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Stigma surrounding dementia is a significant issue affecting individuals and communities leading to discrimination towards those living with the condition. However, the changing paradigm in dementia support to living well with dementia can reduce this stigma and improve community attitudes. A community initiative aimed to address this evaluated the impact of a two-hour education forum involving 92 community members. Presentations from experts, including a person with dementia, addressed dementia-related human rights issues and initiatives to live well with dementia. Attendees completed the new Dementia Community Attitudes Questionnaire (DCAQ) aligned with the evolving paradigm of living well with dementia before and after the forum. Participants with prior dementia education had higher initial scores while those without education showed more significant improvements. Almost all DCAQ items showed post-forum score improvements. This community Dementia Awareness Raising Forum provided an opportunity for people to come together and initiate conversations around dementia resulting in more positive community attitudes., 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.

Myotonia congenita is a hereditary, non-dystrophic skeletal muscle disorder associated with muscle stiffness due to delayed muscle relaxation after contraction. We review myotonia congenita in domesticated animals and humans and investigated suspected myotonia congenita in a flock of Merino sheep in Australia. In 2020, a property in New South Wales reported a four-year history of lambs that would fall on disturbance before rapidly recovering, with 13 affected sheep identified in 2020. Episodes were associated with a short period of tetanic spasms and a stiff gait upon rising. Lambs were otherwise normal between episodes, although over time, lost body condition and occasionally died from misadventure. An inherited condition was considered from limited pedigree information and a preliminary diagnosis of myotonia congenita was made based on clinical presentation. Biochemistry from four sheep found variable, but typically mild increases in creatine kinase (CK) and aspartate aminotransferase (AST). Modified electromyography on six affected sheep found irregular electrical activity within the muscle. For four sheep, there were no consistent significant abnormalities on post mortem examination and histopathology-typical for this condition. A review of the Online Mendelian Inheritance in Man (OMIM) and Online Mendelian Inheritance in Animals (OMIA) databases was conducted to summarise information about myotonia congenita in humans and eight non-human species of animals. Comparing the characteristic clinical presentation, pathology and electromyography data of affected Merino sheep to similar conditions in other species assisted the identification of likely candidate genes. Whole genome sequencing of two affected lambs detected a missense variant in CLCN1 (NC_056057.1:g.107930611C>T; XM_004008136.5:c.844C>T; XP_004008185.4:p.(P282S)), with a predicted deleterious effect on protein function. An SNP genotyping assay was developed, and the variant segregated with the disease in 12 affected sheep and obligate carrier rams under an assumed recessive mode of inheritance. Identifying a likely causal variant and developing a diagnostic test allows screening of suspected affected or carrier Merino sheep for early intervention to reduce propagation of the variant within flocks.

Background: The aim of this study was to describe the proficiency of ChatGPT (GPT-4) on certification style exams from the Canadian Association of Medical Radiation Technologists (CAMRT), and describe its performance across multiple exam attempts., Methods: ChatGPT was prompted with questions from CAMRT practice exams in the disciplines of radiological technology, magnetic resonance (MRI), nuclear medicine and radiation therapy (87-98 questions each). ChatGPT attempted each exam five times. Exam performance was evaluated using descriptive statistics, stratified by discipline and question type (knowledge, application, critical thinking). Light's Kappa was used to assess agreement in answers across attempts., Results: Using a passing grade of 65 %, ChatGPT passed the radiological technology exam only once (20 %), MRI all five times (100 %), nuclear medicine three times (60 %), and radiation therapy all five times (100 %). ChatGPT's performance was best on knowledge questions across all disciplines except radiation therapy. It performed worst on critical thinking questions. Agreement in ChatGPT's responses across attempts was substantial within the disciplines of radiological technology, MRI, and nuclear medicine, and almost perfect for radiation therapy., Conclusion: ChatGPT (GPT-4) was able to pass certification style exams for radiation technologists and therapists, but its performance varied between disciplines. The algorithm demonstrated substantial to almost perfect agreement in the responses it provided across multiple exam attempts. Future research evaluating ChatGPT's performance on standardized tests should consider using repeated measures., (Copyright © 2024. Published by Elsevier Inc.)

Alzheimer's disease (AD) is the most common global dementia and is universally fatal. Most late-stage AD disease-modifying therapies are intravenous and target amyloid beta (Aβ), with only modest effects on disease progression: there remains a high unmet need for convenient, safe, and effective therapeutics. Senescent cells (SC) and the senescence-associated secretory phenotype (SASP) drive AD pathology and increase with AD severity. Preclinical senolytic studies have shown improvements in neuroinflammation, tau, Aβ, and CNS damage; most were conducted in transgenic rodent models with uncertain human translational relevance. In this study, aged cynomolgus monkeys had significant elevation of biomarkers of senescence, SASP, and neurological damage. Intermittent treatment with the senolytic navitoclax induced modest reversible thrombocytopenia; no serious drug-related toxicity was noted. Navitoclax reduced several senescence and SASP biomarkers, with CSF concentrations sufficient for senolysis. Finally, navitoclax reduced TSPO-PET frontal cortex binding and showed trends of improvement in CSF biomarkers of neuroinflammation, neuronal damage, and synaptic dysfunction. Overall, navitoclax administration was safe and well tolerated in aged monkeys, inducing trends of biomarker changes relevant to human neurodegenerative disease., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Edward Greenberg, MD reports financial support was provided by AbbVie Inc. Edward Greenberg MD reports a relationship with AbbVie Inc that includes: employment, equity or stocks, and funding grants. EFG, MV, AS, DRR, YZ, JQW, DWW, EA, MH, CH, RD, MT, KO, WA, LD, HK, JSS, YH, KM, VZ, SY, JM, YF, AV, SW, MD, SJF, and HF are employees of AbbVie and may hold stock. KD was an employee of AbbVie at the time of the study and may hold stock. The design, study conduct, and all funding for this research was provided by AbbVie, the maker of navitoclax (ABT-263). AbbVie participated in the interpretation of data, review, and approval of the publication. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Abstract: Glucocorticoids are key components of the standard-of-care treatment regimens for B-cell malignancy. However, systemic glucocorticoid treatment is associated with several adverse events. ABBV-319 is a CD19-targeting antibody-drug conjugate engineered to reduce glucocorticoid-associated toxicities while possessing 3 distinct mechanisms of action (MOA) to increase therapeutic efficacy: (1) antibody-mediated delivery of a glucocorticoid receptor modulator (GRM) payload to activate apoptosis, (2) inhibition of CD19 signaling, and (3) enhanced fragment crystallizable (Fc)-mediated effector function via afucosylation of the antibody backbone. ABBV-319 elicited potent GRM-driven antitumor activity against multiple malignant B-cell lines in vitro, as well as in cell line-derived xenografts and patient-derived xenografts (PDXs) in vivo. Remarkably, a single dose of ABBV-319 induced sustained tumor regression and enhanced antitumor activity compared with repeated dosing of systemic prednisolone at the maximum tolerated dose in mice. The unconjugated CD19 monoclonal antibody (mAb) also displayed antiproliferative activity in a subset of B-cell lymphoma cell lines through the inhibition of phosphoinositide 3-kinase signaling. Moreover, afucosylation of CD19 mAb enhanced Fc-mediated antibody-dependent cellular cytotoxicity. Notably, ABBV-319 displayed superior efficacy compared with afucosylated CD19 mAb in human CD34+ peripheral blood mononuclear cell-engrafted NSG-Tg(Hu-IL15) transgenic mice, demonstrating enhanced antitumor activity when multiple MOAs are enabled. ABBV-319 also showed durable antitumor activity across multiple B-cell lymphoma PDX models, including nongerminal center B-cell diffuse large B-cell lymphoma and relapsed lymphoma after R-CHOP treatment. Collectively, these data support the ongoing evaluation of ABBV-319 in a phase 1 clinical trial., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance 1,2 . The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour cells or immune cells promotes anti-tumour immunity 3-6 . However, phosphatases are challenging drug targets; in particular, the active site has been considered undruggable. Here we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2 and PTPN1 active-site inhibitor. AC484 treatment in vitro amplifies the response to interferon and promotes the activation and function of several immune cell subsets. In mouse models of cancer resistant to PD-1 blockade, AC484 monotherapy generates potent anti-tumour immunity. We show that AC484 inflames the tumour microenvironment and promotes natural killer cell and CD8 + T cell function by enhancing JAK-STAT signalling and reducing T cell dysfunction. Inhibitors of PTPN2 and PTPN1 offer a promising new strategy for cancer immunotherapy and are currently being evaluated in patients with advanced solid tumours (ClinicalTrials.gov identifier NCT04777994 ). More broadly, our study shows that small-molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding that of antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics that target this important class of enzymes., (© 2023. The Author(s).)

Background: Prior to the coronavirus disease 2019 (COVID-19) pandemic, international clinical placements (ICPs) for nursing students were used to build cultural humility and global awareness. This study explored the influence of ICPs on nursing students' career planning and views of the nursing role; the findings were considered against the evolving pandemic context., Method: A qualitative, descriptive longitudinal study was conducted with 25 preregistration nursing students who participated in an international placement. Semistructured individual interview data were examined using thematic analysis., Results: Participants were interested in patient equity and empowerment, high acuity and variety, health policy, and primary care. Participants developed resilience and nursing confidence. They saw the effects of poor health equity and health policy decisions on population health., Conclusion: ICPs expanded participants' understanding of global interconnectedness and also identified new career possibilities. Postpandemic, nursing education should continue to maintain a global focus on health. [ J Nurs Educ . 2023;62(4):207-214.] .

Background: The COVID-19 global pandemic was declared in March 2020. By June 2022, the total deaths worldwide attributed to COVID-19 numbered over 6.3 million. Health professionals have been significantly impacted worldwide primarily those working on the frontline but also those working in other areas including nursing, midwifery, and paramedic higher education. Studies of occupational stress have focused on the clinical health professional roles but scant attention has been drawn to the pressures on university-based academic staff supporting and preparing professionals for frontline health work., Design and Objectives: This qualitative study sought to explore the challenges experienced by health academics (nurses, midwives and paramedics), during COVID-19 and identify strategies enlisted., Setting and Participants: Six Australian and two United Kingdom universities collaborated, from which 34 health academics were individually interviewed via video or teleconference, using six broad questions. Ethical approval was obtained from the lead site and each participating University., Data Analysis: Thematic analysis of the data was employed collaboratively across institutions, using Braun and Clarke's method., Results: Data analysis generated four major themes describing academics': Experiences of change; perceptions of organisational responses; professional and personal impacts; and strategies to support wellbeing. Stress, anxiety and uncertainty of working from home and teaching in a different way were reported. Strategies included setting workday routine, establishing physical boundaries for home-working and regular online contact with colleagues., Conclusions: The ability of nursing, midwifery and, paramedic academic staff to adapt to a sudden increase in workload, change in teaching practices and technology, while being removed from their work environment, and collegial, academic and technological supports is highlighted. It was recognised that these changes will continue post-COVID and that the way academics deliver education is forever altered., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Active materials have been explored in recent years to demonstrate superluminal group velocities over relatively broad bandwidths, implying a potential path towards bold claims such as information transport beyond the speed of light, as well as antennas and metamaterial cloaks operating over very broad bandwidths. However, causality requires that no portion of an impinging pulse can pass its precursor, implying a fundamental trade-off between bandwidth, velocity and propagation distance. Here, we clarify the general nature of superluminal propagation in active structures and derive a bound on these quantities fundamentally rooted into stability considerations. By applying filter theory, we show that this bound is generally applicable to causal structures of arbitrary complexity, as it applies to each zero-pole pair describing their response. As the system complexity grows, we find that only minor improvements in superluminal bandwidth can be practically achieved. Our results provide physical insights into the limitations of superluminal structures based on active media, implying severe constraints in several recently proposed applications., (© 2022. The Author(s).)

A 74-year-old gentleman with a background of metastatic pancreatic neuroendocrine tumour on combination chemotherapy of Cisplatin and Etoposide presented with a 3-week history of bilateral visual loss. Snellen visual acuity was right 6/9 and left 6/60. Fundus examination revealed clear media with isolated macular oedema in both eyes. Optical coherence tomography of the maculae showed localised bilateral subfoveal serous detachments. Cisplatin was thought to be the causative agent and was withheld following discussion with the treating Oncology team. Eight weeks after withholding Cisplatin, his vision improved with complete resolution of the subretinal fluid. To the authors' knowledge, this is the first report to have illustrated bilateral subfoveal serous detachment caused by Cisplatin which resolved completely with cessation of offending drug.