Exploring a mother's engagement in team sport: An application of an extended theory of planned behaviour.

OBJECTIVES: Mothers of young children are at-risk for low physical activity. Organised team sport provides additional social and mental health benefits above that of physical activity. To better understand engagement in team sport, this study aimed to apply the theory of planned behaviour, with the addition of maternal identity and social support. DESIGN: A prospective two-part online study was conducted two weeks apart to collect data from 122 mothers in Australia (M = 32.22, SD = 4.42). METHODS: Two hierarchical multiple regression analyses were conducted to predict intention and engagement in team sports. A moderation was conducted to determine the effect of social support on the intention-behaviour relationship. RESULTS: Results indicated that 65.1 % of the variance in intention was explained, with years since previously played (ß = -0.17), attitudes (ß = 0.20), subjective norms (ß = 0.41), and perceived behavioural control (ß = 0.16) being significant, and level of team sport social support, and maternal identity being non-significant. Additionally, 65.7 % of the variance in behaviour was explained, with perceived behavioural control (ß = 0.28) and intention (ß = 0.50) being significant, and years since previously played and social supportbeing non-significant. Social support moderated the relationship between intention and engagement, such that social support facilitated engagement. CONCLUSIONS: The findings show support for the predictive ability of the theory and mothers within a sporting context. Behaviour change techniques related to strengthening intention and personal agency could be used to inform interventions intending to increase team sports participation.

Severe sexual abuse in childhood and altered neurophysiological response to reward in female adults.

BACKGROUND: A relatively understudied but growing body of research indicates that individuals with a history of childhood trauma exhibit altered reward processing in adulthood. Research to date has focused on adversity broadly, with studies typically finding evidence of blunted response to rewards in adults with a history of childhood trauma. OBJECTIVE: Given the role of reward processing in risk for psychopathology and the particularly pathogenic nature of sexual abuse (SA), the present study sought to assess whether adults with a history of severe childhood SA exhibit altered neurophysiological response to rewards. PARTICIPANTS AND SETTING: Female adults (N = 105) were included from two study sites that used the same measures of childhood trauma (Childhood Trauma Questionnaire, CTQ), reward processing (Doors Task), and psychopathology (SCID). METHODS: Based on participants' CTQ and SCID responses, three groups were created: Severe SA (n = 36), Clinical Match (with comparable lifetime psychopathology but no-to-minimal SA history; n = 35), and Healthy Controls (n = 34). Group differences in RewP amplitude were assessed. RESULTS: The Severe SA group exhibited larger reward positivity (RewP) amplitude to monetary rewards than the Clinical Match and Healthy Control groups (partial ƞ2 = 0.06, p = .047). This effect remained after covarying for severity of other forms of childhood trauma. CONCLUSIONS: Our study found that severe SA in childhood was related to a heightened response to reward in adulthood. Furthermore, this was not attributable to the severity of other forms of early trauma or comorbid psychopathology. Future studies are needed to identify how heightened reward processing following severe childhood SA may be implicated in the onset and course of psychopathology.

Seamless site-directed mutagenesis in complex cloned DNA sequences using the RedEx method.

Seamless site-directed mutagenesis is an important technique for studying protein functions, tuning enzyme catalytic activities and modifying genetic elements in multiple rounds because it can insert, delete or substitute nucleotides, DNA segments or even entire genes at the target site without introducing any unwanted change. To facilitate seamless site-directed mutagenesis in large plasmids and bacterial artificial chromosomes (BACs) with repetitive sequences, we recently developed the RedEx strategy. Compared with previous methods, our approach achieves the recovery of correct recombinants with high accuracy by circumventing unwanted recombination between repetitive sequences. RedEx readily yields more than 80% accuracy in seamless DNA insertion and deletion in large multimodular polyketide synthase gene clusters, which are among the most difficult targets due to the large number of repetitive DNA sequences in modules encoding almost identical enzymes. Here we present the RedEx method by describing in detail the seamless site-directed mutagenesis in a BAC vector. Overall, the process includes three parts: (1) insertion of the RedEx cassette containing the desired mutation together with selection-counterselection markers flanked by unique restriction sites and 20-bp overlapping sequences into the target site by recombineering, (2) removal of the selection-counterselection markers in the BAC by restriction digestion and (3) circularization of the linear BAC by exonuclease-mediated in vitro DNA annealing. This protocol can be performed within 3 weeks and will enable researchers with DNA cloning experience to master seamless site-directed mutagenesis to accelerate their research.

Shared and unique 3D genomic features of substance use disorders across multiple cell types.

Recent genome-wide association studies (GWAS) have revealed shared genetic components among alcohol, opioid, tobacco and cannabis use disorders. However, the extent of the underlying shared causal variants and effector genes, along with their cellular context, remain unclear. We leveraged our existing 3D genomic datasets comprising high-resolution promoter-focused Capture-C/Hi-C, ATAC-seq and RNA-seq across >50 diverse human cell types to focus on genomic regions that coincide with GWAS loci. Using stratified LD regression, we determined the proportion of genomewide SNP heritability attributable to the features assayed across our cell types by integrating recent GWAS summary statistics for the relevant traits: alcohol use disorder (AUD), tobacco use disorder (TUD), opioid use disorder (OUD) and cannabis use disorder (CanUD). Statistically significant enrichments (P<0.05) were observed in 14 specific cell types, with heritability reaching 9.2-fold for iPSC-derived cortical neurons and neural progenitors, confirming that they are crucial cell types for further functional exploration. Additionally, several pancreatic cell types, notably pancreatic beta cells, showed enrichment for TUD, with heritability enrichments up to 4.8-fold, suggesting genomic overlap with metabolic processes. Further investigation revealed significant positive genetic correlations between T2D with both TUD and CanUD (FDR<0.05) and a significant negative genetic correlation with AUD. Interestingly, after partitioning the heritability for each cell type's cis-regulatory elements, the correlation between T2D and TUD for pancreatic beta cells was greater (r=0.2) than the global genetic correlation value. Our study provides new genomic insights into substance use disorders and implicates cell types where functional follow-up studies could reveal causal variant-gene mechanisms underpinning these disorders.

A natural experiment during lockdown and on-going care-home COVID-19 outbreaks showed a single dose of vaccine reduced hospitalisation and deaths of care-home residents in North West England.

OBJECTIVE: To examine the effectiveness of one dose of the COVID-19 vaccine on care-home residents. STUDY DESIGN: Natural experiment. METHODS: We compared the effectiveness of single doses of Pfizer/BioNTech BNT162b2 (effective at 10 days) and AstraZeneca ChAdOx1 (effective at 14 days) vaccines in vaccinated and control (unvaccinated) homes. Using routine data, all care-homes reporting COVID-19 outbreaks between 11/12/2020 and 12/3/2021 in a sub-region of North West England were included. RESULTS: Of 126 care-homes (4042 residents), with outbreaks, 55 (44%, 1686 residents) reported onset dates before vaccination commenced; 38 (30%, 1304 residents) reported onset < 10 (BNT162b2) and < 14 days (ChAdOx1) after vaccine administration; and 33 (26%, 1052 residents) reported onset > 10 (BNT162b2) and > 14 (ChAdOx1) days after vaccination. Eighty-nine (71%) homes used ChAdOx1 vaccine. A single dose of vaccine before the outbreak onset significantly lowered the risk of symptoms (reduced by 48%), positivity (by 65%), hospitalisation (by 68%), and death (by 81%). Some vaccine effectiveness was also noted in care-homes that received one dose of vaccine within 10-14 days of outbreak onset. The number needed to vaccinate to prevent one resident from COVID-19-related hospitalisation was 34, and death was 17. CONCLUSIONS: This real-world, natural experiment adds to the evidence of COVID-19 vaccine effectiveness from different studies using varying designs. In the context of lockdown's impact on infection rates and on-going care-home outbreaks, a single dose of either ChAdOx1 or BNT162b2 vaccine had a significant impact on reducing COVID-19 related hospitalisation and death in care-home residents. Natural experiments should be used more in public health.

Deutetrabenazine Provides Long-Term Benefit for Tardive Dyskinesia Regardless of Underlying Condition and Dopamine Receptor Antagonist Use: A Post Hoc Analysis of the 3-Year, Open-Label Extension Study.

BACKGROUND: Deutetrabenazine is approved for adults with tardive dyskinesia (TD). Data based on underlying psychiatric condition and baseline dopamine receptor antagonist (DRA) use are limited. METHODS: Patients with TD who completed parent studies ARM-TD or AIM-TD were eligible for the 3-year, open-label extension study (RIM-TD; NCT02198794). In RIM-TD, deutetrabenazine was titrated based on dyskinesia control and tolerability. In this post hoc analysis of RIM-TD, total motor Abnormal Involuntary Movement Scale (AIMS) score and adverse events (AEs) were analyzed by underlying condition and DRA use at parent study baseline. RESULTS: Of 343 patients enrolled in RIM-TD, 336 were included in the analysis by underlying condition, and 337 were included in the analysis by DRA use. One hundred eighty-nine of 205 (92%) patients with psychotic disorders (schizophrenia/schizoaffective disorder) and 65 of 131 (50%) with mood and other disorders (depression/bipolar disorder/other) were receiving a DRA. Mean (SE) deutetrabenazine doses at week 145 were 40.4 (1.13), 38.5 (1.21), 39.9 (1.00), and 38.5 (1.48) mg/d for patients with psychotic disorders, those with mood and other disorders, and those receiving DRAs or not, respectively. Mean (SD) changes in total motor AIMS score from this study baseline to week 145 were -6.3 (4.53), -7.1 (4.92), -6.1 (4.42), and -7.5 (5.19). Exposure-adjusted incidence rates (number of AEs/patient-years) of AEs were similar across groups: any (1.02, 1.71, 1.08, 1.97), serious (0.10, 0.12, 0.10, 0.12), and leading to discontinuation (0.07, 0.05, 0.06, 0.05). CONCLUSIONS: Long-term deutetrabenazine provided clinically meaningful improvements in TD-related movements, with a favorable benefit-risk profile, regardless of underlying condition or DRA use.

Endometrial Cancer: Analysing Patterns of Recurrence and Real-Life Outcome Data Using the 2020 ESGO-ESTRO-ESP Risk Stratification System.

AIMS: To evaluate patterns of recurrence and explore the prognostic differences between the 2018 FIGO staging system and the 2020 ESGO-ESTRO-ESP risk stratification system of endometrial cancer with an emphasis on early-stage disease. BACKGROUND: The incidence of endometrial cancer has risen by around 60% since the 90's. It is projected that by 2035 endometrial cancer will be the sixth most common cause of cancer-related death amongst females. METHODS: This was a retrospective cohort study which included patients treated between 2010 and 2017. Primary endpoints were overall survival (OS) and recurrence-free survival (RFS). Kaplan-Meyer survival analysis was used to assess OS and RFS across different risk groups. Cox proportional hazards regression was used to evaluate prognostic risk factors implicated in recurrence. Different recurrence patterns across the subgroups were analysed with Pearson's chi-square test. RESULTS: The study included 692 patients with a recurrence rate of 14.9%. The median time to recurrence was 17.1 months (IQR:8.8-28.4). The mean OS varied between 97.2 months in the low-risk group to 63.1 months in the high-risk group (p < 0.001). Mean RFS was 96.1 in the low-risk group and 58.9 in the high-risk group (p < 0.001). RFS was predicted by the following factors; high risk group (OR=3.87; p = 0.041), LVSI (OR=2.54, p = 0.005), carcinosarcoma (OR=2.20, p = 0.021) and serous subtype (OR=1.91, p = 0.01). Logistic regression was used to evaluate risk factors for loco-regional and distant recurrence. Patients in the low-risk group were less likely to have distant recurrence (OR=0.08, p = 0.004). Similarly, negative LVSI and Grade 1 cancers were associated with decreased risk of distant recurrence (OR=0.34, p = 0.006 and OR=0.33, p = 0.007, respectively). There were no significant risk factors for loco-regional recurrence. CONCLUSIONS: The 2020 ESGO-ESTRO-ESP risk stratification provides accurate estimates of recurrence risk and survival. Those treated in line with current guidance have significantly better outcomes.

The effects of family support and smartphone-derived homestay on daily mood and depression among sexual and gender minority adolescents.

Sexual and gender minority (SGM) adolescents are at elevated risk for depression. This risk is especially pronounced among adolescents whose home environment is unsupportive or nonaffirming, as these adolescents may face familial rejection due to their identity. Therefore, it is critical to better understand the mechanisms underlying this risk by probing temporally sensitive associations between negative mood and time spent in potentially hostile home environments. The current study included adolescents (N = 141; 43% SGM; 13-18 years old), oversampled for depression history, who completed clinical interviews assessing lifetime psychiatric history and depression severity as well as self-report measures of social support. Participants also installed an app on their personal smartphones, which assessed their daily mood and geolocation-determined mobility patterns over a 6-month follow-up period. Over the 6-month follow-up period, SGM adolescents reported elevated depression severity and lower daily mood relative to non-SGM youth. Interestingly, SGM adolescents who reported low family support experienced lower daily mood than non-SGM adolescents, particularly on days when they spent more time at home. Current findings reinforce evidence for disparities in depression severity among SGM adolescents and highlight family support as a key factor. Specifically, more time spent in home environments with low family support was associated with worse mood among SGM adolescents. These results underscore the need for clinical interventions to support SGM youth, particularly interventions that focus on familial relationships and social support within the home environment. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Brain activity during reappraisal and associations with psychotherapy response in social anxiety and major depression: a randomized trial.

BACKGROUND: Cognitive behavioral therapy (CBT) is an effective treatment for patients with social anxiety disorder (SAD) or major depressive disorder (MDD), yet there is variability in clinical improvement. Though prior research suggests pre-treatment engagement of brain regions supporting cognitive reappraisal (e.g. dorsolateral prefrontal cortex [dlPFC]) foretells CBT response in SAD, it remains unknown if this extends to MDD or is specific to CBT. The current study examined associations between pre-treatment neural activity during reappraisal and clinical improvement in patients with SAD or MDD following a trial of CBT or supportive therapy (ST), a common-factors comparator arm. METHODS: Participants were 75 treatment-seeking patients with SAD (n = 34) or MDD (n = 41) randomized to CBT (n = 40) or ST (n = 35). Before randomization, patients completed a cognitive reappraisal task during functional magnetic resonance imaging. Additionally, patients completed clinician-administered symptom measures and a self-report cognitive reappraisal measure before treatment and every 2 weeks throughout treatment. RESULTS: Results indicated that pre-treatment neural activity during reappraisal differentially predicted CBT and ST response. Specifically, greater trajectories of symptom improvement throughout treatment were associated with less ventrolateral prefrontal cortex (vlPFC) activity for CBT patients, but more vlPFC activity for ST patients. Also, less baseline dlPFC activity corresponded with greater trajectories of self-reported reappraisal improvement, regardless of treatment arm. CONCLUSIONS: If replicated, findings suggest individual differences in brain response during reappraisal may be transdiagnostically associated with treatment-dependent improvement in symptom severity, but improvement in subjective reappraisal following psychotherapy, more broadly.

CRISPR-Cas13b-mediated suppression of HBV replication and protein expression.

BACKGROUND & AIMS: New antiviral approaches that target multiple aspects of the HBV replication cycle to improve rates of functional cure are urgently required. HBV RNA represents a novel therapeutic target. Here, we programmed CRISPR-Cas13b endonuclease to specifically target the HBV pregenomic RNA and viral mRNAs in a novel approach to reduce HBV replication and protein expression. METHODS: Cas13b CRISPR RNAs (crRNAs) were designed to target multiple regions of HBV pregenomic RNA. Mammalian cells transfected with replication competent wild-type HBV DNA of different genotypes, a HBV-expressing stable cell line, a HBV infection model and a hepatitis B surface antigen (HBsAg)-expressing stable cell line were transfected with PspCas13b-BFP (blue fluorescent protein) and crRNA plasmids, and the impact on HBV replication and protein expression was measured. Wild-type HBV DNA, PspCas13b-BFP and crRNA plasmids were simultaneously hydrodynamically injected into mice, and serum HBsAg was measured. PspCas13b mRNA and crRNA were also delivered to a HBsAg-expressing stable cell line via lipid nanoparticles and the impact on secreted HBsAg determined. RESULTS: Our HBV-targeting crRNAs strongly suppressed HBV replication and protein expression in mammalian cells by up to 96% (p <0.0001). HBV protein expression was also reduced in a HBV-expressing stable cell line and in the HBV infection model. CRISPR-Cas13b crRNAs reduced HBsAg expression by 50% (p <0.0001) in vivo. Lipid nanoparticle-encapsulated PspCas13b mRNA reduced secreted HBsAg by 87% (p = 0.0168) in a HBsAg-expressing stable cell line. CONCLUSIONS: Together, these results show that CRISPR-Cas13b can be programmed to specifically target and degrade HBV RNAs to reduce HBV replication and protein expression, demonstrating its potential as a novel therapeutic option for chronic HBV infection. IMPACT AND IMPLICATIONS: Owing to the limitations of current antiviral therapies for hepatitis B, there is an urgent need for new treatments that target multiple aspects of the HBV replication cycle to improve rates of functional cure. Here, we present CRISPR-Cas13b as a novel strategy to target HBV replication and protein expression, paving the way for its development as a potential new treatment option for patients living with chronic hepatitis B.

Morphological and molecular preservation through universal preparation of fresh-frozen tissue samples for multimodal imaging workflows.

The landscape of tissue-based imaging modalities is constantly and rapidly evolving. While formalin-fixed, paraffin-embedded material is still useful for histological imaging, the fixation process irreversibly changes the molecular composition of the sample. Therefore, many imaging approaches require fresh-frozen material to get meaningful results. This is particularly true for molecular imaging techniques such as mass spectrometry imaging, which are widely used to probe the spatial arrangement of the tissue metabolome. As high-quality fresh-frozen tissues are limited in their availability, any sample preparation workflow they are subjected to needs to ensure morphological and molecular preservation of the tissues and be compatible with as many of the established and emerging imaging techniques as possible to obtain the maximum possible insights from the tissues. Here we describe a universal sample preparation workflow, from the initial step of freezing the tissues to the cold embedding in a new hydroxypropyl methylcellulose/polyvinylpyrrolidone-enriched hydrogel and the generation of thin tissue sections for analysis. Moreover, we highlight the optimized storage conditions that limit molecular and morphological degradation of the sections. The protocol is compatible with human and plant tissues and can be easily adapted for the preparation of alternative sample formats (e.g., three-dimensional cell cultures). The integrated workflow is universally compatible with histological tissue analysis, mass spectrometry imaging and imaging mass cytometry, as well as spatial proteomic, genomic and transcriptomic tissue analysis. The protocol can be completed within 4 h and requires minimal prior experience in the preparation of tissue samples for multimodal imaging experiments.

Variant-to-function analysis of the childhood obesity chr12q13 locus implicates rs7132908 as a causal variant within the 3' UTR of FAIM2.

The ch12q13 locus is among the most significant childhood obesity loci identified in genome-wide association studies. This locus resides in a non-coding region within FAIM2; thus, the underlying causal variant(s) presumably influence disease susceptibility via cis-regulation. We implicated rs7132908 as a putative causal variant by leveraging our in-house 3D genomic data and public domain datasets. Using a luciferase reporter assay, we observed allele-specific cis-regulatory activity of the immediate region harboring rs7132908. We generated isogenic human embryonic stem cell lines homozygous for either rs7132908 allele to assess changes in gene expression and chromatin accessibility throughout a differentiation to hypothalamic neurons, a key cell type known to regulate feeding behavior. The rs7132908 obesity risk allele influenced expression of FAIM2 and other genes and decreased the proportion of neurons produced by differentiation. We have functionally validated rs7132908 as a causal obesity variant that temporally regulates nearby effector genes and influences neurodevelopment and survival.

22q11.2 Deletion-Associated Blood-Brain Barrier Permeability Potentiates Systemic Capillary Leak Syndrome Neurologic Features.

We present a case study of a young male with a history of 22q11.2 deletion syndrome (22qDS), diagnosed with systemic capillary leak syndrome (SCLS) who presented with acute onset of diffuse anasarca and sub-comatose obtundation. We hypothesized that his co-presentation of neurological sequelae might be due to blood-brain barrier (BBB) susceptibility conferred by the 22q11.2 deletion, a phenotype that we have previously identified in 22qDS. Using pre- and post-intravenous immunoglobulins (IVIG) patient serum, we studied circulating biomarkers of inflammation and assessed the potential susceptibility of the 22qDS BBB. We employed in vitro cultures of differentiated BBB-like endothelial cells derived from a 22qDS patient and a healthy control. We found evidence of peripheral inflammation and increased serum lipopolysaccharide (LPS) alongside endothelial cells in circulation. We report that the patient's serum significantly impairs barrier function of the 22qDS BBB compared to control. Only two other cases of pediatric SCLS with neurologic symptoms have been reported, and genetic risk factors have been suggested in both instances. As the third case to be reported, our findings are consistent with the hypothesis that genetic susceptibility of the BBB conferred by genes such as claudin-5 deleted in the 22q11.2 region promoted neurologic involvement during SCLS in this patient.

Safety of Deutetrabenazine for the Treatment of Tardive Dyskinesia and Chorea Associated with Huntington Disease.

INTRODUCTION: Deutetrabenazine is a vesicular monoamine transporter 2 inhibitor used to treat tardive dyskinesia (TD) and chorea associated with Huntington disease (HD). To enhance detection of safety signals across individual trials, integrated safety analyses of deutetrabenazine in TD and HD chorea were conducted. METHODS: For TD, safety data were integrated from two 12-week pivotal studies (ARM-TD and AIM-TD) and through week 15 of the open-label extension (OLE) study (RIM-TD). Data were analyzed by deutetrabenazine treatment group and placebo. For HD, safety data were integrated from the 12-week pivotal study (First-HD) and through week 15 of the OLE study (ARC-HD) for patients previously receiving placebo. Integrated deutetrabenazine data were compared with placebo from the pivotal study. RESULTS: For TD, deutetrabenazine (n = 384) was generally well tolerated compared with placebo (n = 130). Adverse event (AE) incidence was numerically higher in the response-driven deutetrabenazine vs the fixed-dose deutetrabenazine and placebo groups, respectively (any AE, 59.5% vs 44.4-50.0% and 53.8%; treatment-related AE, 38.1% vs 18.1-25.0% and 30.8%). Serious AEs were reported for 2.8-8.3% of patients in the deutetrabenazine groups and 6.9% in the placebo group. Common AEs (≥ 4%) included headache, somnolence, nausea, anxiety, fatigue, dry mouth, and diarrhea. AE incidence was higher during the titration vs maintenance periods. For HD, AE incidence was numerically higher with deutetrabenazine (n = 84) vs placebo (n = 45; any AE, 64.3% vs 60.0%; treatment-related AE, 38.1% vs 26.7%); serious AEs were reported for similar proportions for the deutetrabenazine and placebo groups, 2.4% and 2.2%, respectively. Common AEs (≥ 4%) included irritability, fall, depression, dry mouth, and fatigue. CONCLUSIONS: Data from an integrated analysis of studies in TD and an integrated analysis of studies of chorea in HD showed that deutetrabenazine has a favorable safety profile and is well tolerated across indications. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT02291861, NCT02195700, NCT01795859, NCT02198794, NCT01897896.

Unintended movements are often the first sign of Huntington disease. This type of unintended movement is called chorea in Huntington disease. Tardive dyskinesia causes unintended body movements. Deutetrabenazine is a medicine used to treat both types of movements. This report summarizes deutetrabenazine safety across five clinical studies. Safety was assessed via adverse events (side effects). Adverse events were compared between deutetrabenazine and inactive treatment (placebo). Serious adverse events were also compared. Serious adverse events cause substantial impairment or disruption. In tardive dyskinesia and chorea in Huntington disease studies, most patients kept taking deutetrabenazine. Adverse events were not a common reason to stop treatment. For tardive dyskinesia, adverse event rates were similar between deutetrabenazine (≤ 60%) and placebo (54%). Serious adverse event rates were also similar for deutetrabenazine (≤ 8%) and placebo (7%). Adverse events tended to be reported earlier in treatment. Common adverse events were headache, sleepiness, nausea, anxiety, fatigue, dry mouth, and diarrhea. For chorea in Huntington disease, adverse event rates were similar for deutetrabenazine (64%) and placebo (60%). Serious adverse event rates were also similar for deutetrabenazine (2%) and placebo (2%). Irritability, fall, depression, dry mouth, and fatigue were common adverse events. Adverse events were similar between deutetrabenazine and placebo in both conditions. Deutetrabenazine was well tolerated for patients with either tardive dyskinesia or chorea in Huntington disease.

The Royal College of Radiologists National Vulvar Cancer Audit.

AIMS: This audit examined UK vulvar cancer practice from March 2018 to January 2019 and compared it to standards from national and international recommendations. Follow-up data collection in 2020 examined patient outcomes and toxicity. MATERIALS AND METHODS: Audit standards were based on Royal College of Radiologists (RCR) guidance and published literature. A web-based questionnaire was sent to the audit leads at all cancer centres in the UK. Prospective data collection included patient demographics, tumour characteristics, radiotherapy indications, dosimetry, timelines, and follow-up data. The audit targets were 95% compliance with the RCR dose/fractionation schemes in definitive and adjuvant patients, 40% use of intensity modulated radiotherapy (IMRT), 100% of radical patients treated as category 1, and 95% use of gap compensation for category 1 patients. RESULTS: 34/54 UK radiotherapy centres (63%) completed data entry for 152 patients. 23 out of 34 (68%) centres submitted follow-up data for 94 patients. One indicator exceeded the audit target: 98% of radical patients received IMRT. The indicators of RCR dose/fractionation compliance for adjuvant/definitive radiotherapy were achieved by 80%/43% for the primary, 80%/86% for elective lymph nodes, and 21%/21% for pathological lymph nodes. The use of concomitant chemotherapy with radical radiotherapy in suitable patients was achieved by 71%. Other indicators demonstrated that 78% were treated as category 1 and 27% used gap compensation. Acute toxicity was mostly related to skin, gastrointestinal, and genitourinary sites. Grade 3 and Grade 4 toxicities were seen at acceptable rates within the radical and adjuvant groups. Late toxicity was mostly grade 0. CONCLUSION: This audit provides a comprehensive picture of UK practice. IMRT is widely used in the UK, and treatment-related toxicity is moderate. The dose fractionation was very heterogeneous. The designation of vulvar cancer as category 1 was not regularly followed for radical/adjuvant patients, and there was minimal gap compensation during treatment.

Long-term safety, tolerability and efficacy of apomorphine sublingual film in patients with Parkinson's disease complicated by OFF episodes: a phase 3, open-label study.

BACKGROUND: Apomorphine sublingual film (SL-APO) is an on-demand treatment for OFF episodes in patients with Parkinson's disease (PD). OBJECTIVE: To assess the long-term (≥ 3 years) safety/tolerability and efficacy of SL-APO. METHODS: Study CTH-301 ( http://www. CLINICALTRIALS: gov NCT02542696; registered 2015-09-03) was a phase 3, multicentre, open-label study of SL-APO in PD patients with motor fluctuations, comprised of a dose-titration and long-term safety phase. All participants received SL-APO. The primary endpoint was safety/tolerability (treatment-emergent adverse events [TEAEs]) during the long-term safety phase. Efficacy assessments included the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (motor examination), assessed at weeks 24, 36 and 48 during the first year of the long-term safety phase. RESULTS: 496 patients were included and 120 (24.2%) completed the long-term safety phase. Mean duration of SL-APO exposure was 294.3 days. TEAEs related to study drug were experienced by 65.3% of patients (most common: nausea [6.0%], stomatitis [1.8%], lip swelling [1.8%], dizziness [1.6%], oral mucosal erythema [1.6%], mouth ulceration [1.6%]). TEAEs leading to study drug withdrawal were experienced by 34.0% of patients (most common: nausea [5.4%], lip swelling [4.5%], mouth ulceration [2.6%], stomatitis [2.3%]). A clinically meaningful reduction in MDS-UPDRS part III score was observed as soon as 15 min following administration of SL-APO, with peak effects observed approximately 30 min post-dose and sustained up to 90 min post-dose; results were consistent over 48 weeks. CONCLUSIONS: SL-APO was generally well tolerated and efficacious over the long term as an on-demand treatment for OFF episodes in patients with PD.

Targeted Delivery of Abaloparatide to Spinal Fusion Site Accelerates Fusion Process in Rats.

Spinal fusions are performed to treat congenital skeletal malformations, spondylosis, degenerative disk diseases, and other pathologies of the vertebrae that can be resolved by reducing motion between neighboring vertebrae. Unfortunately, up to 100,000 fusion procedures fail per year in the United States, suggesting that efforts to develop new approaches to improve spinal fusions are justified. We have explored whether the use of an osteotropic oligopeptide to target an attached bone anabolic agent to the fusion site might be exploited to both accelerate the mineralization process and improve the overall success rate of spinal fusions. The data presented below demonstrate that subcutaneous administration of a modified abaloparatide conjugated to 20 mer of D-glutamic acid not only localizes at the spinal fusion site but also outperforms the standard of care (topically applied BMP2) in both speed of mineralization (p < 0.05) and overall fusion success rate (p < 0.05) in a posterior lateral spinal fusion model in male and female rats, with no accompanying ectopic mineralization. Because the bone-localizing conjugate can be administered ad libitum post-surgery, and since the procedure appears to improve on standard of care, we conclude that administration of a bone-homing anabolic agent for improvement of spinal fusion surgeries warrants further exploration.

Self-referential processing in anorexia nervosa.

OBJECTIVE: Anorexia nervosa (AN) is a serious psychiatric illness associated with significant medical and psychiatric comorbidity and impairment. Theoretical models of AN and self-report studies suggest that negative self-evaluation (i.e., low self-esteem) is related to the development and maintenance of AN. The goal of this study was to extend findings from self-report methodology using a neurocognitive task that probes self-evaluation implicitly and explicitly. METHOD: We compared female adolescent and adult patients with AN (n = 35) and healthy controls (HC, n = 38) on explicit (i.e., endorsement of words as self-relevant), implicit (recall, recognition, reaction time), and composite (i.e., valence index, bias score, drift rates) indices of self-evaluation. We applied a drift-diffusion model to compute the drift rates, reflecting participants' decision-making process as to whether words were self-relevant. The association between self-evaluation indices and eating disorder severity was examined. RESULTS: There were significant Group × Condition interaction effects for all explicit and implicit measures (all p's ≤ .01), where the AN group endorsed, recalled, and recognized more negative relative to positive words than HC. The AN group had more negative valence index and bias scores, and slower drift rate away from negative words, reflecting more negative self-evaluation. The finding for recall was attenuated when individuals with depression were excluded. Measures of self-evaluation bias were not related to eating disorder severity. DISCUSSION: Using a neurocognitive approach that includes explicit and implicit indices of bias, results suggest that patients with AN have more negative self-evaluation. Due to the cross-sectional design, additional studies are needed to further evaluate directionality. PUBLIC SIGNIFICANCE: Negative self-evaluation/low self-esteem is thought to contribute to eating disorder symptoms. Findings of this study using a neurocognitive task to probe self-evaluation suggested that individuals with anorexia nervosa have more negative self-evaluation, reflected by endorsing and remembering more negative (than positive) words compared to healthy controls, and doing so faster. Targeting the construct of negative self-evaluation in treatment of AN may be warranted.

National Survey of Current Follow-up Protocols for Patients Treated for Endometrial Cancer in the UK.

AIMS: The aim of this study was to establish a baseline of national practice for follow-up after treatment for endometrial cancer in the UK. MATERIALS AND METHODS: An online cross-sectional survey was developed and distributed through the Royal College of Radiologists via an email link to the audit leads of radiotherapy centres in the UK. The survey was conducted from November 2021 to 5 January 2022. The main themes assessed in the survey were the form, frequency and duration of follow-up practices. RESULTS: There were a total of 43/61 (70%) complete responses. 93% of centres had a standard follow-up protocol and 7% who did not have a follow-up protocol discharged patients after the post-operative review. Five centres (13%) used molecular profiling to inform follow-up practices. Patient-initiated follow-up was mainly used in the cohort of patients who had surgery alone with no adjuvant treatment (68%, (19/28)). In the cohort who had face-to-face follow-up, the majority had pelvic examinations as part of their review and total follow-up for five years. 93% of respondents are interested in a national follow-up protocol. CONCLUSION: Our data shows that there is national variation in practise with regard to follow-up of women treated for endometrial cancer. Many of the follow-up practises are based on conventional follow-up regimens and these may fail to address the more holistic needs of cancer survivors. Recent publication of updated guidance from the British Gynaecological Cancer Society may help standardise practise and provide a more relevant approach to follow-up for women treated for endometrial cancer.