Molecular and cellular organization of odorant binding protein genes in Drosophila.

Chemosensation is important for the survival and reproduction of animals. The odorant binding proteins (OBPs) are thought to be involved in chemosensation together with chemosensory receptors. While OBPs were initially considered to deliver hydrophobic odorants to olfactory receptors in the aqueous lymph solution, recent studies suggest more complex roles in various organs. Here, we use GAL4 transgenes to systematically analyze the expression patterns of all 52 members of the Obp gene family and 3 related chemosensory protein genes in adult Drosophila, focusing on chemosensory organs such as the antenna, maxillary palp, pharynx, and labellum, and other organs such as the brain, ventral nerve cord, leg, wing, and intestine. The OBPs were observed to express in diverse organs and in multiple cell types, suggesting that these proteins can indeed carry out diverse functional roles. Also, we constructed 10 labellar-expressing Obp mutants, and obtained behavioral evidence that these OBPs may be involved in bitter sensing. The resources we constructed should be useful for future Drosophila OBP gene family research.

Comammox and unknown ammonia oxidizers contribute to nitrite accumulation in an integrated A-B stage process that incorporates side-stream EBPR (S2EBPR).

A novel integrated pilot-scale A-stage high rate activated sludge, B-stage short-cut biological nitrogen removal and side-stream enhanced biological phosphorus removal (A/B-shortcut N-S2EBPR) process for treating municipal wastewater was demonstrated with the aim to achieve simultaneous and carbon- and energy-efficient N and P removal. In this studied period, an average of 7.62 ± 2.17 mg-N/L nitrite accumulation was achieved through atypical partial nitrification without canonical known NOB out-selection. Network analysis confirms the central hub of microbial community as Nitrospira, which was one to two orders of magnitude higher than canonical aerobic oxidizing bacteria (AOB) in a B-stage nitrification tank. The contribution of comammox Nitrospira as AOB was evidenced by the increased amoB/nxr ratio and higher ammonia oxidation activity. Furthermore, oligotyping analysis of Nitrospira revealed two dominant sub-clusters (microdiveristy) within the Nitrospira. The relative abundance of oligotype II, which is phylogenetically close to Nitrospira_midas_s_31566, exhibited a positive correlation with nitrite accumulation in the same operational period, suggesting its role as comammox Nitrospira. Additionally, the phylogenetic investigation suggested that heterotrophic organisms from the family Comamonadacea and the order Rhodocyclaceae embedding ammonia monooxygenase and hydroxylamine oxidase may function as heterotrophic nitrifiers. This is the first study that elucidated the impact of integrating the S2EBPR on nitrifying populations with implications on short-cut N removal. The unique conditions in the side-stream reactor, such as low ORP, favorable VFA concentrations and composition, seemed to exert different selective forces on nitrifying populations from those in conventional biological nutrient removal processes. The results provide new insights for integrating EBPR with short-cut N removal process for mainstream wastewater treatment.

Behavioural activation to mitigate the psychological impacts of COVID-19 restrictions on older people in England and Wales (BASIL+): a pragmatic randomised controlled trial.

BACKGROUND: Older adults were more likely to be socially isolated during the COVID-19 pandemic, with increased risk of depression and loneliness. We aimed to investigate whether a behavioural activation intervention delivered via telephone could mitigate depression and loneliness in at-risk older people during the COVID-19 pandemic. METHODS: BASIL+ (Behavioural Activation in Social Isolation) was a pragmatic randomised controlled trial conducted among patients recruited from general practices in England and Wales, and was designed to assess the effectiveness of behavioural activation in mitigating depression and loneliness among older people during the COVID-19 pandemic. Eligible participants were aged 65 years and older, socially isolated, with a score of 5 or higher on the Patient Health Questionnaire-9 (PHQ-9), and had multiple long-term conditions. Participants were allocated in a 1:1 ratio to the intervention (behavioural activation) or control groups by use of simple randomisation without stratification. Behavioural activation was delivered by telephone; participants were offered up to eight weekly sessions with trained BASIL+ Support Workers. Behavioural activation was adapted to maintain social connections and encourage socially reinforcing activities. Participants in the control group received usual care with existing COVID-19 wellbeing resources. The primary clinical outcome was self-reported depression severity, assessed by the PHQ-9, at 3 months. Outcomes were assessed masked to allocation and analysis was by treatment allocation. This trial is registered with the ISRCTN registry (ISRCTN63034289). FINDINGS: Between Feb 8, 2021, and Feb 28, 2022, 449 eligible participants were identified and 435 from 26 general practices were recruited and randomly assigned (1:1) to the behavioural activation intervention (n=218) or to the control group (usual care with signposting; n=217). The mean age of participants was 75·7 years (SD 6·7); 270 (62·1%) of 435 participants were female, and 418 (96·1%) were White. Participants in the intervention group attended an average of 5·2 (SD 2·9) of eight remote behavioural activation sessions. The adjusted mean difference in PHQ-9 scores between the control and intervention groups at 3 months was -1·65 (95% CI -2·54 to -0·75, p=0·0003). No adverse events were reported that were attributable to the behavioural activation intervention. INTERPRETATION: Behavioural activation is an effective and potentially scalable intervention that can reduce symptoms of depression and emotional loneliness in at-risk groups in the short term. The findings of this trial add to the range of strategies to improve the mental health of older adults with multiple long-term conditions. These results can be helpful to policy makers beyond the pandemic in reducing the global burden of depression and addressing the health impacts of loneliness, particularly in at-risk groups. FUNDING: UK National Institute for Health and Care Research.

Revisiting the role of Acinetobacter spp. in side-stream enhanced biological phosphorus removal (S2EBPR) systems.

We piloted the incorporation of side-stream enhanced biological phosphorus removal (S2EBPR) with A/B stage short-cut nitrogen removal processes to enable simultaneous carbon-energy-efficient nutrients removal. This unique configuration and system conditions exerted selective force on microbial populations distinct from those in conventional EBPR. Interestingly, effective P removal was achieved with the predominance of Acinetobacter (21.5 ± 0.1 %) with nearly negligible level of known conical PAOs (Ca. Accumulibacter and Tetrasphaera were 0.04 ± 0.10 % and 0.47 ± 0.32 %, respectively). Using a combination of techniques, such as fluorescence in situ hybridization (FISH) coupled with single cell Raman spectroscopy (SCRS), the metabolic tracing of Acinetobacter-like cells exerted PAO-like phenotypic profiling. In addition, comparative metagenomics analysis of the closely related Acinetobacter spp. revealed the EBPR relevant metabolic pathways. Further oligotyping analysis of 16s rRNA V4 region revealed sub-clusters (microdiversity) of the Acinetobacter and revealed that the sub-group (oligo type 1, identical (100 % alignment identity) hits from Acinetobacter_midas_s_49494, and Acinetobacter_midas_s_55652) correlated with EBPR activities parameters, provided strong evidence that the identified Acinetobacter most likely contributed to the overall P removal in our A/B-shortcut N-S2EBPR system. To the best of our knowledge, this is the first study to confirm the in situ EBPR activity of Acinetobacter using combined genomics and SCRS Raman techniques. Further research is needed to identify the specific taxon, and phenotype of the Acinetobacter that are responsible for the P-removal.

Play brick therapy to aid the social skills of children and young people with autism spectrum disorder: the I-SOCIALISE cluster RCT.

Background: Social skills interventions are commonly recommended to help children and young people with autism spectrum disorder develop social skills, but some struggle to engage in these interventions. LEGO® (LEGO System A/S, Billund, Denmark) based therapy, a group social skills intervention, aims to be more interesting and engaging. Objective: To evaluate the clinical effectiveness of LEGO® based therapy on the social and emotional skills of children and young people with autism spectrum disorder in school settings compared with usual support. Secondary objectives included evaluations of cost-effectiveness, acceptability and treatment fidelity. Design: A cluster randomised controlled trial randomly allocating participating schools to either LEGO® based therapy and usual support or usual support only. Setting: Mainstream schools in the north of England. Participants: Children and young people (aged 7-15 years) with autism spectrum disorder, their parent/guardian, an associated teacher/teaching assistant and a facilitator teacher/teaching assistant (intervention schools only). Intervention: Schools randomised to the intervention arm delivered 12 weekly sessions of LEGO® based therapy, which promotes collaborative play and encourages social problem-solving in groups of three children and young people with a facilitator (trained teacher or teaching assistant). Participants received usual support from school and community services. Participants in the control arm received usual support only. Research assistants and statisticians were blind to treatment allocation. Main outcome measure: The social skills subscale of the Social Skills Improvement System (SSIS), completed by the children and young people's unblinded teacher pre randomisation and 20 weeks post randomisation. The SSIS social skills subscale measures social skills including social communication, co-operation, empathy, assertion, responsibility and self-control. Participants completed a number of other pre- and post-randomisation measures of emotional health, quality of life, loneliness, problem behaviours, academic competence, service resource utilisation and adverse events. Results: A total of 250 children and young people from 98 schools were randomised: 127 to the intervention arm and 123 to the control arm. Intention-to-treat analysis of the main outcome measure showed a modest positive difference of 3.74 points (95% confidence interval -0.16 to 7.63 points, standardised effect size 0.18; p = 0.06) in favour of the intervention arm. Statistical significance increased in per-protocol analysis, with a modest positive difference (standardised effect size 0.21; p = 0.036). Cost-effectiveness of the intervention was found in reduced service use costs and a small increase in quality-adjusted life-years. Intervention fidelity and acceptability were positive. No intervention-related adverse events or effects were reported. Conclusions: The primary and pre-planned sensitivity analysis of the primary outcome consistently showed a positive clinical difference, with modest standardised effect sizes of between 0.15 and 0.21. There were positive health economics and qualitative findings, corroborated by the difference between arms for the majority of secondary outcomes, which were not statistically significant but favoured the intervention arm. Post hoc additional analysis was exploratory and was not used in drawing this conclusion. Given the small positive change, LEGO® based therapy for children and young people with autism spectrum disorder in schools should be considered. Limitations: The primary outcome measure was completed by an unblinded teacher (rather than by the facilitator). Future work: The study team recommends future research into LEGO® based therapy, particularly in school environments. Trial registration: This trial is registered as ISRCTN64852382. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (NIHR award ref: 15/49/32) and is published in full in Public Health Research; Vol. 11, No. 12. See the NIHR Funding and Awards website for further award information.

Autism spectrum disorder is characterised by difficulties with social relationships and communication, which can make it difficult to make friends. Social skills training is commonly used to help children and young people learn different social skills, but some children and young people do not enjoy these therapies. LEGO^® (LEGO System A/S, Billund, Denmark) based therapy takes a new approach by focusing on making the process interesting and fun. This research investigated the effect of LEGO^® based therapy groups in schools on the social and emotional abilities of children and young people with autism spectrum disorder. It was a randomised controlled trial, so each school that was taking part was randomly chosen to provide either usual support (from the school or NHS services) or 12 sessions of LEGO^® based therapy with a trained school staff member as well as usual support. Children and young people played one of three roles ­ the 'engineer' (gives instructions), the 'supplier' (finds the pieces) or the 'builder' (builds the model) ­ and worked together. Questionnaires completed by children and young people, their parents/guardians and teachers were used to look at the intervention's effects. The main objective was to see if there was a change in social skills measured by a teacher-completed questionnaire. Results showed that the social skills of children and young people in the LEGO^® based therapy groups did improve a little. We found that the intervention is not very costly for schools to run. Many parents/guardians and teachers thought that the intervention was beneficial and that the children and young people enjoyed it.

Imaging and clinical predictors of acute constipation in patients with acute ischemic stroke.

Background: Constipation symptoms are highly prevalent in acute ischemic stroke, but the clinical and neuroimaging predictors are unknown. This study aimed to identify lesions and clinical features associated with acute constipation. Methods: Data from patients with acute ischemic stroke registered in a hospital-based stroke registry between January 2018 and December 2019 were analyzed. Clinical, laboratory, and imaging features were examined for associations with acute constipation. Using the topographic lesion on diffusion-weighted images, multivariate support vector regression-based lesion-symptom mapping (SVR-LSM) was conducted and compared between the non-constipation and acute constipation groups. Results: A total of 256 patients (mean age 67 years, men: 64%) were included. Acute constipation was noted in 81 patients (32%). Initial stroke severity, represented by initial National Institutes of Health and Stroke Scale (NIHSS) scores, was associated with acute constipation. Laboratory parameters, including fibrin degradation products (FDP), fibrinogen, D-dimer, lipoprotein (a), and free fatty acid levels, also showed statistically significant differences between the non-constipation and constipation groups. FDP, D-dimer, and free fatty acid levels were independently associated with acute constipation in the logistic regression model after adjusting for initial NIHSS scores and potassium levels. SVR-LSM revealed that bilateral lesions in the precentral gyrus, insula, opercular part of the inferior frontal gyrus, the inferior parietal lobule, and lesions in the right middle frontal gyrus were significantly associated with acute constipation. The results were consistent after controlling for the initial NIHSS scores and poststroke potassium levels. When cardioembolic stroke subjects were excluded, the right insular and prefrontal cortex lesions lost their association with acute constipation. Conclusion: Acute constipation symptoms after acute ischemic stroke are mainly related to bilateral lesions in the insula, precentral gyrus, postcentral gyrus, and inferior parietal lobule. Clinically important predictors of acute constipation include initial neurological severity and thromboembolic markers of stroke.

Phenotypic Heterogeneity in Patients with Mutations in the Mitochondrial Complex I Assembly Gene NDUFAF5.

BACKGROUND: Rare mutations in NADH:ubiquinone oxidoreductase complex assembly factor 5 (NDUFAF5) are linked to Leigh syndrome. OBJECTIVE: We aimed to describe clinical characteristics and functional findings in a patient cohort with NDUFAF5 mutations. METHODS: Patients with biallelic NDUFAF5 mutations were recruited from multi-centers in Taiwan. Clinical, laboratory, radiological, and follow-up features were recorded and mitochondrial assays were performed in patients' skin fibroblasts. RESULTS: Nine patients from seven unrelated pedigrees were enrolled, eight homozygous for c.836 T > G (p.Met279Arg) in NDUFAF5 and one compound heterozygous for p.Met279Arg. Onset age had a bimodal distribution. The early-onset group (age <3 years) presented with psychomotor delay, seizure, respiratory failure, and hyponatremia. The late-onset group (age ≥5 years) presented with normal development, but slowly progressive dystonia. Combing 25 previously described patients, the p.Met279Arg variant was exclusively identified in Chinese ancestry. Compared with other groups, patients with late-onset homozygous p.Met279Arg were older at onset (P = 0.008), had less developmental delay (P = 0.01), less hyponatremia (P = 0.01), and better prognosis with preserved ambulatory function into early adulthood (P = 0.01). Bilateral basal ganglia necrosis was a common radiological feature, but brainstem and spinal cord involvement was more common with early-onset patients (P = 0.02). A modifier gene analysis showed higher concomitant mutation burden in early-versus late-onset p.Met279Arg homozygous cases (P = 0.04), consistent with more impaired mitochondrial function in fibroblasts from an early-onset case than a late-onset patient. CONCLUSIONS: The p.Met279Arg variant is a common mutation in our population with phenotypic heterogeneity and divergent prognosis based on age at onset. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Toward Integrating EBPR and the Short-Cut Nitrogen Removal Process in a One-Stage System for Treating High-Strength Wastewater.

Enhanced biological phosphorus removal (EBPR) is an economical and sustainable process for phosphorus removal from wastewater. Despite the widespread application of EBPR for low-strength domestic wastewater treatment, limited investigations have been conducted to apply EBPR to the high-strength wastewaters, particularly, the integration of EBPR and the short-cut nitrogen removal process in the one-stage system remains challenging. Herein, we reported a novel proof-of-concept demonstration of integrating EBPR and nitritation (oxidation of ammonium to nitrite) in a one-stage sequencing batch reactor to achieve simultaneous high-strength phosphorus and short-cut nitrogen removal. Excellent EBPR performance of effluent 0.8 ± 1.0 mg P/L and >99% removal efficiency was achieved fed with synthetic high-strength phosphorus wastewater. Long-term sludge acclimation proved that the dominant polyphosphate accumulating organisms (PAOs), Candidatus Accumulibacter, could evolve to a specific subtype that can tolerate the nitrite inhibition as revealed by operational taxonomic unit (OTU)-based oligotyping analysis. The EBPR kinetic and stoichiometric evaluations combined with the amplicon sequencing proved that the Candidatus Competibacter, as the dominant glycogen accumulating organisms (GAOs), could well coexist with PAOs (15.3-24.9% and 14.2-33.1%, respectively) and did not deteriorate the EBPR performance. The nitrification activity assessment, amplicon sequencing, and functional-based gene marker quantification verified that the unexpected nitrite accumulation (10.7-21.0 mg N/L) in the high-strength EBPR system was likely caused by the nitritation process, in which the nitrite-oxidizing bacteria (NOB) were successfully out-selected (<0.1% relative abundance). We hypothesized that the introduction of the anaerobic phase with high VFA concentrations could be the potential selection force for achieving nitritation based on the literature review and our preliminary batch tests. This study sheds light on developing a new feasible technical route for integrating EBPR with short-cut nitrogen removal for efficient high-strength wastewater treatment.

What credentials are required for robotic-assisted surgery in reconstructive and functional urology?

Introduction: The increasing popularity of robotic assisted surgery (RAS) as it is implemented in to sub specialities poses many challenges to ensuring standards in quality and safety. The area of Reconstructive and Functional Urology (RFU) has a wide range and largely complex heterogeneous procedures. In recent years RFU has started to incorporate RAS as the primary method to undertake these procedures due to improved vision, dexterity, and access to deep cavities. To ensure patient safety majority of institutions maintain minimal requirements to operate using RAS however across specialities and institutions these greatly vary. Methods: A narrative review of all the relevant papers known to the author was conducted. Results: Specific challenges facing RFU is the inability to rely on case numbers as a surrogate means to measure competency as well the ongoing consideration of how to differentiate between surgeons with robotic training and those with the clinical experience specific to RFU. Conclusion: This review explores current models of training and credentialling and assess how it can be adapted to suggest a standardised guideline for RFU to ensure the highest standards of patient care.

Clinical Characteristics, Genetic Features, and Long-Term Outcome of Wilson's Disease in a Taiwanese Population: An 11-Year Follow-Up Study.

OBJECTIVE: aaWilson's disease (WD) is a rare genetic disorder of copper metabolism, and longitudinal follow-up studies are limited. We performed a retrospective analysis to determine the clinical characteristics and long-term outcomes in a large WD cohort. METHODS: aaMedical records of WD patients diagnosed from 2006-2021 at National Taiwan University Hospital were retrospectively evaluated for clinical presentations, neuroimages, genetic information, and follow-up outcomes. RESULTS: aaThe present study enrolled 123 WD patients (mean follow-up: 11.12 ± 7.41 years), including 74 patients (60.2%) with hepatic features and 49 patients (39.8%) with predominantly neuropsychiatric symptoms. Compared to the hepatic group, the neuropsychiatric group exhibited more Kayser-Fleischer rings (77.6% vs. 41.9%, p < 0.01), lower serum ceruloplasmin levels (4.9 ± 3.9 vs. 6.3 ± 3.9 mg/dL, p < 0.01), smaller total brain and subcortical gray matter volumes (p < 0.0001), and worse functional outcomes during follow-up (p = 0.0003). Among patients with available DNA samples (n = 59), the most common mutations were p.R778L (allelic frequency of 22.03%) followed by p.P992L (11.86%) and p.T935M (9.32%). Patients with at least one allele of p.R778L had a younger onset age (p = 0.04), lower ceruloplasmin levels (p < 0.01), lower serum copper levels (p = 0.03), higher percentage of the hepatic form (p = 0.03), and a better functional outcome during follow-up (p = 0.0012) compared to patients with other genetic variations. CONCLUSION: aaThe distinct clinical characteristics and long-term outcomes of patients in our cohort support the ethnic differences regarding the mutational spectrum and clinical presentations in WD.

A novel C19orf12 frameshift mutation in a MPAN pedigree impairs mitochondrial function and connectivity leading to neurodegeneration.

BACKGROUND: Mitochondrial membrane protein‒associated neurodegeneration (MPAN) is a rare genetic disease characterized by progressive neurodegeneration with brain iron accumulations combined with neuronal α-synuclein and tau aggregations. Mutations in C19orf12 have been associated with both autosomal recessive and autosomal dominant inheritance patterns of MPAN. METHODS: We present clinical features and functional evidence from a Taiwanese family with autosomal dominant MPAN caused by a novel heterozygous frameshift and nonsense mutation in C19orf12, c273_274 insA (p.P92Tfs*9). To verify the pathogenicity of the identified variant, we examined the mitochondrial function, morphology, protein aggregation, neuronal apoptosis, and RNA interactome in p.P92Tfs*9 mutant knock-in SH-SY5Y cells created with CRISPR-Cas9 technology. RESULTS: Clinically, the patients with the C19orf12 p.P92Tfs*9 mutation presented with generalized dystonia, retrocollis, cerebellar ataxia, and cognitive decline, starting in their mid-20s. The identified novel frameshift mutation is located in the evolutionarily conserved region of the last exon of C19orf12. In vitro studies revealed that the p.P92Tfs*9 variant is associated with impaired mitochondrial function, reduced ATP production, aberrant mitochondria interconnectivity and ultrastructure. Increased neuronal α-synuclein and tau aggregations, and apoptosis were observed under conditions of mitochondrial stress. Transcriptomic analysis revealed that the expression of genes in clusters related to mitochondrial fission, lipid metabolism, and iron homeostasis pathways was altered in the C19orf12 p.P92Tfs*9 mutant cells compared to control cells. CONCLUSION: Our findings provide clinical, genetic, and mechanistic insight revealing a novel heterozygous C19orf12 frameshift mutation to be a cause of autosomal dominant MPAN, further strengthening the importance of mitochondrial dysfunction in the pathogenesis of MPAN.

I-SOCIALISE: Results from a cluster randomised controlled trial investigating the social competence and isolation of children with autism taking part in LEGO® based therapy ('Play Brick Therapy') clubs in school environments.

LAY ABSTRACT: Autism is characterised by keen interests and differences in social interactions and communication. Activities that help autistic children and young people with social skills are commonly used in UK schools. LEGO® based therapy is a new activity that provides interesting and fun social opportunities for children and young people and involves building LEGO® models together. This study looked at LEGO® based therapy for the social skills of autistic children and young people in schools. It was a randomised controlled trial, meaning each school was randomly chosen (like flipping a coin) to either run LEGO® based therapy groups in school over 12 weeks and have usual support from school or other professionals, or only have usual support from school or other professionals. The effect of the LEGO® based therapy groups was measured by asking children and young people, their parents/guardians, and a teacher at school in both arms of the study to complete some questionnaires. The main objective was to see if the teacher's questionnaire answers about the children and young people's social skills changed between their first and second completions. The social skills of participants in the LEGO® based therapy groups were found to have improved in a small way when compared to usual support only. The study also found that LEGO® based therapy was not very costly for schools to run and parents/guardians and teachers said they thought it was good for their children and young people. We suggest further research into different potential benefits of LEGO® based therapy.

Genetic analysis of IMPDH2 gene in Taiwanese patients with isolated or combined dystonia.

The inosine monophosphate dehydrogenase gene (IMPDH2) was recently reported as a novel gene associated with autosomal dominantly inherited dystonia. We investigated 245 Taiwanese patients with molecularly unassigned isolated or combined dystonia without features of neurodevelopmental disorders and found none had pathogenic variants. Our findings suggest that IMPDH2 may not play a major role in dystonia.

A systematic review of the surgical management of apical pelvic organ prolapse.

INTRODUCTION AND HYPOTHESIS: This systematic review (PROSPERO:CRD42022275789) is aimed at comparing qualitatively the success, recurrence, and complication rates of sacrocolpopexy with concomitant hysterectomy, hysteropexy, sacrospinous fixation (SSF) with and without vaginal hysterectomy (VH) and uterosacral fixation (USF) with and without VH. METHODS: A systematic search was performed using Embase, PubMed, Scopus, and Cochrane databases for studies published from 2011, on women with apical pelvic organ prolapse requiring surgical interventions. Risk of bias was assessed via the National Institutes of Health study quality assessment tool. The primary outcomes are the success and recurrence rate of each technique, for ≥12 months' follow-up. Findings were summarised qualitatively. RESULTS: A total of 21 studies were included. Overall significant findings for a high success and low recurrence rate are summarised as: minimally invasive sacrocolpopexy (MISC) is superior to abdominal sacrocolpopexy (ASC); sacrospinous hysteropexy (SSHP) is superior to USF + VH, which is superior to uterosacral hysteropexy and mesh hysteropexy (MHP). Significant findings related to complications include: MISC recorded a lower overall complication rate than ASC except in mesh exposure; USF + VH tends to perform better than SSHP and SSF, with SSHP performing better than MHP in faecal incontinence and overactive bladder rates. CONCLUSION: There is no evidence to conclude that hysterectomy is superior to uterine-sparing approaches. MISC should be considered over ASC given similar efficacy and reduced complications. Superiority of MHP is unproven against native tissue hysteropexy. Further studies under standardised settings are required for direct comparisons between the surgical management methods.

One session treatment (OST) is equivalent to multi-session cognitive behavioral therapy (CBT) in children with specific phobias (ASPECT): results from a national non-inferiority randomized controlled trial.

BACKGROUND: 5%-10% children and young people (CYP) experience specific phobias that impact daily functioning. Cognitive Behaviour Therapy (CBT) is recommended but has limitations. One Session Treatment (OST), a briefer alternative incorporating CBT principles, has demonstrated efficacy. The Alleviating Specific Phobias Experienced by Children Trial (ASPECT) investigated the non-inferiority of OST compared to multi-session CBT for treating specific phobias in CYP. METHODS: ASPECT was a pragmatic, multi-center, non-inferiority randomized controlled trial in 26 CAMHS sites, three voluntary agency services, and one university-based CYP well-being service. CYP aged 7-16 years with specific phobia were randomized to receive OST or CBT. Clinical non-inferiority and a nested cost-effectiveness evaluation was assessed 6-months post-randomization using the Behavioural Avoidance Task (BAT). Secondary outcome measures included the Anxiety Disorder Interview Schedule, Child Anxiety Impact Scale, Revised Children's Anxiety Depression Scale, goal-based outcome measure, and EQ-5DY and CHU-9D, collected blind at baseline and six-months. RESULTS: 268 CYPs were randomized to OST (n = 134) or CBT (n = 134). Mean BAT scores at 6 months were similar across groups in both intention-to-treat (ITT) and per-protocol (PP) populations (CBT: 7.1 (ITT, n = 76), 7.4 (PP, n = 57), OST: 7.4 (ITT, n = 73), 7.6 (PP, n = 56), on the standardized scale-adjusted mean difference for CBT compared to OST -0.123, 95% CI -0.449 to 0.202 (ITT), mean difference -0.204, 95% CI -0.579 to 0.171 (PP)). These findings were wholly below the standardized non-inferiority limit of 0.4, suggesting that OST is non-inferior to CBT. No between-group differences were found on secondary outcomes. OST marginally decreased mean service use costs and maintained similar mean Quality Adjusted Life Years compared to CBT. CONCLUSIONS: One Session Treatment has similar clinical effectiveness to CBT for specific phobias in CYP and may be a cost-saving alternative.

Clinical Characteristics, Genetic Features, and Long-Term Outcome of Wilson’s Disease in a Taiwanese Population: An 11-Year Follow-Up Study

Objective@#aaWilson’s disease (WD) is a rare genetic disorder of copper metabolism, and longitudinal follow-up studies are limited. We performed a retrospective analysis to determine the clinical characteristics and long-term outcomes in a large WD cohort. @*Methods@#aaMedical records of WD patients diagnosed from 2006–2021 at National Taiwan University Hospital were retrospectively evaluated for clinical presentations, neuroimages, genetic information, and follow-up outcomes. @*Results@#aaThe present study enrolled 123 WD patients (mean follow-up: 11.12 ± 7.41 years), including 74 patients (60.2%) with hepatic features and 49 patients (39.8%) with predominantly neuropsychiatric symptoms. Compared to the hepatic group, the neuropsychiatric group exhibited more Kayser-Fleischer rings (77.6% vs. 41.9%, p < 0.01), lower serum ceruloplasmin levels (4.9 ± 3.9 vs. 6.3 ± 3.9 mg/dL, p < 0.01), smaller total brain and subcortical gray matter volumes (p < 0.0001), and worse functional outcomes during follow-up (p = 0.0003). Among patients with available DNA samples (n = 59), the most common mutations were p.R778L (allelic frequency of 22.03%) followed by p.P992L (11.86%) and p.T935M (9.32%). Patients with at least one allele of p.R778L had a younger onset age (p = 0.04), lower ceruloplasmin levels (p < 0.01), lower serum copper levels (p = 0.03), higher percentage of the hepatic form (p = 0.03), and a better functional outcome during follow-up (p = 0.0012) compared to patients with other genetic variations. @*Conclusion@#aaThe distinct clinical characteristics and long-term outcomes of patients in our cohort support the ethnic differences regarding the mutational spectrum and clinical presentations in WD.

One-session treatment compared with multisession CBT in children aged 7-16 years with specific phobias: the ASPECT non-inferiority RCT.

BACKGROUND: Up to 10% of children and young people have a specific phobia that can significantly affect their mental health, development and daily functioning. Cognitive-behavioural therapy-based interventions remain the dominant treatment, but limitations to their provision warrant investigation into low-intensity alternatives. One-session treatment is one such alternative that shares cognitive-behavioural therapy principles but has a shorter treatment period. OBJECTIVE: This research investigated the non-inferiority of one-session treatment to cognitive-behavioural therapy for treating specific phobias in children and young people. The acceptability and cost-effectiveness of one-session treatment were examined. DESIGN: A pragmatic, multicentre, non-inferiority randomised controlled trial, with embedded economic and qualitative evaluations. SETTINGS: There were 26 sites, including 12 NHS trusts. PARTICIPANTS: Participants were aged 7-16 years and had a specific phobia defined in accordance with established international clinical criteria. INTERVENTIONS: Participants were randomised 1 : 1 to receive one-session treatment or usual-care cognitive-behavioural therapy, and were stratified according to age and phobia severity. Outcome assessors remained blind to treatment allocation. MAIN OUTCOME MEASURES: The primary outcome measure was the Behavioural Avoidance Task at 6 months' follow-up. Secondary outcomes included the Anxiety Disorder Interview Schedule, Child Anxiety Impact Scale, Revised Children's Anxiety and Depression Scale, a goal-based outcome measure, Child Health Utility 9D, EuroQol-5 Dimensions Youth version and resource usage. Treatment fidelity was assessed using the Cognitive Behaviour Therapy Scale for Children and Young People and the One-Session Treatment Rating Scale. RESULTS: A total of 274 participants were recruited, with 268 participants randomised to one-session treatment (n = 134) or cognitive-behavioural therapy (n = 134). A total of 197 participants contributed some data, with 149 participants in the intention-to-treat analysis and 113 in the per-protocol analysis. Mean Behavioural Avoidance Task scores at 6 months were similar across treatment groups when both intention-to-treat and per-protocol analyses were applied [cognitive-behavioural therapy: 7.1 (intention to treat), 7.4 (per protocol); one-session treatment: 7.4 (intention to treat), 7.6 (per protocol); on the standardised scale adjusted mean difference for cognitive-behavioural therapy compared with one-session treatment -0.123, 95% confidence interval -0.449 to 0.202 (intention to treat), mean difference -0.204, 95% confidence interval -0.579 to 0.171 (per protocol)]. These findings were wholly below the standardised non-inferiority limit of 0.4, which suggests that one-session treatment is non-inferior to cognitive-behavioural therapy. No between-group differences in secondary outcome measures were found. The health economics evaluation suggested that, compared with cognitive-behavioural therapy, one-session treatment marginally decreased the mean service use costs and maintained similar mean quality-adjusted life-year improvement. Nested qualitative evaluation found one-session treatment to be considered acceptable by those who received it, their parents/guardians and clinicians. No adverse events occurred as a result of phobia treatment. LIMITATIONS: The COVID-19 pandemic meant that 48 children and young people could not complete the primary outcome measure. Service waiting times resulted in some participants not starting therapy before follow-up. CONCLUSIONS: One-session treatment for specific phobia in UK-based child mental health treatment centres is as clinically effective as multisession cognitive-behavioural therapy and highly likely to be cost-saving. Future work could involve improving the implementation of one-session treatment through training and commissioning of improved care pathways. TRIAL REGISTRATION: This trial is registered as ISRCTN19883421. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 42. See the NIHR Journals Library website for further project information.

A phobia is an intense, ongoing fear of an everyday object or situation. The phobia causes distress and the person with the phobia avoids that object or situation. Many children and young people have phobias that affect their daily lives. Cognitive­behavioural therapy helps by changing what people do or think when they have a phobia and is the most common treatment approach. However, cognitive­behavioural therapy is expensive, takes time and is not always easy to get. Different treatments are needed to help children and young people with specific phobias. One such therapy is one-session treatment, which works in similar ways to cognitive­behavioural therapy but takes place over one main 3-hour session. Our study, called ASPECT (Alleviating Specific Phobias Experienced by Children Trial), compared these two treatments to examine whether or not one-session treatment is as effective as cognitive­behavioural therapy. Overall, 274 children and young people aged 7­16 years from 26 sites nationally helped with our research, of whom 268 received either cognitive­behavioural therapy or one-session treatment. The results at 6 months found that one-session treatment and cognitive­behavioural therapy worked as well as each other for treating phobias in children and young people. We also found evidence that one-session treatment is cheaper than cognitive­behavioural therapy. We spoke with children and young people, their parents/guardians and the therapists of the single-session treatment, and we found one-session treatment to be acceptable for their needs. Future research could explore how to make one-session treatment more easily available for children and young people with specific phobias because it can save time and money, and works just as well as cognitive­behavioural therapy.

Periurethral and Anterior Vaginal Wall Masses: Etiology, Presentation, and Treatment Outcomes.

OBJECTIVE: To describe the etiology and presenting symptoms of periurethral and anterior vaginal wall masses in a large series of patients in an academic institution. METHODS: A retrospective chart review of 126 patients presenting and undergoing treatment for periurethral and anterior vaginal wall masses between November 2001 and July 2021 was completed. Clinicopathologic data were extracted. Ethics approval was obtained. The primary objective of this study was to determine the etiology of these masses; secondary objectives included determining the rates of presenting symptoms, complications, resolution of stress urinary incontinence (SUI), and de novo SUI. RESULTS: The median age of patients was 42 years. The most common etiology was urethral diverticula (39.7%), followed by Skene gland cysts or abscesses (30.2%). The rate of malignancy was 1.6%, and the rate of infection was 21.4%. The most common presenting symptoms were sensation of mass (78.6%), dyspareunia (52.4%), and discharge (46.0%). The rate of surgical complications was 9.5%. Three patients had recurrence on follow-up, but there were no recurrent urethral diverticula after excision. The rate of de novo SUI was 5.6%. The rate of resolution of SUI was 67.6%, and all patients who had slings reported resolution of SUI. CONCLUSION: Urethral diverticula and Skene gland cysts or abscesses accounted for 70% of periurethral and anterior vaginal wall masses in this series. Treatment by complete excision is usually successful.

Hyperthermic Intraperitoneal Chemotherapy (HIPEC): An Overview of the Molecular and Cellular Mechanisms of Actions and Effects on Epithelial Ovarian Cancers.

Most patients with epithelial ovarian cancers (EOCs) are at advanced stages (stage III-IV), for which the recurrence rate is high and the 5-year survival rate is low. The most effective treatment for advanced diseases involves a debulking surgery followed by adjuvant intravenous chemotherapy with carboplatin and paclitaxel. Nevertheless, systemic treatment with intravenous chemotherapeutic agents for peritoneal metastasis appears to be less effective due to the poor blood supply to the peritoneal surface with low drug penetration into tumor nodules. Based on this reason, hyperthermic intraperitoneal chemotherapy (HIPEC) emerges as a new therapeutic alternative. By convection and diffusion, the hyperthermic chemotherapeutic agents can directly contact intraperitoneal tumors and produce cytotoxicity. In a two-compartment model, the peritoneal-plasma barrier blocks the leakage of chemotherapeutic agents from peritoneal cavity and tumor tissues to local vessels, thus maintaining a higher concentration of chemotherapeutic agents within the tumor tissues to facilitate tumor apoptosis and a lower concentration of chemotherapeutic agents within the local vessels to decrease systemic toxicity. In this review, we discuss the molecular and cellular mechanisms of HIPEC actions and the effects on EOCs, including the progression-free survival (PFS), disease-free survival (DFS) and overall survival (OS). For primary advanced ovarian cancers, more studies are agreeing that patients undergoing HIPEC have better surgical and clinical (PFS; OS) outcomes than those not, although one study reported no differences in the PFS and OS. For recurrent ovarian cancers, studies have revealed better DFS and OS in patients undergoing HIPEC than those in patients not undergoing HIPEC, although one study reported no differences in the PFS. HIPEC appears comparable to traditional intravenous chemotherapy in treating advanced EOCs. Overall, HIPEC has demonstrated some therapeutic benefits in many randomized phase III trials when combined with the standard cytoreductive surgeries for advanced EOCs. Nevertheless, many unknown aspects of HIPEC, including detailed mechanisms of actions, along with the effectiveness and safety for the treatment of EOCs, warrant further investigation.

CFTR Modulators: From Mechanism to Targeted Therapeutics.

People with cystic fibrosis (CF) suffer from a multi-organ disorder caused by loss-of-function variants in the gene encoding the epithelial anion channel cystic fibrosis transmembrane conductance regulator (CFTR). Tremendous progress has been made in both basic and clinical sciences over the past three decades since the identification of the CFTR gene. Over 90% of people with CF now have access to therapies targeting dysfunctional CFTR. This success was made possible by numerous studies in the field that incrementally paved the way for the development of small molecules known as CFTR modulators. The advent of CFTR modulators transformed this life-threatening illness into a treatable disease by directly binding to the CFTR protein and correcting defects induced by pathogenic variants. In this chapter, we trace the trajectory of structural and functional studies that brought CF therapies from bench to bedside, with an emphasis on mechanistic understanding of CFTR modulators.