health NHS Foundation Trust, Birmingham, UK; 5Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology and UCL, London, UK Abstract: About one third of patients with epilepsy are refractory to medical treatment. For these patients, alternative treatment options include implantable neurostimulation devices such as vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation systems (RNS). We conducted a systematic literature review to assess the available evidence on the clinical efficacy of these devices in patients with refractory epilepsy across their lifespan. VNS has the largest evidence base, and numerous randomized controlled trials and open-label studies support its use in the treatment of refractory epilepsy. It was approved by the US Food and Drug Administration in 1997 for treatment of partial seizures, but has also shown significant benefit in the treatment of generalized seizures. Results in adult populations have been more encouraging than in pediatric populations, where more studies are required. VNS is considered a safe and well-tolerated treatment, and serious side effects are rare. DBS is a well-established treatment for several movement disorders, and has a small evidence base for treatment of refractory epilepsy. Stimulation of the anterior nucleus of the thalamus has shown the most encouraging results, where significant decreases in seizure frequency were reported. Other potential targets include the centromedian thalamic nucleus, hippocampus, cerebellum, and basal ganglia structures. Preliminary results on RNS, new-generation implantable neurostimulation devices which stimulate brain structures only when epileptic activity is detected, are encouraging. Overall, implantable neurostimulation devices appear to be a safe and beneficial treatment option for patients in whom medical treatment has failed to adequately control their epilepsy. Further large-scale randomized controlled trials are required to provide a sufficient evidence base for the inclusion of DBS and RNS in clinical guidelines. Keywords: deep brain stimulation, epilepsy, implantable neurostimulation device, responsive neurostimulation, seizures, vagus nerve stimulation

BackgroundSutureless and rapid deployment aortic valve replacement (SUAVR) has become an alternative to conventional aortic valve replacement (CAVR) for aortic stenosis (AS) treatment due to its advantages in reducing surgery time and improving outcomes. This study aimed to assess the cost-utility of SUAVR vs. CAVR treatment for patients with moderate to severe AS in Thailand.MethodsA two-part constructed model was used to estimate the lifetime costs and quality-adjusted life years (QALYs) from both societal and healthcare perspectives. Data on short-term mortality, complications, cost, and utility data were obtained from the Thai population. Long-term clinical data were derived from clinical studies. Costs and QALYs were discounted annually at 3% and presented as 2022 values. The incremental cost-effectiveness ratio (ICER) was calculated to determine additional cost per QALY gained. Deterministic and probabilistic sensitivity analyses were performed.ResultsSUAVR treatment incurred higher costs compared with CAVR treatment from both societal (THB 1,733,355 [USD 147,897] vs THB 1,220,643 [USD 104,150]) and healthcare provider perspectives (THB 1,594,174 [USD 136,022] vs THB 1,065,460 [USD 90,910]). In addition, SUAVR treatment resulted in lower health outcomes, with 6.20 life-years (LYs) and 4.95 QALYs, while CAVR treatment achieved 6.29 LYs and 5.08 QALYs. SUAVR treatment was considered as a dominated treatment strategy using both perspectives. Sensitivity analyses indicated the significant impact of changes in utilities and long-term mortality on the model.ConclusionSUAVR treatment is not a cost-effective treatment strategy compared with CAVR treatment for patients with moderate-severe AS in Thailand, as it leads to higher costs and inferior health outcomes. Other important issues related to specific patients such as those with minimally invasive surgery, those undergoing AVR with concomitant procedures, and those with calcified and small aortic root should be taken into account.

Abstract To determine the prevalence, right ventricular (RV) characteristics, and outcomes of primary isolated RV failure (PI-RVF) after heart transplant (HTX). PI-RVF was defined as (1) the need for mechanical circulatory support post-transplant, or (2) evidence of RVF post-transplant as measured by right atrial pressure (RAP) > 15 mmHg, cardiac index of

The expansion of the area towards suburban areas accompanied by suburbanization has an impact on the conversion of productive agricultural land and transportation movement systems. This study aims to analyse land use change works as a determinant of environmental degradation in suburban areas, the effect of land use changes, socio-economic activities, population mobility and transportation systems on environmental quality degradation, and models for handling land use, population mobility, transportation infrastructure and system management transportation towards sustainable development of suburban areas. This study uses a sequential qualitative-quantitative approach. Data obtained through observation, survey and documentation. The results of the study show that the intensity of land use change coupled with population mobility, in addition to affecting the urban transportation system based on the pattern of origin and destination of travel, also has an impact on the environmental quality degradation of suburban areas. Changes in land use, socioeconomic activities, population mobility and transportation systems has an effect in the environmental quality degradation of suburban areas with a coefficient of determination of 95.65 percent. This study recommends the application of a land use management model, population mobility, and transportation infrastructure towards the sustainability of the suburbs of Makassar City, Indonesia.

Abstract Background Control and elimination of the liver fluke (Opisthorchis viverrini) is a primary preventive strategy against cholangiocarcinoma in Southeast Asia. A sensitive parasitological diagnostic method is required to facilitate a surveillance and control program. In this study, we evaluated the performance of Mini Parasep® SF stool concentrator kit (stool kit) compared with Kato-Katz (KK) and the quantitative formalin-ethyl acetate concentration technique (FECT) for detection of O. viverrini and co-endemic parasitic infections. Methods A cross-sectional survey for parasitic infection in residents aged > 15 years in a community in Kalasin province, Northeast Thailand, was conducted in 2018. Fecal samples were collected and screened by KK method, and a subset of samples was further examined by the stool kit and FECT methods. The results were analyzed for prevalence of parasitic infections in addition to the diagnostic performance of the methods for qualitative and quantitative detection of helminthiases. Results The initial survey of parasitic infection determined by the KK method (n = 567) showed the prevalence of O. viverrini was 32.63%, followed by Taenia 2.65%, echinostomes 1.76%, hookworms 1.41%, Trichuris trichiura 0.53% and Strongyloides stercoralis 0.53%. Within a subset of samples tested with multiple diagnostics (n = 150), the detection rates of O. viverrini by the stool kit, FECT and KK methods were 27.3%, 30.7% and 28.7%, respectively. The diagnostic sensitivity for opisthorchiasis was similar for FECT (75.5%), KK(66.0%) and the stool kit (67.3%). For other parasitic infections, FECT and stool kit methods performed better than KK, particularly in detecting minute intestinal flukes (MIF), S. stercoralis and coinfections. When measuring the intensity of O. viverrini infection (fecal egg counts), the stool kit results showed a significant positive correlation with KK and FECT (P