A case series to test the acceptability, feasibility and preliminary efficacy of AVATAR therapy in anorexia nervosa.

BACKGROUND: Patients with anorexia nervosa tend to experience an inner "eating disorder" voice. They struggle to recognise and assert their own identity over the illness's identity and relate to it from a powerless and subordinate position. AVATAR therapy was developed to help patients with psychosis to gain greater power and control over distressing voices. The goal of this study was to test the feasibility, acceptability, safety and preliminary efficacy of an adaptation of AVATAR therapy for anorexia nervosa. METHODS: Twelve adult patients with anorexia nervosa were recruited. Ten completed an assessment session and between five to seven therapy sessions. The assessment session consisted in the creation of an avatar to represent the "eating disorder". This was accomplished by manipulating auditory and visual characteristics through a specialist computer software. During the therapy sessions, patients interacted with the avatar to assert their own desires and will. Patients completed baseline, end of intervention and follow-up (4-week) online questionnaires. A non-concurrent multiple baselines single case experimental design (SCED) was used (A1BA2). Feasibility, acceptability, safety and preliminary efficacy of the intervention were assessed. RESULTS: The therapy met pre-specified criteria relating to (1) Feasibility: sample recruited within three months; retention rate at the end of the treatment phase = 81.9%; therapy completion rate = 90.1%. (2) Safety: no serious adverse events associated with the intervention. (3) Acceptability: mean ratings = 7.5 (SD = 2.61) out of ten, on a 0-10 scale of acceptability (10 = complete satisfaction). With regards to efficacy, participants reported significantly lower levels of distress associated with the eating disorder voice and higher levels of self-compassion at the end of treatment. No other significant changes were observed in frequency of the eating disorder voice, voice's characteristics, such as omnipotence and malevolence, eating disorder symptoms and symptoms of anxiety, depression and stress. Patients' feedback indicated that the therapy had helped with their ability to stand up to the illness, make positive changes around eating, and increase their motivation to recover and self-compassion. CONCLUSION: AVATAR therapy for anorexia nervosa is feasible, acceptable and safe for patients. Larger studies are needed to test clinical efficacy. TRIAL REGISTRATION: The study was pre-registered on the clinicaltrials.gov registry (https://clinicaltrials.gov/ct2/show/NCT04778423).

People with anorexia nervosa often struggle with connecting to their identity beyond the illness. They tend to relate to the eating disorder from a powerless and submissive position. The aim of this study was to test AVATAR therapy for anorexia nervosa. The goal of the intervention was to help patients to assert themselves, their identity, will, power and desires, when confronted with the "voice" of the illness. Twelve patients with anorexia nervosa were recruited and 10 completed one assessment session and five to seven therapy sessions. During the assessment session, patients were guided by the therapist to create a representation of their illness ("the avatar") by manipulating visual and auditory characteristics through a computer software. During treatment, they were supported by the therapist to assert themselves over the illness, responding to the abusive and critical comments of the eating disorder delivered by "the avatar". Patients' qualitative feedback indicated that the therapy was meaningful to them, and that it helped to recognise their own voice as distinct from the illness. The distress perceived in relation to the eating disorder voice decreased over time, and feelings of self-compassion increased at the end of therapy. Findings point towards the acceptability and usefulness of AVATAR therapy for anorexia nervosa. Larger studies are needed expand these results.

Misregulation of mitochondria-lysosome contact dynamics in Charcot-Marie-Tooth Type 2B disease Rab7 mutant sensory peripheral neurons.

Inter-organelle contact sites between mitochondria and lysosomes mediate the crosstalk and bidirectional regulation of their dynamics in health and disease. However, mitochondria-lysosome contact sites and their misregulation have not been investigated in peripheral sensory neurons. Charcot-Marie-Tooth type 2B disease is an autosomal dominant axonal neuropathy affecting peripheral sensory neurons caused by mutations in the GTPase Rab7. Using live super-resolution and confocal time-lapse microscopy, we showed that mitochondria-lysosome contact sites dynamically form in the soma and axons of peripheral sensory neurons. Interestingly, Charcot-Marie-Tooth type 2B mutant Rab7 led to prolonged mitochondria-lysosome contact site tethering preferentially in the axons of peripheral sensory neurons, due to impaired Rab7 GTP hydrolysis-mediated contact site untethering. We further generated a Charcot-Marie-Tooth type 2B mutant Rab7 knock-in mouse model which exhibited prolonged axonal mitochondria-lysosome contact site tethering and defective downstream axonal mitochondrial dynamics due to impaired Rab7 GTP hydrolysis as well as fragmented mitochondria in the axon of the sciatic nerve. Importantly, mutant Rab7 mice further demonstrated preferential sensory behavioral abnormalities and neuropathy, highlighting an important role for mutant Rab7 in driving degeneration of peripheral sensory neurons. Together, this study identifies an important role for mitochondria-lysosome contact sites in the pathogenesis of peripheral neuropathy.

Loss of function of the ALS-associated NEK1 kinase disrupts microtubule homeostasis and nuclear import.

Loss-of-function variants in NIMA-related kinase 1 (NEK1) constitute a major genetic cause of amyotrophic lateral sclerosis (ALS), accounting for 2 to 3% of all cases. However, how NEK1 mutations cause motor neuron (MN) dysfunction is unknown. Using mass spectrometry analyses for NEK1 interactors and NEK1-dependent expression changes, we find functional enrichment for proteins involved in the microtubule cytoskeleton and nucleocytoplasmic transport. We show that α-tubulin and importin-ß1, two key proteins involved in these processes, are phosphorylated by NEK1 in vitro. NEK1 is essential for motor control and survival in Drosophila models in vivo, while using several induced pluripotent stem cell (iPSC)-MN models, including NEK1 knockdown, kinase inhibition, and a patient mutation, we find evidence for disruptions in microtubule homeostasis and nuclear import. Notably, stabilizing microtubules with two distinct classes of drugs restored NEK1-dependent deficits in both pathways. The capacity of NEK1 to modulate these processes that are critically involved in ALS pathophysiology renders this kinase a formidable therapeutic candidate.

Shot Talk: Development and Pilot Test of a Theory of Planned Behavior Campaign to Combat College Student COVID-19 Vaccine Hesitancy.

Among college students, evidence of relatively lower levels of concern of COVID-19 infection, rapid rates of transmission, and lagging vaccination rates substantiates a need to combat college student COVID-19 vaccine hesitancy. This two-phase study comprised formative research, development, and pilot testing of a campaign to combat COVID-19 vaccine hesitancy among college students. In phase one, focus group discussions with college students (N = 48) uncovered their specific attitudes, subjective norms, and perceived behavioral control toward the COVID-19 vaccine. Thematic analysis revealed concerns about vaccine safety, efficacy, cost, and politicization, as well as perceived barriers to accessing information and the vaccine itself. Guided by formative research from phase one and the theory of planned behavior, phase two comprised campaign development and pilot testing. Participants (N = 30) completed a pretest and posttest survey assessing TPB constructs and awareness of information toward COVID-19 vaccination surrounding a two-week peer-to-peer campaign called Shot Talk. Results revealed increases in safety-related attitudes, perceived behavioral control, and awareness of information regarding COVID-19 vaccination. Practical implications for theory-driven campaigns and strategic messaging for primary COVID-19 vaccination and beyond are discussed.

Understanding clinical decision-making in mesothelioma care: a mixed methods study.

INTRODUCTION: Malignant pleural mesothelioma is a rare, incurable cancer arising from previous asbestos exposure; patients have a poor prognosis, with a median survival rate of 8-14 months. Variation in mesothelioma clinical decision-making remains common with a lack of multidisciplinary knowledge sharing, leading to inconsistencies in treatment decisions. The study aimed to explore which factors impacted on clinicians' decision-making in mesothelioma care, with a view to optimising the mesothelioma care pathway. METHODS: This mixed methods study consisted of documentary analysis of local and national guidelines, policies or documents pertaining to mesothelioma care pathways, secondary analysis of mesothelioma patient data, and interviews with clinicians attending lung cancer and/or mesothelioma-specific multidisciplinary team meetings. The study took place at three National Health Service trusts in England. Documentations relating to patients' treatment pathways were collated and reviewed qualitatively. Records of patients with mesothelioma were extracted from hospital patient records and data collected on diagnosis date, treatment, mortality rates, survival postdiagnosis, age and clinical care team. Data were statistically analysed. Interviews with clinicians explored influences on clinical decision-making, including challenges or barriers involved. Data were thematically analysed. The Strengthening the Reporting of Observational Studies in Epidemiology reporting checklist was used. RESULTS: There were differences in the structure and delivery of mesothelioma treatment and care between trusts. Four main themes were identified: 'collaboration and communication', 'evidence base and knowledge', 'role of the clinician' and 'role of the patient'. Two cross-cutting themes relating to the role of the mesothelioma nurse specialist and the impact of COVID-19 were identified. DISCUSSION: There is a need to review the structure of mesothelioma multidisciplinary team meetings to ensure patients are reviewed by clinicians with appropriate knowledge, expertise and understanding of how, why and when decisions should be made. There is a need for expert clinicians in mesothelioma care to promote an up-to-date evidence and knowledge base within the wider multidisciplinary team.

Virtual surgical education for foundation doctors in the United Kingdom during COVID-19 pandemic: A qualitative study.

Background: Foundation training in the UK has been impacted by the COVID-19 pandemic. Surgical education in particular has been impacted due to the reduced exposure of teaching in theatres and clinics. To combat this waning exposure, an online teaching series for the foundation doctors, in affiliation with the Royal College of Surgeons of Edinburgh, was designed and delivered nationally during the pandemic. The aim of this study is to assess the feasibility and the reception of an online teaching programme to become an integral part of surgical education. Methods: A series of virtual teaching sessions lasting between 30 and 60 mintues were delivered live by senior surgical trainees and consultants to foundation trainees nationwide. Online feedback was completed after each session and the results were analysed using Microsoft Excel™. Results: 95.2% of the foundation trainees felt more confident on the subjects taught and were satisfied with the teaching series. The majority of the trainees preferred sessions which were short, held every two or three weeks, delivered by senior surgeons, covering a wide range of surgical specialties and conditions. Conclusion: An online surgical teaching series has been shown to be well received by foundation trainees. It provides a realistic opportunity to have a blended learning environment for surgical training nationally during the pandemic.

Student intentions to engage instructors in mental health-related conversations: An application of the theory of planned behavior.

OBJECTIVE: Considering that college students experience mental health issues and college counseling centers are overwhelmed, this study identifies instructors as a potential mental health resource for students. This study utilizes the theory of planned behavior to investigate the relationship between students' attitudes, injunctive and descriptive norms, perceived behavioral control, and their intentions to engage their instructors in mental health conversations. PARTICIPANTS: Participants were 311 undergraduate students at a small, private university in Southern California. METHODS: Participants were recruited through a Communication subject pool and completed an online survey about engaging instructors in these conversations. RESULTS: Results of a regression analysis indicate that all theoretical constructs positively predict students' intentions to discuss mental health with an instructor. CONCLUSIONS: By providing insight into students' intentions to utilize instructors as mental health resources on campus, these findings yield practical implications for better preparing universities and their faculty to engage in students' mental health.

Why Do Some Americans Resist COVID-19 Prevention Behavior? An Analysis of Issue Importance, Message Fatigue, and Reactance Regarding COVID-19 Messaging.

Despite the rapid transmission of and death toll claimed by COVID-19, there is evidence of resistance toward behaviors shown to effectively prevent and slow the spread of the disease, such as mask wearing and social distancing. This study applies psychological reactance theory to examine COVID-19 message factors (i.e., message fatigue, issue importance) that may be linked to nonadherence to CDC recommendations via the experience of reactance. Participants (N = 268) were current U.S. residents over the age of 18 who completed an online survey about their perceptions of COVID-19 messaging in general as well as toward a specific COVID-19 message they recalled. Results of structural equation modeling indicated that perceived freedom threat toward a COVID-19 message was predicted positively by message fatigue and negatively by issue importance. Greater perceived freedom threat was linked to greater reactance, which in turn was associated with lower levels of adherence to hygiene- and social-related COVID-19 preventive behavior. Notably, the negative association between reactance and social-related adherence was stronger than that between reactance and hygiene-related adherence. Implications for the role of reactance in risk and crisis communication as well as for public health messaging during the COVID-19 pandemic are discussed.

Measuring Glucose Uptake in Drosophila Models of TDP-43 Proteinopathy.

Amyotrophic lateral sclerosis is a neurodegenerative disorder causing progressive muscle weakness and death within 2-5 years following diagnosis. Clinical manifestations include weight loss, dyslipidemia, and hypermetabolism; however, it remains unclear how these relate to motor neuron degeneration. Using a Drosophila model of TDP-43 proteinopathy that recapitulates several features of ALS including cytoplasmic inclusions, locomotor dysfunction, and reduced lifespan, we recently identified broad ranging metabolic deficits. Among these, glycolysis was found to be upregulated and genetic interaction experiments provided evidence for a compensatory neuroprotective mechanism. Indeed, despite upregulation of phosphofructokinase, the rate limiting enzyme in glycolysis, an increase in glycolysis using dietary and genetic manipulations was shown to mitigate locomotor dysfunction and increased lifespan in fly models of TDP-43 proteinopathy. To further investigate the effect on TDP-43 proteinopathy on glycolytic flux in motor neurons, a previously reported genetically encoded, FRET-based sensor, FLII12Pglu-700µÎ´6, was used. This sensor is comprised of a bacterial glucose-sensing domain and cyan and yellow fluorescent proteins as the FRET pair. Upon glucose binding, the sensor undergoes a conformational change allowing FRET to occur. Using FLII12Pglu-700µÎ´6, glucose uptake was found to be significantly increased in motor neurons expressing TDP-43G298S, an ALS causing variant. Here, we show how to measure glucose uptake, ex vivo, in larval ventral nerve cord preparations expressing the glucose sensor FLII12Pglu-700µÎ´6 in the context of TDP-43 proteinopathy. This approach can be used to measure glucose uptake and assess glycolytic flux in different cell types or in the context of various mutations causing ALS and related neurodegenerative disorders.

TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6.

Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative disease in which 97% of patients exhibit cytoplasmic aggregates containing the RNA binding protein TDP-43. Using tagged ribosome affinity purifications in Drosophila models of TDP-43 proteinopathy, we identified TDP-43 dependent translational alterations in motor neurons impacting the spliceosome, pentose phosphate and oxidative phosphorylation pathways. A subset of the mRNAs with altered ribosome association are also enriched in TDP-43 complexes suggesting that they may be direct targets. Among these, dlp mRNA, which encodes the glypican Dally like protein (Dlp)/GPC6, a wingless (Wg/Wnt) signaling regulator is insolubilized both in flies and patient tissues with TDP-43 pathology. While Dlp/GPC6 forms puncta in the Drosophila neuropil and ALS spinal cords, it is reduced at the neuromuscular synapse in flies suggesting compartment specific effects of TDP-43 proteinopathy. These findings together with genetic interaction data show that Dlp/GPC6 is a novel, physiologically relevant target of TDP-43 proteinopathy.

Recommendations for improving follow-up care for patients with mesothelioma: a qualitative study comprising documentary analysis, interviews and consultation meetings.

OBJECTIVES: The study aim was to explore experiences of patients with pleural mesothelioma of follow-up care in three National Health Service (NHS) Trusts to develop recommendations for practice. DESIGN: The study design was qualitative and comprised three interlinked phases: a documentary analysis, interviews and consultation meetings. Altheide and Johnson's Analytic Realism theoretical framework guided the thematic data analysis process. SETTING: The study was conducted in three NHS Trusts in South England. Two were secondary care settings and the third was a tertiary centre. PARTICIPANTS: The secondary care trusts saw 15-20 patients with new mesothelioma per year and the tertiary centre 30-40. The tertiary centre had a designated mesothelioma team. Twenty-one patients met the inclusion criteria: >18 years, mesothelioma diagnosis and in follow-up care. Non-English speaking participants, those unable to provide written informed consent or those whom the clinical team felt would find participation too distressing were excluded. All participants were white, 71% were 70-79 years old and 71% were men. Three consultation meetings were conducted with key stakeholders including mesothelioma nurse specialists, patients with mesothelioma, carers and local clinical commissioning group members. MAIN OUTCOME MEASURES: Specific outcomes were to gain a detailed understanding of mesothelioma follow-up care pathways and processes and to develop coproduced recommendations for practice. RESULTS: Mesothelioma pathways were not always distinct from lung cancer care pathways. All trusts provided follow-up information and resources but there was varied information on how to access local support groups, research or clinical trial participation. Five themes were developed relating to people; processes; places; purpose and perception of care. Coproduced recommendations for improving mesothelioma follow-up pathways were developed following the consultation meetings. CONCLUSIONS: This study has developed recommendations which identify the need for patients with pleural mesothelioma to access consistent, specialist, streamlined mesothelioma care, centred around specialist mesothelioma nurses and respiratory consultants, with input from the wider multidisciplinary team.

Are there benefits to maintaining Covid-19 pandemic pathways for the long-term? A surgical assessment unit based study.

BACKGROUND: The Covid-19 pandemic has led to the introduction of conservative non-operative approaches to surgical management favouring community driven care. The aim of this study was to determine the effect of these pathways on patients attending a surgical assessment unit (SAU). METHOD: This was a retrospective observational cohort study. We included all consecutive attendances to the SAU in April 2020 (Covid-19 period) and April 2019 (pre-Covid-19). The Covid-19 period saw a shift in clinical practice towards a more conservative approach to the management of acute surgical presentations. The primary outcome measure was 30-day readmission. The secondary outcome measures were length of hospital stay, inpatient investigations undertaken and 30-day mortality. RESULTS: A total of 451 patients were included. This represented 277 and 174 attendances in pre-Covid-19, and Covid-19 groups respectively. The rates of unplanned 30-day readmission rates in the Covid-19 and pre-Covid-19 periods were 16.7% and 12.6% respectively (P = 0.232). There were significantly fewer planned follow-ups in the Covid-19 (36.2%) compared to the pre-Covid-19 group (49.1%; P < 0.01; OR 1.7, 95% CI 1.15-2.51). There were no significant differences in length of hospital stay (P = 0.802), and 30-day mortality rate (P = 0.716; OR 1.9, 95% CI 0.38-9.54) between the two periods. CONCLUSION: There were no differences in 30-day readmission rates, length of hospital stay, and 30-day mortality with the changes to pathways. Our findings suggest the resource efficient conservative Covid-19 pathways could potentially continue long-term. However, further multi-centre studies with larger sample sizes and longer follow-up duration will be required to validate our findings.

Transcriptome analyses reveal SR45 to be a neutral splicing regulator and a suppressor of innate immunity in Arabidopsis thaliana.

BACKGROUND: Regulation of pre-mRNA splicing diversifies protein products and affects many biological processes. Arabidopsis thaliana Serine/Arginine-rich 45 (SR45), regulates pre-mRNA splicing by interacting with other regulatory proteins and spliceosomal subunits. Although SR45 has orthologs in diverse eukaryotes, including human RNPS1, the sr45-1 null mutant is viable. Narrow flower petals and reduced seed formation suggest that SR45 regulates genes involved in diverse processes, including reproduction. To understand how SR45 is involved in the regulation of reproductive processes, we studied mRNA from the wild-type and sr45-1 inflorescences using RNA-seq, and identified SR45-bound RNAs by immunoprecipitation. RESULTS: Using a variety of bioinformatics tools, we identified a total of 358 SR45 differentially regulated (SDR) genes, 542 SR45-dependent alternative splicing (SAS) events, and 1812 SR45-associated RNAs (SARs). There is little overlap between SDR genes and SAS genes, and neither set of genes is enriched for flower or seed development. However, transcripts from reproductive process genes are significantly overrepresented in SARs. In exploring the fate of SARs, we found that a total of 81 SARs are subject to alternative splicing, while 14 of them are known Nonsense-Mediated Decay (NMD) targets. Motifs related to GGNGG are enriched both in SARs and near different types of SAS events, suggesting that SR45 recognizes this motif directly. Genes involved in plant defense are significantly over-represented among genes whose expression is suppressed by SR45, and sr45-1 plants do indeed show enhanced immunity. CONCLUSION: We find that SR45 is a suppressor of innate immunity. We find that a single motif (GGNGG) is highly enriched in both RNAs bound by SR45 and in sequences near SR45- dependent alternative splicing events in inflorescence tissue. We find that the alternative splicing events regulated by SR45 are enriched for this motif whether the effect of SR45 is activation or repression of the particular event. Thus, our data suggests that SR45 acts to control splice site choice in a way that defies simple categorization as an activator or repressor of splicing.

Malignant pleural mesothelioma: an update on investigation, diagnosis and treatment.

Malignant pleural mesothelioma is an aggressive malignancy of the pleural surface, predominantly caused by prior asbestos exposure. There is a global epidemic of malignant pleural mesothelioma underway, and incidence rates are predicted to peak in the next few years.This article summarises the epidemiology and pathogenesis of malignant pleural mesothelioma, before describing some key factors in the patient experience and outlining common symptoms. Diagnostic approaches are reviewed, including imaging techniques and the role of various biomarkers. Treatment options are summarised, including the importance of palliative care and methods of controlling pleural effusions. The evidence for chemotherapy, radiotherapy and surgery is reviewed, both in the palliative setting and in the context of trimodality treatment. An algorithm for managing malignant pleural effusion in malignant pleural mesothelioma patients is presented. Finally new treatment developments and novel therapeutic approaches are summarised.

A systematic literature review comparing the psychological care needs of patients with mesothelioma and advanced lung cancer.

PURPOSE: Psychological distress which adversely affects a person's experience of cancer has been shown to be highly prevalent in patients with mesothelioma. Historically, the assumption has been made that the evidence guiding the supportive care needs for lung cancer is relevant to those with mesothelioma. The objective of the study was to evaluate if the psychological care needs differ between patients with pleural mesothelioma and those with advanced lung cancer. METHODS: A search of MEDLINE, CINAHL, PsycARTICLES, Psychology and Behavioural Sciences Collection, PsycINFO databases, grey literature and the Cochrane Library of Systematic Reviews identified 17 studies meeting a predefined inclusion criteria. These were critically appraised for quality. Data relating to psychological experiences was extracted which was then synthesised narratively and through a process of meta ethnography. RESULTS: Common themes identified across the studies created 10 key concepts. These were uncertainty, normality, hope/hopelessness, stigma/blame/guilt, family/carer concern, physical symptoms, experience of diagnosis, iatrogenic distress, financial/legal and death and dying. Key similarities and differences were identified between the mesothelioma and lung cancer evidence. CONCLUSIONS: There is limited research exploring the lived experiences of those with mesothelioma and lung cancer, with the majority of them having methodological and/or reporting concerns compromising the conclusions made. However, reoccurring themes in the evidence were found suggesting a number of areas where the psychological experience of mesothelioma differs from that of advanced lung cancer. These findings warrant further research to explore further and if proven, the need for the provision of specialist mesothelioma care services is affirmed.

High-throughput, automated quantification of white matter neurons in mild malformation of cortical development in epilepsy.

INTRODUCTION: In epilepsy, the diagnosis of mild Malformation of Cortical Development type II (mMCD II) predominantly relies on the histopathological assessment of heterotopic neurons in the white matter. The exact diagnostic criteria for mMCD II are still ill-defined, mainly because findings from previous studies were contradictory due to small sample size, and the use of different stains and quantitative systems. Advance in technology leading to the development of whole slide imaging with high-throughput, automated quantitative analysis (WSA) may overcome these differences, and may provide objective, rapid, and reliable quantitation of white matter neurons in epilepsy. This study quantified the density of NeuN immunopositive neurons in the white matter of up to 142 epilepsy and control cases using WSA. Quantitative data from WSA was compared to two other systems, semi-automated quantitation, and the widely accepted method of stereology, to assess the reliability and quality of results from WSA. RESULTS: All quantitative systems showed a higher density of white matter neurons in epilepsy cases compared to controls (P = 0.002). We found that, in particular, WSA with user-defined region of interest (manual) was superior in terms of larger sampled size, ease of use, time consumption, and accuracy in region selection and cell recognition compared to other methods. Using results from WSA manual, we proposed a threshold value for the classification of mMCD II, where 78% of patients now classified with mMCD II were seizure-free at the second post-operatively follow up. CONCLUSION: This study confirms the potential role of WSA in future quantitative diagnostic histology, especially for the histopathological diagnosis of mMCD.