Mechanisms of manipulation: a systematic review of the literature on immediate anatomical structural or positional changes in response to manually delivered high-velocity, low-amplitude spinal manipulation.

BACKGROUND: Spinal manipulation (SM) has been claimed to change anatomy, either in structure or position, and that these changes may be the cause of clinical improvements. The aim of this systematic review was to evaluate and synthesise the peer-reviewed literature on the current evidence of anatomical changes in response to SM. METHODS: The review was registered with PROSPERO (CRD42022304971) and reporting was guided by the standards of the PRISMA Statement. We searched Medline, Embase, CINAHL, AMED, Cochrane Library all databases, PEDro, and the Index to Chiropractic Literature from inception to 11 March 2022 and updated on 06 June 2023. Search terms included manipulation, adjustment, chiropractic, osteopathy, spine and spine-related structures. We included primary research studies that compared outcomes with and without SM regardless of study design. Manipulation was defined as high-velocity, low-amplitude thrust delivered by hand to the spine or directly related joints. Included studies objectively measured a potential change in an anatomical structure or in position. We developed a novel list of methodological quality items in addition to a short, customized list of risk of bias (RoB) items. We used quality and RoB items together to determine whether an article was credible or not credible. We sought differences in outcomes between SM and control groups for randomised controlled trials and crossover studies, and between pre- and post-SM outcomes for other study designs. We reported, in narrative form, whether there was a change or not. RESULTS: The search retrieved 19,572 articles and 20 of those were included for review. Study topics included vertebral position (n = 3) facet joint space (n = 5), spinal stiffness (n = 3), resting muscle thickness (n = 6), intervertebral disc pressure (n = 1), myofascial hysteresis (n = 1), and further damage to already damaged arteries (n = 1). Eight articles were considered credible. The credible articles indicated that lumbar facet joint space increased and spinal stiffness decreased but that the resting muscle thickness did not change. CONCLUSION: We found few studies on this topic. However, there are two promising areas for future study: facet joint space and spinal stiffness. A research strategy should be developed with funding for high quality research centres.

Task shifting for musculoskeletal disorders in Norwegian primary care: a qualitative interview study of general practitioners and specialist musculoskeletal physiotherapists.

OBJECTIVE: To explore the views of general practitioners and physiotherapists on the current model of care for patients with musculoskeletal disorders in Norwegian primary care, and if the English First Contact Practitioner model, where patients have access to multiple professional groups with musculoskeletal health expertise, could inform service development. DESIGN, SETTING, AND SUBJECTS: We analysed interviews with five GPs and 11 physiotherapists and used Lipsky's theories about street-level bureaucracy and Foucault's theories of mechanisms of power and institutional structures to explore task shifting and cooperation between different professions. RESULTS AND INTERPRETATION: The empirical material reflected a multi-faceted discourse about skill-mix in primary care, where financial factors, perceptions about competence, and task preferences moderated attitudes to task shifting. Competition and cooperation coexist between the professions, and the seemingly gradual blurring between historical hegemony and new models of care creates both alliances and rivalries. Examples of deviations from the Choosing Wisely principles and evidence-based practice indicate that both general practitioners and physiotherapists balance the roles of patient advocate, gatekeeper, and homo economicus, in a context where task shifting is challenged by established practice. It appears that the management of patients with musculoskeletal disorders is fragmented and to some extent reflects a supply-driven system.

The demand on primary care is placing increasing pressure on general practitioners.Multidisciplinary teamwork has potential to improve primary care, for both healthcare professionals and for patients.In this study, it appeared that both competition and cooperation exist between general practitioners and physiotherapists around the management of patients with musculoskeletal disorders in primary care.There is a case for change in service delivery for patients with musculoskeletal disorders in Norwegian primary care.

High-resolution visualization and assessment of basal and OXPHOS-induced mitophagy in H9c2 cardiomyoblasts.

Mitochondria are susceptible to damage resulting from their activity as energy providers. Damaged mitochondria can cause harm to the cell and thus mitochondria are subjected to elaborate quality-control mechanisms including elimination via lysosomal degradation in a process termed mitophagy. Basal mitophagy is a house-keeping mechanism fine-tuning the number of mitochondria according to the metabolic state of the cell. However, the molecular mechanisms underlying basal mitophagy remain largely elusive. In this study, we visualized and assessed the level of mitophagy in H9c2 cardiomyoblasts at basal conditions and after OXPHOS induction by galactose adaptation. We used cells with a stable expression of a pH-sensitive fluorescent mitochondrial reporter and applied state-of-the-art imaging techniques and image analysis. Our data showed a significant increase in acidic mitochondria after galactose adaptation. Using a machine-learning approach we also demonstrated increased mitochondrial fragmentation by OXPHOS induction. Furthermore, super-resolution microscopy of live cells enabled capturing of mitochondrial fragments within lysosomes as well as dynamic transfer of mitochondrial contents to lysosomes. Applying correlative light and electron microscopy we revealed the ultrastructure of the acidic mitochondria confirming their proximity to the mitochondrial network, ER and lysosomes. Finally, exploiting siRNA knockdown strategy combined with flux perturbation with lysosomal inhibitors, we demonstrated the importance of both canonical as well as non-canonical autophagy mediators in lysosomal degradation of mitochondria after OXPHOS induction. Taken together, our high-resolution imaging approaches applied on H9c2 cells provide novel insights on mitophagy during physiologically relevant conditions. The implication of redundant underlying mechanisms highlights the fundamental importance of mitophagy.Abbreviations: ATG: autophagy related; ATG7: autophagy related 7; ATP: adenosine triphosphate; BafA1: bafilomycin A1; CLEM: correlative light and electron microscopy; EGFP: enhanced green fluorescent protein; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; OXPHOS: oxidative phosphorylation; PepA: pepstatin A; PLA: proximity ligation assay; PRKN: parkin RBR E3 ubiquitin protein ligase; RAB5A: RAB5A, member RAS oncogene family; RAB7A: RAB7A, member RAS oncogene family; RAB9A: RAB9A, member RAS oncogene family; ROS: reactive oxygen species; SIM: structured illumination microscopy; siRNA: short interfering RNA; SYNJ2BP: synaptojanin 2 binding protein; TEM: transmission electron microscopy; TOMM20: translocase of outer mitochondrial membrane 20; ULK1: unc-51 like kinase 1.

Reading intervention for students with intellectual disabilities without functional speech who require augmentative and alternative communication: a multiple single-case design with four randomized baselines.

BACKGROUND: Literacy is one of the most important skills a students can achieve, as it provides access to information and communication. Unfortunately, literacy skills are not easily acquired, especially for students with intellectual disabilities who require augmentative and alternative communication (AAC). There are many barriers to literacy acquisition, some due to low expectations from parents and teachers and lack of evidence-based reading programs and reading materials adapted for AAC. Barriers as a result of extensive support needs is also a real factor. This trial aims to deliver reading instructions to 40 students with intellectual disabilities who require AAC and contribute in the debate on how to best support this population through reading instructions to maximizes their reading skills. METHODOLOGY: Forty non-verbal or minimally verbal students (age 6-14) with intellectual disabilities who require AAC will be part of a reading intervention with a multiple single-case design with four randomized baselines. The intervention period will last for 18 months and will commence in March 2023. The students will receive the intervention in a one-to-one format, working systematically with a reading material that contains phonological awareness and decoding tasks based on the Accessible Literacy Learning (ALL) developed by Janice Light and David McNaughton. All the teachers will be trained to deliver the reading intervention. DISCUSSION: The reading material "Lesing for alle" (Reading for all) is based on and follow the strategies behind the research of ALL. The current trial will through a reading intervention contribute to move beyond only teaching sight words and combine several reading components such as sound blending, letter-sound correspondence, phoneme segmentation, shared reading, recognition of sight words, and decoding. The strategies and methods in use is built on the existing science of reading, especially what has been effective in teaching reading for students with intellectual disabilities who require AAC. There is limited generalizability of prior findings in reading-related phonological processing interventions to different populations of them who use AAC specially outside of the USA. More research is needed to understand how programs designed to improve reading skills across other settings understand the program's long-term effects and to study the effectiveness when delivered by educators who are not speech language therapists or researchers. TRIAL REGISTRATION: NCT05709405 . Registered 23 January 2023.

Chronic Rhinosinusitis Outcome Registry (CHRINOSOR): Establishment of an International Outcome Registry Driven by mHealth Technology.

BACKGROUND: Real-world evidence (RWE) is a valuable instrument to better understand the patient journey and effectiveness of therapies. RWE on the prevalence of uncontrolled chronic rhinosinusitis (CRS) and CRS natural course of disease across Europe is scarce. In addition, there is limited RWE that enables comparison of the effectiveness of marketed therapies including topical or systemic corticosteroids, sinus surgery, or biologics. OBJECTIVE: To establish an international CHRonic rhINOSinusitis Outcome Registry (CHRINOSOR) based on real-world data collection enabled by mobile health technology. METHODOLOGY: A digital platform, Galenus Health, supporting patients and physicians in the management of chronic respiratory diseases, is used to collect data on patient profile, disease history, patient outcomes, and a set of relevant clinical outcomes. Adult patients with a diagnosis of CRS are eligible for inclusion. RESULTS: A collaborative scientific network of 17 university ear-nose-throat (ENT) clinics from 10 European countries has been established with the aim to collect real-world data in a longitudinal and standardized manner. The Galenus Health digital platform is currently being implemented in these ENT clinics taking into account legal, privacy, and data security aspects. Up to 300 patients have already been included. CONCLUSIONS: CHRINOSOR is a collaborative effort that aims at improving our understanding of CRS, its comorbidities, and the effectiveness of its treatments. Ultimately, these insights will guide us as scientific community to develop future care pathways informed by RWE.

TRIM27 is an autophagy substrate facilitating mitochondria clustering and mitophagy via phosphorylated TBK1.

Tripartite motif-containing protein 27 (TRIM27/also called RFP) is a multifunctional ubiquitin E3 ligase involved in numerous cellular functions, such as proliferation, apoptosis, regulation of the NF-kB pathway, endosomal recycling and the innate immune response. TRIM27 interacts directly with TANK-binding kinase 1 (TBK1) and regulates its stability. TBK1 in complex with autophagy receptors is recruited to ubiquitin chains assembled on the mitochondrial outer membrane promoting mitophagy. Here, we identify TRIM27 as an autophagy substrate, depending on ATG7, ATG9 and autophagy receptors for its lysosomal degradation. We show that TRIM27 forms ubiquitylated cytoplasmic bodies that co-localize with autophagy receptors. Surprisingly, we observed that induced expression of EGFP-TRIM27 in HEK293 FlpIn TRIM27 knockout cells mediates mitochondrial clustering. TRIM27 interacts with autophagy receptor SQSTM1/p62, and the TRIM27-mediated mitochondrial clustering is facilitated by SQSTM/p62. We show that phosphorylated TBK1 is recruited to the clustered mitochondria. Moreover, induced mitophagy activity is reduced in HEK293 FlpIn TRIM27 knockout cells, while re-introduction of EGFP-TRIM27 completely restores the mitophagy activity. Inhibition of TBK1 reduces mitophagy in HEK293 FlpIn cells and in the reconstituted EGFP-TRIM27-expressing cells, but not in HEK293 FlpIn TRIM27 knockout cells. Altogether, these data reveal novel roles for TRIM27 in mitophagy, facilitating mitochondrial clustering via SQSTM1/p62 and mitophagy via stabilization of phosphorylated TBK1 on mitochondria.

Hypo-osmotic stress induces the epithelial alarmin IL-33 in the colonic barrier of ulcerative colitis.

Epithelial alarmins are gaining interest as therapeutic targets for chronic inflammation. The nuclear alarmin interleukin-33 (IL-33) is upregulated in the colonic mucosa of acute ulcerative colitis (UC) and may represent an early instigator of the inflammatory cascade. However, it is not clear what signals drive the expression of IL-33 in the colonic mucosa, nor is the exact role of IL-33 elucidated. We established an ex vivo model using endoscopic colonic biopsies from healthy controls and UC patients. Colonic biopsies exposed to hypo-osmotic medium induced a strong nuclear IL-33 expression in colonic crypts in both healthy controls and UC biopsies. Mucosal IL33 mRNA was also significantly increased following hypo-osmotic stress in healthy controls compared to non-stimulated biopsies (fold change 3.9, p-value < 0.02). We observed a modest induction of IL-33 in response to TGF-beta-1 stimulation, whereas responsiveness to inflammatory cytokines TNF and IFN-gamma was negligible. In conclusion our findings indicate that epithelial IL-33 is induced by hypo-osmotic stress, rather than prototypic proinflammatory cytokines in colonic ex vivo biopsies. This is a novel finding, linking a potent cytokine and alarmin of the innate immune system with cellular stress mechanisms and mucosal inflammation.

Remote Teaching and School Refusal Behavior - Lessons Learned from the COVID-19 Pandemic.

When the Norwegian government closed down schools and kindergartens in response to the increased spread of COVID-19, the use of homeschooling raised concerns about students with school refusal behavior and the school system's ability to address their special needs in these circumstances. Six students referred to the school absenteeism team were interviewed about their circumstances, using an author-developed interview. The results indicate that the students rated homeschooling as very satisfactory. Students with school refusal behavior participated in homeschooling and their attendance continued during the initial reopening of schools.

Childhood Disintegrative Disorder (CDD): Symptomatology of the Norwegian Patient Population and Parents' Experiences of Patient Regression.

Childhood Disintegrative Disorder (CDD) is a rare and little researched developmental disorder characterised by regression in language and social skills after a period of seemingly normal development until at least the age of 2 years. The study contacted all parents of CDD patients in Norway to assess patient symptomatology and parents' experiences of regression via questionnaire or interview. There were 12 participants. Symptomatology was in-line with previous studies, with universal regression in language and social skills and onset predominantly at 2-4 years. Regression was connected to feelings of 'loss' and uncertainty over the prognosis for CDD patients. The study supported CDD diagnostic criteria and showed that CDD patient regression has profound implications for parental well-being.

What are we optimizing for in autism screening? Examination of algorithmic changes in the M-CHAT.

The present study objectives were to examine the performance of the new M-CHAT-R algorithm to the original M-CHAT algorithm. The main purpose was to examine if the algorithmic changes increase identification of children later diagnosed with ASD, and to examine if there is a trade-off when changing algorithms. We included 54,463 screened cases from the Norwegian Mother and Child Cohort Study. Children were screened using the 23 items of the M-CHAT at 18 months. Further, the performance of the M-CHAT-R algorithm was compared to the M-CHAT algorithm on the 23-items. In total, 337 individuals were later diagnosed with ASD. Using M-CHAT-R algorithm decreased the number of correctly identified ASD children by 12 compared to M-CHAT, with no children with ASD screening negative on the M-CHAT criteria subsequently screening positive utilizing the M-CHAT-R algorithm. A nonparametric McNemar's test determined a statistically significant difference in identifying ASD utilizing the M-CHAT-R algorithm. The present study examined the application of 20-item MCHAT-R scoring criterion to the 23-item MCHAT. We found that this resulted in decreased sensitivity and increased specificity for identifying children with ASD, which is a trade-off that needs further investigation in terms of cost-effectiveness. However, further research is needed to optimize screening for ASD in the early developmental period to increase identification of false negatives.

Collaborative healthcare education programmes for continuing professional education in low and middle-income countries: A Best Evidence Medical Education (BEME) systematic review. BEME Guide No. 65.

BACKGROUND: Large discrepancies exist between standards of healthcare provision in high-income (HICs) and low and middle-income countries (LMICs). The root cause is often financial, resulting in poor infrastructure and under-resourced education and healthcare systems. Continuing professional education (CPE) programmes improve staff knowledge, skills, retention, and practice, but remain costly and rare in low-resource settings. One potential solution involves healthcare education collaborations between institutions in HICs and LMICs to provide culturally appropriate CPE in LMICs. To be effective, educational partnerships must address the challenges arising from differences in cultural norms, language, available technology and organisational structures within collaborating countries. METHODS: Seven databases and other sources were systematically searched on 7 July 2020 for relevant studies. Citations, abstracts, and studies were screened and consensus was reached on which to include within the review. 54 studies were assessed regarding the type of educational programme involved, the nature of HIC/LMIC collaboration and quality of the study design. RESULTS: Studies varied greatly regarding the types and numbers of healthcare professionals involved, pedagogical and delivery methods, and the ways in which collaboration was undertaken. Barriers and enablers of collaboration were identified and discussed. The key findings were: 1. The methodological quality of reporting in the studies was generally poor. 2. The way in which HIC/LMIC healthcare education collaboration is undertaken varies according to many factors, including what is to be delivered, the learner group, the context, and the resources available. 3. Western bias was a major barrier. 4. The key to developing successful collaborations was the quality, nature, and duration of the relationships between those involved. CONCLUSION: This review provides insights into factors that underpin successful HIC/LMIC healthcare CPE collaborations and outlines inequities and quality issues in reporting.

SAMM50 acts with p62 in piecemeal basal- and OXPHOS-induced mitophagy of SAM and MICOS components.

Mitophagy is the degradation of surplus or damaged mitochondria by autophagy. In addition to programmed and stress-induced mitophagy, basal mitophagy processes exert organelle quality control. Here, we show that the sorting and assembly machinery (SAM) complex protein SAMM50 interacts directly with ATG8 family proteins and p62/SQSTM1 to act as a receptor for a basal mitophagy of components of the SAM and mitochondrial contact site and cristae organizing system (MICOS) complexes. SAMM50 regulates mitochondrial architecture by controlling formation and assembly of the MICOS complex decisive for normal cristae morphology and exerts quality control of MICOS components. To this end, SAMM50 recruits ATG8 family proteins through a canonical LIR motif and interacts with p62/SQSTM1 to mediate basal mitophagy of SAM and MICOS components. Upon metabolic switch to oxidative phosphorylation, SAMM50 and p62 cooperate to mediate efficient mitophagy.

Regulation of Golgi turnover by CALCOCO1-mediated selective autophagy.

The Golgi complex is essential for the processing, sorting, and trafficking of newly synthesized proteins and lipids. Golgi turnover is regulated to meet different cellular physiological demands. The role of autophagy in the turnover of Golgi, however, has not been clarified. Here we show that CALCOCO1 binds the Golgi-resident palmitoyltransferase ZDHHC17 to facilitate Golgi degradation by autophagy during starvation. Depletion of CALCOCO1 in cells causes expansion of the Golgi and accumulation of its structural and membrane proteins. ZDHHC17 itself is degraded by autophagy together with other Golgi membrane proteins such as TMEM165. Taken together, our data suggest a model in which CALCOCO1 mediates selective Golgiphagy to control Golgi size and morphology in eukaryotic cells via its interaction with ZDHHC17.

CALCOCO1 acts with VAMP-associated proteins to mediate ER-phagy.

The endoplasmic reticulum (ER) plays important roles in protein synthesis and folding, and calcium storage. The volume of the ER and expression of its resident proteins are increased in response to nutrient stress. ER-phagy, a selective form of autophagy, is involved in the degradation of the excess components of the ER to restore homeostasis. Six ER-resident proteins have been identified as ER-phagy receptors so far. In this study, we have identified CALCOCO1 as a novel ER-phagy receptor for the degradation of the tubular ER in response to proteotoxic and nutrient stress. CALCOCO1 is a homomeric protein that binds directly to ATG8 proteins via LIR- and UDS-interacting region (UIR) motifs acting co-dependently. CALCOCO1-mediated ER-phagy requires interaction with VAMP-associated proteins VAPA and VAPB on the ER membranes via a conserved FFAT-like motif. Depletion of CALCOCO1 causes expansion of the ER and inefficient basal autophagy flux. Unlike the other ER-phagy receptors, CALCOCO1 is peripherally associated with the ER. Therefore, we define CALCOCO1 as a soluble ER-phagy receptor.

Exploring what patients with musculoskeletal conditions want from first point-of-contact health practitioners.

OBJECTIVES: This research was conducted to support the development of the Musculoskeletal (MSK) Health Capabilities Framework to ensure that the framework reflected patients' priorities. The aim of this study was to explore what patients with MSK problems want from their initial consultation with a first contact health practitioner and, from the patient perspective, what characterizes a good first contact health practitioner. METHODS: Focus groups were held in four locations across England. Sixteen participants, aged 19-75 years and with a self-declared MSK condition, took part (11 female, five male). Participants discussed the questions they want answered when first going to see a health professional about an MSK problem and how they would describe a good first contact health provider. RESULTS: Participants wanted answers to questions about the nature of the problem, the management of the problem, where to get information and support to help themselves, what activities they can do and what the future holds. Values and behaviours they expect and value from first contact health practitioners include good communication skills, appreciation of impact, a willingness to discuss alternative and complementary therapies, shared decision-making and an awareness of their own limitations and when to refer. CONCLUSION: The MSK core capabilities framework for first contact health practitioners aims to ensure a person-centred approach in the first stages of managing any MSK problem with which a person may present. The focus groups enabled the developers of the framework to achieve a greater understanding of patient priorities, expectations and needs and allowed the patient perspective to be included in this national framework.

The expression of the long NEAT1_2 isoform is associated with human epidermal growth factor receptor 2-positive breast cancers.

The long non-coding RNA NEAT1 locus is transcribed into two overlapping isoforms, NEAT1_1 and NEAT1_2, of which the latter is essential for the assembly of nuclear paraspeckles. NEAT1 is abnormally expressed in a wide variety of human cancers. Emerging evidence suggests that the two isoforms have distinct functions in gene expression regulation, and recently it was shown that NEAT1_2, but not NEAT1_1, expression predicts poor clinical outcome in cancer. Here, we report that NEAT1_2 expression correlates with HER2-positive breast cancers and high-grade disease. We provide evidence that NEAT1_1 and NEAT1_2 have distinct expression pattern among different intrinsic breast cancer subtypes. Finally, we show that NEAT1_2 expression and paraspeckle formation increase upon lactation in humans, confirming what has previously been demonstrated in mice.

Piloting the Use of a Short Observation List for ASD-Symptoms in Day-Care: Challenges and Further Possibilities.

Early symptoms of autism spectrum disorder (ASD) develop through the second year of life, making a stable ASD diagnosis possible around 24 months of age. However, in general, children with ASD are diagnosed later. In this study we explored the use of a short observation list to detect symptoms associated with ASD in children 12-24 months of age attending typical day-care centers. The results indicate that a short observation list used by day-care teachers does not reveal sufficient properties to be independently used in young children in day-care centers. Further studies should explore multiple and repeated measures for early detection of symptoms associated with ASD in typical day-care centers.

NIMA-related kinase 9-mediated phosphorylation of the microtubule-associated LC3B protein at Thr-50 suppresses selective autophagy of p62/sequestosome 1.

Human ATG8 family proteins (ATG8s) are active in all steps of the macroautophagy pathway, and their lipidation is essential for autophagosome formation. Lipidated ATG8s anchored to the outer surface of the phagophore serve as scaffolds for binding of other core autophagy proteins and various effector proteins involved in trafficking or fusion events, whereas those at the inner surface are needed for assembly of selective autophagy substrates. Their scaffolding role depends on specific interactions between the LC3-interacting region (LIR) docking site (LDS) in ATG8s and LIR motifs in various interaction partners. LC3B is phosphorylated at Thr-50 within the LDS by serine/threonine kinase (STK) 3 and STK4. Here, we identified LIR motifs in STK3 and atypical protein kinase Cζ (PKCζ) and never in mitosis A (NIMA)-related kinase 9 (NEK9). All three kinases phosphorylated LC3B Thr-50 in vitro A phospho-mimicking substitution of Thr-50 impaired binding of several LIR-containing proteins, such as ATG4B, FYVE, and coiled-coil domain-containing 1 (FYCO1), and autophagy cargo receptors p62/sequestosome 1 (SQSTM1) and neighbor of BRCA1 gene (NBR1). NEK9 knockdown or knockout enhanced degradation of the autophagy receptor and substrate p62. Of note, the suppression of p62 degradation was mediated by NEK9-mediated phosphorylation of LC3B Thr-50. Consistently, reconstitution of LC3B-KO cells with the phospho-mimicking T50E variant inhibited autophagic p62 degradation. PKCζ knockdown did not affect autophagic p62 degradation, whereas STK3/4 knockouts inhibited autophagic p62 degradation independently of LC3B Thr-50 phosphorylation. Our findings suggest that NEK9 suppresses LC3B-mediated autophagy of p62 by phosphorylating Thr-50 within the LDS of LC3B.

The use of an e-learning module on return to work advice for physiotherapists - A prospective cohort study.

Background: Nonspecific low back pain (LBP) can progress to chronic disability and prolonged absence from work. Despite clinical and professional guidelines, physiotherapists often fail to address return to work outcomes. Aims: The aim of this exploratory study was to determine whether an e-learning resource tailored to physiotherapy practice could affect physiotherapists' attitudes and beliefs regarding return to work advice for their patients. Design: A prospective interventional cohort study (pilot). Methods: Participants were recruited via the Chartered Society of Physiotherapy website. Responses on a clinical vignette, the Health Care Providers' Pain and Impairment Scale (HC-Pairs), and the Behavioral Constructs Questionnaire (BCQ) were collected online at baseline (Q1) and 2-months post-intervention (Q2). Results: Fifty-four physiotherapists completed Q1 and the response rate for Q2 was 44/54 (81%). Changes in the degree of agreement with guidelines indicated that the intervention made an impact on respondents (kappa 0.345; p = 0.003). HC-Pairs and BCQ results showed a nonstatistically significant trend toward the target behavior. Conclusions: There is a need for interventions to improve adherence with advice for return to work following nonspecific LBP. An e-learning tool for physiotherapists on advising patients regarding return to work has potential to positively affect self-reported clinical behavior.

TRIM32, but not its muscular dystrophy-associated mutant, positively regulates and is targeted to autophagic degradation by p62/SQSTM1.

The tripartite motif (TRIM) proteins constitute a family of ubiquitin E3 ligases involved in a multitude of cellular processes, including protein homeostasis and autophagy. TRIM32 is characterized by six protein-protein interaction domains termed NHL, various point mutations in which are associated with limb-girdle-muscular dystrophy 2H (LGMD2H). Here, we show that TRIM32 is an autophagy substrate. Lysosomal degradation of TRIM32 was dependent on ATG7 and blocked by knockout of the five autophagy receptors p62 (also known as SQSTM1), NBR1, NDP52 (also known as CALCOCO2), TAX1BP1 and OPTN, pointing towards degradation by selective autophagy. p62 directed TRIM32 to lysosomal degradation, while TRIM32 mono-ubiquitylated p62 on lysine residues involved in regulation of p62 activity. Loss of TRIM32 impaired p62 sequestration, while reintroduction of TRIM32 facilitated p62 dot formation and its autophagic degradation. A TRIM32LGMD2H disease mutant was unable to undergo autophagic degradation and to mono-ubiquitylate p62, and its reintroduction into the TRIM32-knockout cells did not affect p62 dot formation. In light of the important roles of autophagy and p62 in muscle cell proteostasis, our results point towards impaired TRIM32-mediated regulation of p62 activity as a pathological mechanisms in LGMD2H.