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The analysis of extractables and leachables and subsequent risk assessment is an important aspect of the determination of biocompatibility for many medical devices. Leachable chemicals have the potential to pose a toxicological risk to patients, and therefore it is required that they be adequately characterized and assessed for potential safety concerns. One important consideration in the assessment of leachables is the choice of a suitable simulating solvent intended to replicate the use condition for the device and its biological environment. This aspect of study design is especially difficult for blood-contacting medical devices due to the complexity of simulating the biological matrix. This publication reports a comparison of the extracting power of different binary solvent mixtures and saline in comparison with whole blood for a bloodline tubing set connected to a hemodialyzer. Ten different known extractables, spanning a range of physicochemical properties and molecular weights, were quantified. The results indicated that for low-molecular-weight analytes, a suitable exaggeration for whole blood can be obtained using a low-concentration ethanol/water mixture (≈20%), and in general, extracted quantity increases with the concentration of alcohol cosolvent. For polyvinylpyrrolidone, the opposite trend was observed, as solubility of the polymer was found to decrease with increasing alcohol concentration, resulting in lower extracted quantities at high alcohol concentrations. Analysis of ethanol/water concentrations in the extract solutions post extraction indicated no change in solvent composition., (© PDA, Inc. 2024.)

Osteomyelitis of the sphenoid wing is a rare clinical entity that can result in significant morbidity due to cranio-orbital infection. This entity has never previously been described as a complication of orbital decompression. An elderly patient developed relapsing orbital cellulitis and cranio-orbital abscesses following orbital decompression. Multiple attempts at incision and drainage with extended antibiotic therapy failed to eliminate the infection. The patient's clinical course was indicative of sphenoid osteomyelitis at the prior decompression site. A combined craniotomy-orbitotomy with debridement of the involved portion of the sphenoid resulted in resolution of the patient's clinical symptoms. Surgeons should be aware of the possibility of this rare infection following any surgery in which bone is structurally modified or removed, including orbital decompression.

Objective: Trauma, social support and stress have been identified as factors which may be associated with the bipolar disorder illness course. However, these are yet to be examined in prospective studies as predictors of illness outcomes and overall quality of life in bipolar disorder., Method: One hundred and fourteen participants ( N = 97; 85.1% female) living with bipolar disorder I (41.2%) or II (58.8%) completed a semi-structured interview and a range of self-report measures assessing trauma history, social support, perceived stress, depression, anxiety, mania, suicidality, number of mood episodes and quality of life, at baseline and 6-month follow-up., Results: Childhood cumulative trauma, social support and perceived stress accounted for a substantial and significant portion of the variance in quality of life (62%; 23.6%), anxiety severity (34.6%; 24.5%) and depression severity (49.6%; 26.7%), at both baseline and 6-month follow-up. Perceived stress made significant unique contributions to the prediction of all outcomes, and social support made significant unique contributions to depression and quality of life in bipolar disorder., Conclusion: Stress and social support play an important role in bipolar disorder and in quality of life for people living with this condition. Given that stress and social support are modifiable risk factors, this provides a promising direction for future intervention-based research., 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.

Objective: To gain consensus on the definitions and descriptions of the domains of the Outcome Measures in Rheumatology (OMERACT) core domain set for rheumatology trials evaluating shared decision making (SDM) interventions., Methods: Following the OMERACT Handbook methods, our Working Group (WG), comprised of 90 members, including 17 patient research partners (PRPs) and 73 clinicians and researchers, had six virtual meetings in addition to email exchanges to develop draft definitions and descriptions. The WG then conducted an international survey of its members to gain consensus on the definitions and descriptions. Finally, the WG members had virtual meetings and e-mail exchanges to review survey results and finalize names, definitions and descriptions of the domains., Results: WG members contributed to developing the definitions. Fifty-two members representing four continents and 13 countries completed the survey, including 15 PRPs, 33 clinicians and 37 researchers. PRPs and clinicians/researchers agreed with all definitions and descriptions with agreements ranging from 87% to 100%. Respondents suggested wording changes to the names, definitions and descriptions to better reflect the domains. Discussions led to further simplification and clarification to address common questions/concerns about the domains., Conclusion: Our WG reached consensus on the definitions and descriptions of the domains of the core domain set for rheumatology trials of SDM interventions. This step is crucial to understand each domain and provides the foundation to identify instruments to measure each domain for inclusion in the Core Outcome Measurement Set., Clinical Significance: The current study provides consensus-based definitions and descriptions for the domains of the OMERACT core domain set for shared decision making interventions from patients/caregivers, clinicians and researchers. This is a crucial step to understand each domain and provides the foundation to identify instruments to measure each domain for inclusion in the Core Outcome Measurement Set for trials of SDM interventions., Competing Interests: Declaration of competing interest Karine Toupin-April, Simon Décary, Maarten de Wit, Florian Naye, Alexa Meara, Jennifer L. Barton, Liana Fraenkel, Linda C. Li, Peter Brooks, Beverley Shea, Dawn Stacey, Cathie Hofstetter, Marieke Voshaar, Maria E. Suarez-Almazor, Tanya Meade, Janet Elizabeth Jull, Willemina Campbell, Rieke Alten, Esi M. Morgan, Ayano Kelly, Lara J. Maxwell, Francis Guillemin, Dorcas Beaton, Yasser El-Miedany, Shikha Mittoo, Tiffany Westrich Robertson, Susan J. Bartlett, Melissa Mannion, Samah Ismail Nasef, Adewale Adebajo, Laurent Arnaud, Tiffany K. Gill, Ellen Moholt, Jennifer Burt, Aruni Jayatilleke, Ihsane Hmamouchi, David Carrott, Kate Mather, Ajesh Maharaj, Saurab Sharma, Francesco Caso, Christopher Fong, Allyson Jones, Regina Greer-Smith, Akpabio Akpabio, Valerie Umaefulam, Sara Monti, Grayson Schultz, Rebecca R. Lee, Glen Stewart Hazlewood, Claire E.H. Barber, Dorthe B. Berthelsen, Laure Gossec, Sabrina May Nielsen, Sabrina Cavallo, Sonam Kiwalkar, Hemalatha Srinivasalu, Deb Constien, Vicki Evans and Peter Tugwell have nothing to disclose. Anne Boel is employed by UCB Pharma, B.V. Netherlands. Simon Stones is employed by Envision Pharma Group, Wilmslow, UK. Robin Christensen reports other potential COI from Lecture: Research Methods (Pfizer, DK; 2017), other from Lecture: GRADE Lecture (Celgene, DK; 2017), other from Ad Board Lecture: CAM (Orkla Health, DK; 2017), other from Project Grant: "GreenWhistle" (Mundipharma, 2019), other from Lecture: Diet in RMD (Novartis, DK; 2019), other from Consultancy Report: Network MA's (Biogen, DK; 2017), other from Ad Board Lecture: GRADE (Lilly, DK; 2017), other from Consultancy Report: GRADE (Celgene, 2018), other from Lecture: Network MA's (LEO; 2020), outside the submitted work; and Musculoskeletal Statistics Unit, The Parker Institute is grateful for the financial support received from public and private foundations, companies and private individuals over the years. The Parker Institute is supported by a core grant from the Oak Foundation; The Oak Foundation is a group of philanthropic organizations that, since its establishment in 1983, has given grants to not-for-profit organizations around the world. Annelies Boonen reports grants from Abbvie, grants from Celgene, other from UCB, other from Galapagos, other from Eli Lilly, outside the submitted work. Lyn March reports personal fees from Pfizer Australia, personal fees from Abbvie Australia, grants from Janssen Australia, outside the submitted work; Dr March is a member of OMERACT executive that receives arms-length funding from 9 companies. Willemina Campbell received OMERACT funded travel to a conference to attend meetings in regard to this paper. Jasvinder Singh reports personal fees from Crealta/Horizon, Medisys, Fidia, UBM LLC, Trio health, Medscape, WebMD, Adept Field Solutions, Clinical Care options, Clearview healthcare partners, Putnam associates, Focus forward, Navigant consulting, Spherix, Practice Point communications, the National Institutes of Health and the American College of Rheumatology, personal fees from Simply Speaking, other from Vaxart pharmaceuticals and Charlotte's Web Holdings (current); Amarin, Viking, and Moderna (previously owned), non-financial support from FDA Arthritis Advisory Committee, non-financial support from Steering committee of OMERACT, an international organization that develops measures for clinical trials and receives arms’ length funding from 12 pharmaceutical companies, non-financial support from Veterans Affairs Rheumatology Field Advisory Committee, non-financial support from Editor and the Director of the UAB Cochrane Musculoskeletal Group Satellite Center on Network Meta-analysis, outside the submitted work. Francisco J. Blanco reports grants from Gedeon Richter Plc., Bristol-Myers Squibb International Corporation (BMSIC), Sun Pharma Global FZE, Celgene Corporation, Janssen Cilag International N.V, Janssen Research & Development, Viela Bio, Inc., Astrazeneca AB, UCB BIOSCIENCES GMBH, UCB BIOPHARMA SPRL, AbbVie Deutschland GmbH & Co.KG, Merck KGaA, Amgen, Inc., Novartis Farmacéutica, S.A., Boehringer Ingelheim España, S.A, CSL Behring, LLC, Glaxosmithkline Research & Development Limited, Pfizer Inc, Lilly S.A., Corbus Pharmaceuticals Inc., Biohope Scientific Solutions for Human Health S.L., Centrexion Therapeutics Corp., Sanofi, MEIJI FARMA S.A., Kiniksa Pharmaceuticals, Ltd. Grunenthal, Asofarma Mexico, Gebro Pharma, Roche, Galapagos, Regeneron; outside the submitted work. Anthony P. Fernandez reports personal fees and other from AbbVie, grants, personal fees and other from Novartis, grants, personal fees and other from Mallinkrodt, other from Corbus, other from Pfizer, outside the submitted work. Sarah Mackie reports: Consultancy on behalf of her institution for Roche/Chugai, Sanofi, AbbVie, AstraZeneca, Pfizer; Investigator on clinical trials for Sanofi, GSK, Sparrow; speaking/lecturing on behalf of her institution for Roche/Chugai, Vifor, Pfizer, UCB, Novartis and AbbVie; chief investigator on STERLING-PMR trial, funded by NIHR; patron of the charity PMRGCAuk. No personal remuneration was received for any of the above activities. Support from Roche/Chugai to attend EULAR2019 in person and from Pfizer to attend ACR Convergence 2021 virtually. She is supported in part by the NIHR Leeds Biomedical Research Centre. The views expressed in this article are those of the authors and not necessarily those of the NIHR, the NIHR Leeds Biomedical Research Centre, the National Health Service or the UK Department of Health and Social Care. Elena Nikiphorou reports personal fees and other from AbbVie, personal fees and other from Eli-Lilly, personal fees and other from Gilead, personal fees and other from Celltrion, personal fees and other from Pfizer, other from Sanofi, outside the submitted work. Victor S. Sloan reports and paid consultant to various pharmaceutical companies and healthcare consultancies providing advice on clinical research and advisory committee preparation outside the scope of the submitted work. He is a shareholder in UCB Pharma. He is in the Peace Corps. This is his personal work, and does not reflect the opinion of the Peace Corps or the United States Government. Vibeke Strand reports consulting fees from AbbVie, Amgen, Arena, AstraZeneca, BMS, Boehringer Ingelheim, Celltrion, CORRONA, Crescendo/Myriad, Equillium, Genentech/Roche, GSK, Horizon, Inmedix, Janssen, Eli Lilly, Novartis, Pfizer, Regeneron Pharmaceuticals Inc., Samsung, Sandoz, Sanofi, TwoXAR and UCB, outside the submitted work. Esi M. Morgan reports grant support from Agency for Healthcare Research and Quality and Pfizer., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by an expanded polyglutamine tract in the widely expressed ataxin-1 (ATXN1) protein. To elucidate anatomical regions and cell types that underlie mutant ATXN1-induced disease phenotypes, we developed a floxed conditional knockin mouse (f-ATXN1146Q/2Q) with mouse Atxn1 coding exons replaced by human ATXN1 exons encoding 146 glutamines. f-ATXN1146Q/2Q mice manifested SCA1-like phenotypes including motor and cognitive deficits, wasting, and decreased survival. Central nervous system (CNS) contributions to disease were revealed using f-ATXN1146Q/2Q;Nestin-Cre mice, which showed improved rotarod, open field, and Barnes maze performance by 6-12 weeks of age. In contrast, striatal contributions to motor deficits using f-ATXN1146Q/2Q;Rgs9-Cre mice revealed that mice lacking ATXN1146Q/2Q in striatal medium-spiny neurons showed a trending improvement in rotarod performance at 30 weeks of age. Surprisingly, a prominent role for muscle contributions to disease was revealed in f-ATXN1146Q/2Q;ACTA1-Cre mice based on their recovery from kyphosis and absence of muscle pathology. Collectively, data from the targeted conditional deletion of the expanded allele demonstrated CNS and peripheral contributions to disease and highlighted the need to consider muscle in addition to the brain for optimal SCA1 therapeutics.

Background: The experience of cumulative trauma may be common in bipolar disorder (BD). However, it is not frequently reported as most studies focus on childhood trauma without examining differences in the amount of trauma experienced. This systematic review aimed to determine the prevalence of lifetime cumulative trauma in BD as well as explore associated illness outcomes., Methods: A systematic review was completed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Both the prevalence and outcomes of cumulative trauma in BD were assessed. Five electronic databases were searched (Embase, MEDLINE, PsycINFO, Web of Science, and PTSD Pubs) for records from January 2010 until December 2022., Results: A total of 20 studies, with 9304 participants were included in the narrative synthesis. At least one-third of BD participants had experienced cumulative trauma, with a prevalence range from 29% to 82%. The main outcomes associated with a history of cumulative trauma were earlier age of onset, longer episode duration, more lifetime mood episodes, greater likelihood of experiencing psychotic features, and higher likelihood of past suicide attempts., Limitations: This review has been limited by the lack of studies directly assessing cumulative trauma in BD., Conclusions: Cumulative trauma is prevalent in BD. Preliminary evidence indicates an association with a range of adverse outcomes, emphasizing the need for clinicians to obtain a detailed trauma history and to consider these risks in the management of the disorder. Future studies should report on the prevalence of cumulative trauma, particularly in adulthood as this area remains unexplored., (© 2024 The Authors. Journal of Clinical Psychology published by Wiley Periodicals LLC.)

Background: Tinnitus is burdensome to many patients. Sound amplification and masking therapy has been useful for some patients., Method: Retrospective chart review of patients treated for tinnitus at a single academic medical center over a 12-month period. Information on treatment course and outcomes was collected and analyzed. Statistical comparisons were made using a t-test for paired means., Results: In 2021, 141 patients were evaluated for tinnitus sound amplification and masking therapy at our medical center. Average age at presentation was 55.2. Average onset was 6-7 years before presentation. Tinnitus perception was decreased in patients who received a trial of amplification and masking therapy, from 9.2 out of 20 at baseline to 6.1 with amplification and 3.2 with amplification and masking at the initial visit. The difference in each of these values is statistically significant. Nine patients recorded a Tinnitus Handicap Index (THI), which measures tinnitus burden, before and after being treated with amplification and masking therapy. These nine patients saw a decrease in THI from 39.6/100 to 19.1/100, which was also statistically significant., Limitations: This study has several limitations. Our data are from a single clinic over one year with limited follow up information, and it is a retrospective study., Conclusion: Our data showed benefit in sound amplification and masking therapy for the treatment of tinnitus. Patients treated with amplification and masking therapy showed a statistically significant decrease in perception of their tinnitus during their in-office demonstration. Long term data are still needed. Our data contribute to the broader discussion on the proper treatment course of tinnitus and the most effective measures., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Many studies have reported high rates of anxiety in adults with rheumatoid arthritis (RA). The aim of this systematic review was to examine those findings and determine the overall prevalence, severity, and commonly used measures of anxiety in individuals with RA., Methods: Six databases were searched from January 2000 without restrictions on language/location, study design, or gray literature. All identified studies that examined anxiety prevalence and severity in adults with RA, as assessed with clinical diagnostic interview and/or standardized self-report measures, were considered for inclusion. Quality assessment of included studies was conducted using a modified Newcastle-Ottawa Evaluation Scale, and the findings were synthesized via a narrative approach., Results: Across the 47 studies (n = 11,085 participants), the sample size ranged from 60 to 1,321 participants with seven studies including healthy controls or groups with other health conditions. The studies were conducted across 23 countries, and anxiety prevalence ranged from 2.4% to 77%, predominantly determined with standardized self-report measures, of which Hospital Anxiety and Depression scale was used most frequently; only eight studies used a clinical diagnostic interview to confirm a specific anxiety diagnosis. Notable associations with anxiety in RA were physical disability, pain, disease activity, depression, and quality of life., Conclusion: The reported prevalence of anxiety in RA varied widely potentially because of use of different self-report measures and cutoff points. Such cutoff points will need to be standardized to clinical thresholds to inform appropriate interventions for anxiety comorbidity in RA., (© 2023 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

This systematic review aimed to explore social and occupational functioning levels in individuals with BPD and whether this varies according to symptomatic status, age, or gender. A multi-database search was conducted for articles, and of the 1164 records identified, 19 were included in this review. Of the 15 studies reporting on social functioning, 13 indicated significant levels of impairment, and of the 14 studies reporting on global functioning, all indicated significant impairment across both clinical and in-remission populations. Occupational functioning was primarily assessed as either a part of global functioning or by subscales within social functioning, highlighting a lack of use of dedicated measures for its assessment. This systematic review found that individuals with BPD experience a range of significant impairments in functioning persisting across the lifespan. Further studies are warranted to explore levels of functional impairment across all functional domains and factors associated with continual functional impairment in this population.

Background: Perinatal mental health disorders are one of the leading causes of maternal illness and suffering and care and services need to be well coordinated by an interprofessional team who are skilled in working collaboratively., Aim: The aim of this paper is to describe the design and evaluation of an innovative interprofessional education initiative to increase midwives and other health professional students' knowledge and skills in caring collaboratively for women with psychosocial issues in the perinatal period, including women experiencing domestic and family violence., Methods: The Psychosocial Interprofessional Perinatal Education workshop was designed for midwifery, psychology, social work and medical students. It provided a simulated learning experience with case studies based on real life situations. Students undertook pre and post surveys to measure changes in students' perceptions of interprofessional collaboration and their experiences of participating in the interprofessional simulation-based learning activity. Quantitative survey data were analysed using paired t-tests and a qualitative content analysis was undertaken on the open-ended questions in the survey., Findings: Comparison of pre and post surveys found students from all disciplines reported feeling more confident working interprofessionally following the workshop. The following categories were generated from analysis of the open ended survey data: Greater understanding of each others' roles; Recognising benefits of interprofessional collaboration; Building on sense of professional identity; Respecting each other and creating a level playing field; and Filling a pedagogical gap., Conclusion: Through this innovative, simulated interprofessional education workshop students developed skills essential for future collaborative practice to support women and families experiencing psychosocial distress., Competing Interests: Declaration of interest The authors declare that they have no conflicts of interest associated with this manuscript., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by an expanded polyglutamine tract in the widely expressed ATXN1 protein. To elucidate anatomical regions and cell types that underlie mutant ATXN1-induced disease phenotypes, we developed a floxed conditional knockout mouse model ( f-ATXN1 146Q/2Q ) having mouse Atxn1 coding exons replaced by human exons encoding 146 glutamines. F-ATXN1 146Q/2Q mice manifest SCA1-like phenotypes including motor and cognitive deficits, wasting, and decreased survival. CNS contributions to disease were revealed using ATXN1 146Q/2Q ; Nestin-Cre mice, that showed improved rotarod, open field and Barnes maze performances. Striatal contributions to motor deficits were examined using f-ATXN1 146Q/2Q ; Rgs9-Cre mice. Mice lacking striatal ATXN1 146Q/2Q had improved rotarod performance late in disease. Muscle contributions to disease were revealed in f-ATXN1 146Q/2Q ; ACTA1-Cre mice which lacked muscle pathology and kyphosis seen in f-ATXN1 146Q/2Q mice. Kyphosis was not improved in f-ATXN1 146Q/2Q ;Nestin - Cre mice. Thus, optimal SCA1 therapeutics will require targeting mutant ATXN1 toxic actions in multiple brain regions and muscle.

Background: Trauma is highly prevalent in bipolar disorder, and while considerable research has been undertaken in relation to childhood trauma, little is known about the experience and the impact of exposure to multiple trauma types across the lifespan, otherwise known as cumulative trauma. This study aimed to examine the prevalence of cumulative trauma in bipolar disorder and explore its association with illness and other outcomes., Methods: Participants were recruited online globally and comprised 114 adults aged 23 to 73 years with BD-I (41.2 %) or BD-II (58.8 %). Participants completed an online questionnaire containing items regarding symptoms and trauma history followed by a diagnostic interview to confirm their BD diagnosis and assess BD symptoms., Results: Cumulative trauma accounted for most of the trauma exposure across both childhood (n = 89; 78.1 %) and adulthood (n = 72; 63.2 %). Those with lifetime cumulative trauma (n = 64; 56 %) were more likely to experience at least one other co-morbid mental health condition in addition to their BD diagnosis (88 %) and report significantly lower ratings of perceived social support compared to those who did not experience any cumulative trauma (N = 15; 13 %)., Limitations: This study has been limited by the cross-sectional retrospective design as well as the use of self-selection to participate., Conclusions: Cumulative trauma is highly prevalent in bipolar disorder and is associated with greater likelihood of experiencing a psychiatric comorbidity and decreased levels of social support. More research is needed to explore the nature of this relationship and determine whether increasing social support may be of benefit., Competing Interests: Conflict of interest The authors have no conflicts of interest to declare., (Copyright © 2022. Published by Elsevier B.V.)

Bacground: Exposure therapy is a core component of the evidence-based treatment of anxiety, obsessive-compulsive disorder (OCD), and posttraumatic stress disorder (PTSD). Despite this, many clinicians fail to use exposure therapy in clinical practice, with research highlighting a number of potential barriers. Those findings raise serious concerns regarding the effective dissemination and delivery of evidence-based treatments that in turn have a major impact on client care and cost-effectiveness of psychological interventions., Aims: The present study aims to examine barriers to the use of exposure therapy in the clinical practice of Australian psychologists treating anxiety, OCD and PTSD., Method: One hundred registered psychologists, aged between 23 and 71 years and 84% female, participated in this study via online survey., Results: Results suggest that the most common barriers to the use of exposure therapy include lack of confidence, negative beliefs about exposure therapy, insufficient underpinning theoretical knowledge, client-specific barriers, and logistical limitations., Conclusions: Future research may further examine those barriers and the components of additional training and supervision that can increase the uptake of exposure therapy, particularly in clinical areas where it is a gold standard of practice., (© 2022 Wiley Periodicals LLC.)

Spinocerebellar ataxia type 1 (SCA1) is a dominant trinucleotide repeat neurodegenerative disease characterized by motor dysfunction, cognitive impairment, and premature death. Degeneration of cerebellar Purkinje cells is a frequent and prominent pathological feature of SCA1. We previously showed that transport of ATXN1 to Purkinje cell nuclei is required for pathology, where mutant ATXN1 alters transcription. To examine the role of ATXN1 nuclear localization broadly in SCA1-like disease pathogenesis, CRISPR-Cas9 was used to develop a mouse with an amino acid alteration (K772T) in the nuclear localization sequence of the expanded ATXN1 protein. Characterization of these mice indicates that proper nuclear localization of mutant ATXN1 contributes to many disease-like phenotypes including motor dysfunction, cognitive deficits, and premature lethality. RNA sequencing analysis of genes with expression corrected to WT levels in Atxn1 175QK772T/2Q mice indicates that transcriptomic aspects of SCA1 pathogenesis differ between the cerebellum, brainstem, cerebral cortex, hippocampus, and striatum., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of the study was to investigate the association of surgical margin conditions, including positive specimen margins revised to negative relative to local recurrence, disease-free survival, and overall survival (OS) within a cohort of HPV-mediated oropharyngeal squamous cell carcinoma (OPSCC) who underwent en bloc resection via transoral robotic surgery (TORS)., Materials and Methods: Retrospective cohort of patients with untreated HPV-mediated OPSCC cT1 or T2 undergoing TORS resection between October 2014 and March 2020. The methodologic description of our interdisciplinary institutional approach, number of cut-through margins (CTMs) during intraoperative consultation, percentage of final positive margin cases, and disease-free survival and OS stratified by margin status and margin tumor-free distance is identified., Results: 135 patients with primary cT1/T2 HPV-mediated OPSCC met inclusion criteria. Twenty-eight of 135 (20.7%) specimens revealed CTM and were revised during the same operative setting. Three of 135 (2.2%) surgical cases had positive final margin status. Local control rate was 97%. On univariate analysis, margin distance did not impact OS. CTM and final positive margins had lower OS than initially negative margins (p = 0.044). Pathologic N-stage significantly impacted OS (p < 0.001)., Conclusions: High local control rate and low final positive margin status confound the study of specimen margin-based techniques in HPV-mediated OPSCC resected en bloc with TORS. Pathologic N-stage may impact OS more than margin status. Larger numbers are needed to confirm differences., (© 2022 S. Karger AG, Basel.)

Mobile phones are playing an increasingly important role in supporting mental health, by providing confidential, accessible and scalable support for individuals who may not seek or have means of accessing professional help. There are concerns, however, that many apps claiming to support mental health do not meet professional, ethical or evidence-based standards. App store search algorithms favour popularity (reviews and downloads) and commercial factors (in-app purchases), with what appears to be low prioritisation of safety or effectiveness features. In this paper, the most visible 100 apps for "depression", "anxiety" and/or "mood" on the Google Play and Apple App stores were selected for assessment using the American Psychiatric Association App Evaluation model. This model systematically assesses apps across five broad steps: accessibility, integrity, clinical and research evidence base, user engagement and interoperability. Assessment is hierarchical, with the most fundamental requirements of apps assessed first, with apps excluded at each step if they do not meet the criteria. The relationship between app quality and app store visibility was first analysed. App quality was also compared across four different app function types: mental health promotion or psychoeducation; monitoring or tracking; assessment or prevention; and intervention or treatment. Of the 92 apps assessed (after eight failed to meet inclusion criteria), half failed to meet the first criterion step of accessibility, and a further 20% of the remaining apps failed to meet the second criterion step of security and privacy. Only three of the 10 apps most visible on app stores met the criteria for research/clinical base and engagement/ease of use, and only one app fulfilled all five criterion steps of the evaluation model. Quality did not differ significantly across app function type. There was no significant correlation between app quality and app store visibility, which presents a potential risk to vulnerable consumers. The findings of this review highlight the need for greater accountability of app developers to meet, and report, at least minimum quality and integrity standards for their apps. Recommendations are also provided to assist users and clinicians to make informed choices in their selection of reputable and effective mental health apps., Competing Interests: Author NR declares that she is one of the creators of two apps assessed in this study (MoodPrism and MoodMission). This does not constitute a conflict of interest as this author was not one of the two research assistants responsible for rating all the apps. The authors, therefore, declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Rickard, Kurt and Meade.)

Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene for which no therapies are available. HTT mutation causes protein misfolding and aggregation, preferentially affecting medium spiny neurons (MSNs) of the basal ganglia. Transcriptional perturbations in synaptic genes and neuroinflammation are key processes that precede MSN dysfunction and motor symptom onset. Understanding the interplay between these processes is crucial to develop effective therapeutic strategies to treat HD. We investigated the role of protein kinase CK2α', a kinase upregulated in MSNs in HD and previously associated with Parkinson's disease (PD), in the regulation of neuroinflammation and synaptic function in HD. We used the heterozygous knock-in zQ175 HD mouse model and compared that to zQ175 mice lacking one allele of CK2α' (zQ175:CK2α' (±) ). CK2α' haploinsufficiency in zQ175 mice resulted in decreased levels of pro-inflammatory cytokines, HTT aggregation, astrogliosis and transcriptional alterations of synaptic genes related to glutamatergic signaling. zQ175:CK2α' (±) mice also presented increased frequency of striatal miniature excitatory postsynaptic currents (mEPSCs), an indicator of synaptic activity, and improved motor coordination compared to zQ175 mice. Neuropathological and phenotypic changes mediated by CK2α' were connected to alpha-synuclein (α-syn) dysregulation and correlated with differences in α-syn serine 129 phosphorylation (pS129-α-syn), a post-translational modification involved in α-synucleinopathy and shown to be regulated by CK2 in PD. pS129-α-syn was increased in the nuclei of MSNs in zQ175 mice and in the striatum of patients with HD, and it decreased in zQ175:CK2α' (±) mice. Collectively, our data established a novel connection between CK2α', neuroinflammation and synaptic gene dysregulation with synucleinopathy in HD and suggested common molecular mechanisms of neurodegeneration between HD and PD. Our results also support CK2α' inhibition as a potential therapeutic strategy to modulate neuronal function and neuroprotection in HD., (© 2022. The Author(s).)

Age-dependent differences in methylation at specific cytosine-guanine (CpG) sites have been used in "epigenetic clock" formulas to predict age. Deviations of epigenetic age from chronological age are informative of health status and are associated with adverse health outcomes, including mortality. In most cases, epigenetic clocks are performed on methylation from DNA extracted from circulating blood cells. However, the effect of neoplastic cells in the circulation on estimation and interpretation of epigenetic clocks is not well understood. Here, we explored this using Fischer 344 (F344) rats, a strain that often develops large granular lymphocyte leukemia (LGLL). We found clear histological markers of LGLL pathology in the spleens and livers of 27 out of 61 rats aged 17-27 months. We assessed DNA methylation by reduced representation bisulfite sequencing with coverage of 3 million cytosine residues. Although LGLL broadly increased DNA methylation variability, it did not change epigenetic aging. Despite this, the inclusion of rats with LGLL in clock training sets significantly altered predictor selection probability at 83 of 121 commonly utilized CpG sites. Furthermore, models trained on rat samples that included individuals with LGLL had greater absolute age error than those trained exclusively rats free of LGLL (39% increase; p < .0001). We conclude that the epigenetic signals for aging and LGLL are distinct, such that LGLL assessment is not necessary for valid measures of epigenetic age in F344 rats. The precision and architecture of constructed epigenetic clock formulas, however, can be influenced by the presence of neoplastic hematopoietic cells in training set populations., (Published by Oxford University Press on behalf of The Gerontological Society of America 2021.)

Individual associations between lifestyle behaviours and mental health have been established; however, evidence on the clustering of these behaviours and the subsequent impact on mental health is limited. The purpose of this study was to examine cross-sectional and longitudinal associations between combined unhealthy lifestyle behaviours (physical activity, sitting time, sleep duration, processed meat consumption, vegetable consumption, fruit consumption, smoking status, alcohol consumption) and the development of psychological distress (measured using the Kessler Psychological Distress Scale) in a large Australian sample. Participants were 163,707 Australian adults from the 45 and Up Study. Data from baseline (2006-2009) and follow-up wave 1 (2012) were analysed using binary logistic regression. The odds of reporting high or very high psychological distress at follow-up were significantly higher for those reporting five (AOR = 2.36; 95% CI 1.41-3.97, p = 0.001) or six or more (AOR = 3.04; 95% CI 1.62-5.69, p = 0.001) unhealthy lifestyle behaviours, in comparison to those reporting no unhealthy lifestyle behaviours at baseline. These findings suggest that a holistic, multi-faceted lifestyle approach addressing multiple behaviours may be required to support and promote positive mental health and to reduce the likelihood of psychological distress.

Objectives: The fear-avoidance model (FAM) is used to explain pain-related disability and design targeted interventions for people with chronic low back pain. While treatment engagement is critical, it is unknown how treatment moderates the FAM., Methods: This study examined whether pathways within the FAM were moderated by treatment engagement in 508 people with chronic low back pain. Measures of disability, pain, fear, catastrophizing, anxiety, depression, and self-efficacy were collected through self-report, and descriptors of treatment engaged within the last month (physical activity type, medication, allied and medical health practitioner). Moderated mediation analyses were performed to examine the conditional effect of treatment engagement on fear-avoidance pathways., Results: The conditional effect of anxiety on disability was only significant for people who did not report any treatment engagement in the last month (B=1.03, 95% confidence interval: 0.53-1.53, P<0.001). The effect of depression increased for people reporting more different types of treatment in the last month (1 level of treatment increase, B=0.27, 95% confidence interval: 0.05-0.50, P=0.019). Conversely, greater treatment engagement had a positive influence on the mediating effect of self-efficacy. That is, the effect of pain on efficacy reduced with greater treatment engagement, with a concomitant increased effect of self-efficacy on disability., Discussion: Clinicians should explore the history and rationale behind patient treatment seeking behavior to ensure this is not reinforcing the negative effects of depressive symptoms on pain-related disability., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)