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Jonathan A Coulter,1 Suneil Jain,2 Karl T Butterworth,2 Laura Taggart,2 Glenn Dickson,2 Stephen J McMahon,3 Wendy Hyland,1 Mark F Muir,3 Coleman Trainor,2 Alan Hounsell,2,4 Joe M O'Sullivan,2,4 Giuseppe Schettino,2 Fred Currell,3 David G Hirst,1 Kevin M Prise21School of Pharmacy, McClay Research Centre, 2Centre for Cancer Research and Cell Biology, 3School of Mathematics and Physics, Queens University Belfast, 4Belfast Health and Social Care Trust, Belfast, IrelandBackground: This follow-up study aims to determine the physical parameters which govern the differential radiosensitization capacity of two tumor cell lines and one immortalized normal cell line to 1.9 nm gold nanoparticles. In addition to comparing the uptake potential, localization, and cytotoxicity of 1.9 nm gold nanoparticles, the current study also draws on comparisons between nanoparticle size and total nanoparticle uptake based on previously published data.Methods: We quantified gold nanoparticle uptake using atomic emission spectroscopy and imaged intracellular localization by transmission electron microscopy. Cell growth delay and clonogenic assays were used to determine cytotoxicity and radiosensitization potential, respectively. Mechanistic data were obtained by Western blot, flow cytometry, and assays for reactive oxygen species.Results: Gold nanoparticle uptake was preferentially observed in tumor cells, resulting in an increased expression of cleaved caspase proteins and an accumulation of cells in sub G1 phase. Despite this, gold nanoparticle cytotoxicity remained low, with immortalized normal cells exhibiting an LD50 concentration approximately 14 times higher than tumor cells. The surviving fraction for gold nanoparticle-treated cells at 3 Gy compared with that of untreated control cells indicated a strong dependence on cell type in respect to radiosensitization potential.Conclusion: Gold nanoparticles were most avidly endocytosed and localized within cytoplasmic vesicles during the first 6 hours of exposure. The lack of significant cytotoxicity in the absence of radiation, and the generation of gold nanoparticle-induced reactive oxygen species provide a potential mechanism for previously reported radiosensitization at megavoltage energies.Keywords: endocytosis, proliferation, reactive oxygen species, transmission electron microscopy

Dystroglycan is an essential component of the dystrophin-glycoprotein complex that links the actin-associated cytoskeleton to the extracellular matrix (ECM). Dystroglycan, encoded by the DAG1 gene, is proteolytically cleaved into α-Dystroglycan, a highly glycosylated protein that binds to ECM ligands, and β-Dystroglycan, a transmembrane protein non-covalently linked to α-Dystroglycan. Biallelic variants in DAG1 cause primary dystroglycanopathies with a wide phenotypic variability. Through exome sequencing we identified heterozygous truncating DAG1 variants in 18 individuals from 10 unrelated families. Five variants were stop gains and five were frameshift; with the majority localized in α-Dystroglycan (90%). Segregation analysis was available for seven families, with one variant being de novo, three dominantly inherited and three inherited from an asymptomatic parent. WGS performed in six patients excluded the presence of additional deep intronic DAG1 variants. The most common clinical features were the presence of high CK levels (18/18), myalgia (9/18) and muscle hypertrophy (3/18). Mild levels of learning or social difficulties were also observed in some patients (4/18). Histological analysis was performed in eight patients and showed the presence of mild dystrophic or myopathic changes. Dystroglycan immunostaining, either β-Dystroglycan or α-Dystroglycan, was reduced in four out of five patients. RNAseq data from muscle biopsies from two unrelated patients showed the expression of both wild-type and truncated alleles, indicating that nonsense-mediated decay is not triggered by these alleles. To date, few studies have reported the presence of heterozygous truncating DAG1 variants in asymptomatic or pauci-symptomatic individuals. Here, we describe 18 additional individuals with AD DAG1 hyperCKemia with mild muscular manifestations. Expression of both the truncated and wild-type alleles argues against haploinsufficiency as the underlying pathomechanisms in DAG1 -AD individuals. [ABSTRACT FROM AUTHOR]

Low cerebrospinal (CSF) arginine vasopressin (AVP) concentration is a biomarker of social impairment in low-social monkeys and children with autism, suggesting that AVP administration may improve primate social functioning. However, AVP administration also increases aggression, at least in "neurotypical" animals with intact AVP signaling. Here, we tested the effects of a voluntary drug administration method in low-social male rhesus monkeys with high autistic-like trait burden. Monkeys received nebulized AVP or placebo, using a within-subjects design. Study 1 (N = 8) investigated the effects of AVP administration on social cognition in two tests comparing responses to social versus nonsocial stimuli. Test 1: Placebo-administered monkeys lacked face recognition memory, whereas face recognition memory was "rescued" following AVP administration. In contrast, object recognition memory was intact and did not differ between administration conditions. Test 2: Placebo-administered monkeys did not respond to conspecific social communication cues, whereas following AVP administration, they reciprocated affiliative communication cues with species-typical affiliative responses. Importantly, AVP administration did not increase aggressive responses to conspecific aggressive or affiliative overtures. Study 2 (N = 4) evaluated the pharmacokinetics of this administration method. Following AVP nebulization, we observed a linear increase in cisternal CSF AVP levels, and a quadratic rise and fall in blood AVP levels. These findings indicate that nebulized AVP likely penetrates the central nervous system, selectively promotes species-typical responses to social information, and does not induce aggression in low-social individuals. Nebulized AVP therefore may hold promise for managing similar social symptoms in people with autism, particularly in very young or lower functioning individuals., Competing Interests: Competing interests statement:The Board of Trustees of the Leland Stanford Junior University filed a US patent application, 11,951,149 (“Intranasal Vasopressin Treatment for Social Deficits in Children with Autism”). This patent has not been licensed.

Bulimia nervosa (BN) is characterized by recurrent loss of control over eating (LOC) and inappropriate compensatory behaviors. Although cognitive-behavioral therapy (CBT) is efficacious for BN, many patients continue to experience symptoms at posttreatment. One potential driver of this low treatment response may be low mood, which maintains BN symptoms through negative reinforcement. Thus, it is important to understand how mood changes over enhanced cognitive-behavioral therapy (CBT-E) and whether these changes are associated with improved treatment outcomes. Participants (N = 56) with BN-spectrum eating disorders (EDs) received 16 sessions of the focused version of CBT-E. The Eating Disorder Examination (EDE) was used to measure ED symptoms (global ED pathology, frequency of binge episodes, and compensatory behaviors) at pre- and posttreatment. Latent growth mixture modeling (LGMM) of affective ratings via digital self-monitoring identified latent growth classes. Kruskal-Wallis H tests examined the effect of trajectory of change in mood on pre- to posttreatment symptom change. LGMM yielded a four-class model that best fit the data representing distinct mood trajectories over the course of treatment: (a) highest baseline mood, linear improving; (b) moderate baseline mood, stable; (c) moderate baseline mood, quadratic worsening; and (d) lowest baseline mood, quadratic improving. Participants who demonstrated worsening mood over treatment (i.e., individuals in the "moderate baseline mood, quadratic worsening" class) had significantly higher EDE global scores at posttreatment and follow-up compared to participants with stable mood across treatment. Change in LOC eating frequency and compensatory behaviors across treatment did not significantly differ by mood class. The main effect of mood class or interaction effect between time and mood class on objective binge episodes, subjective binge episodes, and compensatory behaviors was not significant. There were no significant differences in global ED pathology at either posttreatment or follow-up for any other class comparisons. These results suggest that certain trajectories of change in mood during treatment are particularly associated with change in pre- to posttreatment EDE global score. If replicated, our findings could suggest that future iterations of CBT-E should target mood early in treatment in order to maximize reductions in global eating pathology., (Copyright © 2024 Association for Behavioral and Cognitive Therapies. Published by Elsevier Ltd. All rights reserved.)

Cannabis use is prevalent among individuals with binge eating (BE; i.e., the inability to control eating behavior). Yet, only two studies to date (both over 20 years old) have tested if cannabis use relates to clinical severity among BE samples. Characterizing the relationship between cannabis use, eating disorder (ED) severity, and other psychiatric symptoms in BE samples is necessary for informing screening and clinical recommendations. The present study characterized cannabis use among adults with BE and tested between-group and within-group relationships between cannabis use and eating disorder symptoms, alcohol consumption and symptoms, and depression symptoms. Participants ( N = 165) were treatment-seeking adults with at least once weekly BE in the past 3 months who completed clinical interviews and self-report measures before treatment. Over 23% of participants reported cannabis use in the past 3 months, with most persons using cannabis reported using "once or twice" or "monthly." Most persons using cannabis reported cannabis-related symptoms. Persons using cannabis reported significantly greater alcohol consumption and were more likely to report alcohol-related symptoms compared to persons not using cannabis. No associations were observed between cannabis use, eating disorder symptoms, and depressions symptoms. These findings indicate that a notable subset of patients with BE use cannabis and experience cannabis-related problems, and that cannabis and alcohol use may be related for these individuals. Considering legal and sociocultural shifts in cannabis availability and prevalence, results from the present study support screening for cannabis and alcohol use patterns in patients with BE. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Binge-spectrum eating disorders (EDs; bulimia nervosa, binge eating disorder) often develop during adolescence and are associated with serious psychological and physical consequences. Current treatments for adolescents are highly behavioral in nature and while efficacious, many patients do not reach remission indicating that current treatments fail to target a key maintenance factor for EDs. One potential maintenance factor is poor family functioning (FF). In particular, high family conflict (e.g., arguing, critical comments) and low family cohesion (e.g., warmth, support) are known to maintain ED behaviors. Poor FF can (1) cause or exacerbate an adolescent's use of ED behaviors to cope with life stress and/or (2) inhibit parents from being a resource to adolescents during ED treatment. Attachment-Based Family Therapy (ABFT) is specifically designed to improve FF, and thus may be a promising adjunct to behavioral ED intervention strategies. ABFT, however, has not been tested in adolescents with binge-spectrum EDs. Thus, the current study is the first to evaluate a 16-week adapted ABFT treatment for adolescents with EDs ( N = 8, M age = 16.00, 71.43% female, 71.43% White) fusing together behavioral treatment for EDs with ABFT for highest possible impact. Eight families were treated in an open pilot trial to examine treatment feasibility, acceptability, and preliminary efficacy on FF and eating pathology. Overall, findings were promising. ABFT + B treatment was feasible and acceptable and showed preliminary evidence that it could improve FF and ED behaviors. Future research will test this intervention in a larger sample and further examine the role of FF in maintaining ED symptoms., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Inhibitory control, one's ability to inhibit automatic responses to desirable stimuli, may be inadequately targeted in interventions for loss-of-control eating (LOC). Promising evidence has identified inhibitory control trainings (ICTs) as an avenue to target inhibitory control directly; however, effects of ICTs on real-world behavior are limited. Compared to typical computerized trainings, virtual reality (VR) presents several potential advantages that may address key shortcomings of traditional ICTs, i.e. poor approximation to everyday life. The present study utilized a 2 × 2 factorial design of treatment type (ICT vs sham) by treatment modality (VR vs standard computer), which allows for increased statistical power by collapsing across conditions. Our primary aim was to examine the feasibility and acceptability of six weeks of daily training among groups. A secondary aim was to preliminarily assess main and interactive effects of treatment type and modality on target engagement and efficacy (i.e., training compliance, change in LOC episodes, inhibitory control, and implicit liking of foods). Participants (N = 35) with ≥1×/weekly LOC were assigned to one of four conditions and completed ICTs daily for six weeks. The trainings were feasible and acceptable, evinced by high retention and compliance across time and condition. Although completing daily trainings across treatment types and modalities was associated with large decreases in LOC, there were no meaningful effects of either treatment type or modality, nor a significant interaction effect, on LOC or mechanistic variables. Future research should aim to increase the efficacy of ICT (both standard and VR-based) and test in fully-powered clinical trials., Competing Interests: Declaration of competing interest None of the authors report a conflict of interest. All study procedures were approved by the Drexel University Institutional Review Board (Protocol # 1906007227). All authors contributed to the study conception, design, data management, data analysis, and/or writing of the manuscript. All authors commented on previous versions of the manuscript, and all authors read and approved the final manuscript. Correspondence concerning this article should be addressed to Stephanie M. Manasse, Ph.D., smm522@drexel.edu, 3201 Chestnut St. Stratton Hall, Rm. 244, Philadelphia, PA, 19104, United States. The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background and Objectives: The prevalence and progression of respiratory muscle dysfunction in patients with limb girdle muscular dystrophies (LGMDs) has been only partially described to date. Most reports include cross-sectional data on a limited number of patients making it difficult to gain a wider perspective on respiratory involvement throughout the course of the disease and to compare the most prevalent LGMD subtypes., Methods: We reviewed the results of spirometry studies collected longitudinally in our cohort of patients in routine clinical visits from 2002 to 2020 along with additional clinical and genetic data. A linear mixed model was used to investigate the factors associated with the progression of respiratory dysfunction., Results: We followed up 156 patients with 5 different forms of LGMDs for a median of 8 years (range 1-25 years). Of them, 53 patients had pathogenic variants in the Capn3 gene, 47 patients in the Dysf gene, 24 patients in the Fkrp gene, 19 in the Ano5 gene, and 13 in one of the sarcoglycan genes (SCG). At baseline, 58 patients (37.1%) had a forced vital capacity percentage predicted (FVCpp) below 80%, while 14 patients (8.9%) had peak cough flow (PCF) values below 270 L/min. As a subgroup, FKRP was the group with a higher number of patients having FVC <80% and/or PCF <270 L/min at initial assessment (66%). We observed a progressive decline in FVCpp and PCF measurements over time, being age, use of wheelchair, and LGMD subtype independent factors associated with this decline. Fkrp and sarcoglycan patients had a quicker decline in their FVC (Kaplan-Meier curve, F test, p < 0.001 and p = 0.02, respectively). Only 7 of the 58 patients with low FVCpp values reported symptoms of respiratory dysfunction, which are commonly reported by patients with FVCpp below 50%-60%. The number of patients ventilated increased from 2 to 8 during follow-up., Discussion: Respiratory dysfunction is a frequent complication of patients with LGMDs that needs to be carefully studied and has direct implications in the care offered in daily clinics. Respiratory dysfunction is associated with disease progression because it is especially seen in patients who are full-time wheelchair users, being more frequent in patients with mutations in the Fkrp and sarcoglycan genes., Competing Interests: The authors report no relevant disclosures. Go to Neurology.org/NG for full disclosures, (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Purpose: Fear of weight gain may play a central role in maintaining eating disorders (EDs), but research on the role of fear of weight gain during cognitive behavioral therapy (CBT-E) for binge-spectrum EDs is sparse. We examined changes in fear of weight gain during CBT-E for binge-spectrum EDs. We investigated whether fear of weight gain predicted loss of control (LOC) eating or weight change., Methods: Participants (N = 63) were adults of any gender recruited as part of a larger trial. Participants received 12 sessions of CBT-E, completed diagnostic assessments at pre-, mid-, and post-treatment, and completed brief surveys before sessions., Results: Fear of weight gain decreased across treatment, moderated by diagnosis. Those with bulimia nervosa spectrum EDs (BN-spectrum), compared to binge eating disorder, reported higher fear of weight gain at baseline and experienced a larger decrease in fear across treatment. Those reporting higher fear of weight gain at a given session experienced more frequent LOC episodes the following week. Fear of weight gain was not associated with session-by-session changes in BMI., Conclusion: CBT-E results in decreases in fear of weight gain, but levels remain high at post-treatment, especially for those with BN-spectrum EDs. Future interventions should consider targeting fear of weight gain as a maintaining factor for LOC episodes TRIAL REGISTRATION: NCT04076553., Level of Evidence: Level II controlled trial without randomization., (© 2023. The Author(s).)

Objective: Adjunctive mobile health (mHealth) technologies offer promise for improving treatment response to enhanced cognitive-behavior therapy (CBT-E) among individuals with binge-spectrum eating disorders, but research on the key "active" components of these technologies has been very limited. The present study will use a full factorial design to (1) evaluate the optimal combination of complexity of two commonly used mHealth components (i.e., self-monitoring and microinterventions) alongside CBT-E and (2) test whether the optimal complexity level of these interventions is moderated by baseline self-regulation. Secondary aims of the present study include evaluating target engagement associated with each level of these intervention components and quantifying the component interaction effects (i.e., partially additive, fully additive, or synergistic effects)., Method: Two hundred and sixty-four participants with binge-spectrum eating disorders will be randomized to six treatment conditions determined by the combination of self-monitoring condition (i.e., standard self-monitoring or skills monitoring) and microinterventions condition (i.e., no microinterventions, automated microinterventions, or just-in-time adaptive interventions) as an augmentation to 16 sessions of CBT-E. Treatment outcomes will be measured using the Eating Disorder Examination and compared by treatment condition using multilevel models., Results: Results will clarify the "active" components in mHealth interventions for binge eating., Discussion: The present study will provide critical insight into the efficacy of commonly used digital intervention components (i.e., skills monitoring and microinterventions) alongside CBT-E. Furthermore, results of this study may inform personalization of digital intervention intensity based on patient profiles of self-regulation., Public Significance: This study will examine the relative effectiveness of commonly used components of application-based interventions as an augmentation to cognitive-behavioral therapy for binge eating. Findings from this study will inform the development of an optimized digital intervention for individuals with binge eating., (© 2022 Wiley Periodicals LLC.)

Eating disorders (EDs) are complex psychiatric diagnoses requiring specialized care. Family-based treatment (FBT) is the first-line treatment for adolescent anorexia nervosa and is also efficacious for other EDs. This study describes practice changes due to the implementation of an integrated interdisciplinary FBT-aligned treatment program for EDs at a large tertiary care hospital in the United States. We examined the feasibility and acceptability of implementation, barriers to implementation, and impact on providers' roles over a one-year period. Practice changes came with shifts in roles, and were largely experienced as acceptable with good suitability. Barriers identified may inform future interdisciplinary implementation efforts., Competing Interests: Conflict of Interest Statement Financial Disclosure: Dr. Le Grange receives royalties from Guilford Press and Routledge for books on family-based treatment and is co-director of the Training Institute for Child and Adolescent Eating Disorders, LLC, which trains professionals in FBT and other treatment modalities. Dr. Forsberg receives royalties from Routledge Press for a book on supervision in FBT. On behalf of all identified authors, we wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.

Purpose: Up to 44% of individuals with bulimia nervosa (BN) experience worsening of symptoms after cognitive behavior therapy (CBT). Identifying risk for post-treatment worsening of symptoms using latent trajectories of change in eating disorder (ED) symptoms during treatment could allow for personalization of treatment to improve long-term outcomes METHODS: Participants (N = 56) with BN-spectrum EDs received 16 sessions of CBT and completed digital self-monitoring of eating episodes and ED behaviors. The Eating Disorder Examination was used to measured ED symptoms at post-treatment and 3-month follow-up. Latent growth mixture modeling of digital self-monitoring data identified latent growth classes. Kruskal-Wallis H tests examined effect of trajectory of change in ED symptoms on post-treatment to follow-up symptom change., Results: Multi-class models of change in binge eating, compensatory behaviors, and regular eating improved fit over one-class models. Individuals with high frequency-rapid response in binge eating (H(1) = 10.68, p =0 .001, η 2  = 0.24) had greater recurrence of compensatory behaviors compared to individuals with low frequency-static response. Individuals with static change in regular eating exhibited greater recurrence of binge eating than individuals with moderate response (H(1) = 8.99, p = 0.003, η 2  = 0.20)., Conclusion: Trajectories of change in ED symptoms predict post-treatment worsening of symptoms. Personalized treatment approaches should be evaluated among individuals at risk of poor long-term outcomes., Level of Evidence: IV, evidence obtained from multiple time series., Trial Registration: ClinicalTrials.gov registration number NCT03673540, registration date: September 17, 2018., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: Emotion regulation (ER) deficits are associated with illness severity in individuals with bulimia nervosa. We examined whether baseline ER abilities are associated with remission following enhanced cognitive behavioural therapy for eating disorders (CBT-E)., Method: Participants (N = 50, 85.0% female) receiving CBT-E completed a measure (yielding a global score and six subscale scores) of ER pre-treatment. Remission was assessed by the Eating Disorder Examination at post-treatment and follow-up. Analyses tested associations between baseline ER and behavioural, cognitive, or full remission at post-treatment and three-month follow-up., Results: Lower global ER abilities, measured by the Difficulties in Emotion Regulation Scale, were associated with lower likelihood of behavioural and full, but not cognitive, remission at post-treatment. Specifically, individuals low in emotional clarity and impulse control were less likely to be behaviourally remitted. Those low in emotional acceptance, awareness, clarity, or strategies to manage emotion were less likely to be fully remitted. Global ER scores were not associated with any remission type at follow-up., Discussion: Baseline ER deficits were associated with lower likelihood of behavioural or full remission at post-treatment. However, ER was less associated with remission at follow-up, indicating that ER is most important during treatment. Findings highlight a need for targeted treatments aimed at improving ER., (© 2022 Eating Disorders Association and John Wiley & Sons Ltd.)