WRN inhibition leads to its chromatin-associated degradation via the PIAS4-RNF4-p97/VCP axis.

Synthetic lethality provides an attractive strategy for developing targeted cancer therapies. For example, cancer cells with high levels of microsatellite instability (MSI-H) are dependent on the Werner (WRN) helicase for survival. However, the mechanisms that regulate WRN spatiotemporal dynamics remain poorly understood. Here, we used single-molecule tracking (SMT) in combination with a WRN inhibitor to examine WRN dynamics within the nuclei of living cancer cells. WRN inhibition traps the helicase on chromatin, requiring p97/VCP for extraction and proteasomal degradation in a MSI-H dependent manner. Using a phenotypic screen, we identify the PIAS4-RNF4 axis as the pathway responsible for WRN degradation. Finally, we show that co-inhibition of WRN and SUMOylation has an additive toxic effect in MSI-H cells and confirm the in vivo activity of WRN inhibition using an MSI-H mouse xenograft model. This work elucidates a regulatory mechanism for WRN that may facilitate identification of new therapeutic modalities, and highlights the use of SMT as a tool for drug discovery and mechanism-of-action studies.

Optimized Properties and Synthesis of Photoactivatable Diazoketorhodamines Facilitate and Enhance High-Throughput Single-Molecule Tracking.

Photoactivatable (PA) rhodamine dyes are widely used in single-molecule tracking (SMT) and a variety of other fluorescence-based imaging modalities. One of the most commonly employed scaffolds uses a diazoketone to lock the rhodamine in the nonfluorescent closed form, which can be activated with 405 nm light. However, poor properties of previously reported dyes require significant washing, which can be resource- and cost-intensive, especially when performing microscopy in a large scale and high-throughput fashion. Here, we report improved diazoketorhodamines that perform exceptionally well in single-molecule tracking microscopy. We also report on the optimization of an improved synthetic method for further iteration and tailoring of diazoketorhodamines to the requirements of a specific user.

Implicit Motor Imagery of the Foot and Hand in People with Achilles Tendinopathy: A Left Right Judgement Study.

OBJECTIVE: To determine if impairment in motor imagery processes is present in Achilles tendinopathy (AT), as demonstrated by a reduced ability to quickly and accurately identify the laterality (left-right judgement) of a pictured limb. Additionally, this study aimed to use a novel data pooling approach to combine data collected at 3 different sites via meta-analytical techniques that allow exploration of heterogeneity. DESIGN: Multi-site case-control study. METHODS: Three independent studies with similar protocols were conducted by separate research groups. Each study-site evaluated left/right judgement performance for images of feet and hands using Recognise© software and compared performance between people with AT and healthy controls. Results from each study-site were independently collated, then combined in a meta-analysis. RESULTS: In total, 126 participants (40 unilateral, 22 bilateral AT cases, 61 controls) were included. There were no differences between AT cases and controls for hand image accuracy and reaction time. Contrary to the hypothesis, there were no differences in performance between those with AT and controls for foot image reaction time, however there were conflicting findings for foot accuracy, based on four separate analyses. There were no differences between the affected and unaffected sides in people with unilateral AT. CONCLUSIONS: Impairments in motor imagery performance for hands were not found in this study, and we found inconsistent results for foot accuracy. This contrasts to studies in persistent pain of limbs, face and knee osteoarthritis, and suggests that differences in pathoetiology or patient demographics may uniquely influence proprioceptive representation.

Sensory Processing in People With and Without Tendinopathy: A Systematic Review With Meta-analysis of Local, Regional, and Remote Sites in Upper- and Lower-Limb Conditions.

OBJECTIVE: To synthesize results of somatosensory processing tests in people with upper- and lower-limb tendinopathy, compared to controls. DESIGN: Systematic review with meta-analysis. LITERATURE SEARCH: Four electronic databases (MEDLINE, CINAHL Plus, SPORTDiscus, and Embase) were searched. STUDY SELECTION CRITERIA: Included studies measured a domain of sensory processing and compared a tendinopathy group to a healthy control group. DATA SYNTHESIS: Meta-analysis was conducted for outcomes with homogeneous data from at least 2 studies. Upper- and lower-limb conditions were compared and outcomes were examined by measurement site (local, regional, or remote to location of pain). RESULTS: Of the 30 studies included, 18 investigated lateral elbow tendinopathy. The most commonly assessed outcome measures were pressure pain threshold (PPT) and thermal pain threshold. There was moderate evidence for local and regional reduction of PPT in upper-limb tendinopathies, but not at remote sites. In lower-limb tendinopathies, there was conflicting evidence regarding reduced PPT at local sites and limited evidence of normal PPT at remote sites. There was moderate evidence of sensitization of thermal pain threshold at local sites in upper-limb tendinopathies and limited evidence of no difference in thermal pain threshold in lower-limb tendinopathies. Findings across other domains were variable. CONCLUSION: Sensory processing was different between upper-limb tendinopathy and lower-limb tendinopathy. Upper-limb tendinopathies showed signs consistent with primary and secondary hyperalgesia, but lower-limb tendinopathies did not. There was mixed evidence for primary hyperalgesia and limited evidence against secondary hyperalgesia. J Orthop Sports Phys Ther 2021;51(1):12-26. doi:10.2519/jospt.2021.9417.

An algorithm for managing adults who refuse medical treatment in New South Wales.

OBJECTIVES: The assessment and management of a patient who refuses medical treatment requires clinical skill, and consideration of the relevant law and the patient's decision-making capacity. Psychiatrists are often asked to advise in these situations. We aimed to develop an algorithm describing the relevant legal pathways to assist clinicians, especially psychiatrists, working in New South Wales (NSW), Australia. METHODS: We reviewed the academic literature on treatment refusal, relevant legislation, judicial rulings and NSW Health policy directives and guidelines. We consulted with clinicians and representatives of relevant tribunals. RESULTS: We developed an algorithm for managing patients who refuse medical treatment in NSW. The algorithm emphases the evaluation of decision-making capacity and tracks separate pathways depending upon a person's status under the Mental Health Act 2007 (NSW). CONCLUSIONS: The algorithm provides a clear decision tree for clinicians responding to a patient refusing medical treatment in NSW.

'My husband is possessed by a jinn': a case study in transcultural mental health.

Objectives The objective of this study was to discuss jinn possession in Muslim culture, and the importance of understanding cultural differences in mental health. Conclusion It is important to understand cultural and religious differences in psychiatry, as it affects the way patients perceive and attribute symptoms. It also helps clinicians to reach an accurate diagnosis and provide appropriate treatments. Beliefs about jinn possession should not automatically be regarded as delusional. In alleged cases of jinn possession, clinicians should consider all the biopsychosocial, cultural and spiritual factors that are unique to the individual. Further research is still needed in this area.

Communication of a schizophrenia diagnosis: A qualitative study of patients' perspectives.

BACKGROUND: Transparent diagnostic communication is considered best practice for clinicians. However, while patients expect to receive a schizophrenia diagnosis from their psychiatrist, research suggests mental health clinicians are often reluctant to provide this information to patients. AIM: This study examines the perceptions of people with schizophrenia surrounding the communication of this diagnosis. METHODS: A generic qualitative methodological approach was used. A total of 14 patients with schizophrenia were recruited through community mental health services (n = 10) and the Australia Schizophrenia Research Bank (ASRB; n = 4) in New South Wales (NSW), Australia. Semi-structured interviews were used to explore the experiences and perceptions of people with schizophrenia about the way a schizophrenia diagnosis was communicated by mental health clinicians. Interviews were recorded, transcribed, codes generated and thematic analysis undertaken aided by NVivo. RESULTS: The majority of participants felt it was beneficial to receive a diagnosis despite acknowledging the distress this information sometimes caused, with many reporting this knowledge gave a sense of relief. It helped to understand their experiences and behaviours, improved their trust in the psychiatric system and increased treatment adherence. However, many reported difficulty in obtaining information about their condition, its treatment and prognosis, and expressed dissatisfaction with the way a diagnosis of schizophrenia was communicated. DISCUSSION: Insight into the perceptions and experiences of patients with schizophrenia about how a diagnosis of schizophrenia is communicated is a key outcome of this research. This knowledge will inform the development of future training programmes for mental health clinicians, and influence the clinical practice of health professionals treating patients with schizophrenia.