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Predicting the mechanical properties of powder mixtures without extensive experimentation is important for model driven design in solid dosage form manufacture. Here, a new binary interaction-based model is proposed for predicting the compressibility and compactability of directly compressed pharmaceutical powder mixtures based on the mixture composition. The model is validated using blends of MCC, lactose and paracetamol or ibuprofen. Both compressibility and compactability profiles are predicted well for a variety of blend compositions of ternary mixtures for the two formulations. The model performs well over a wide range of compositions for both blends and better than either an ideal mixing model or a ternary interaction model. A design of experiments which reduces the amount of API required for fitting the model parameters for a new formulation is proposed to reduce amount of API required. The design requires only three blends containing API. The model gives similar performance to the well-known Reynolds et al. model (2017) when trained using the same data sets. The binary interaction model approach is generalizable to other powder mixture properties. The model presented in this work is limited to curve-fitting of empirical compaction models for mixtures of common pharmaceutical powders and is not intended to provide guidance on the practical operating space (or design space) limits., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Analyze the implementation of diagnosis-related groups (DRGs) in Chile with a view to optimizing the distribution of public resources., Methods: A chronological narrative analysis of the main milestones was complemented by simulated application of DRGs through emulated competition and cluster analysis for evaluative purposes., Results: In 2001, DRGs were introduced in Chile in an academic context. The National Health Fund (FONASA) began using DRGs in the private sector. A public sector pilot was launched in 2015. After nearly two decades of progress, in 2020 FONASA established the DRG program as a payment mechanism for public hospitals. However, the COVID-19 pandemic slowed its development. In 2022, implementation was resumed. After evaluating the program, it was evident that the hospital clusters that had been predefined for differentiated payment did not successfully differentiate homogeneous groups. In 2023, the program was reformed, financing was increased, a single cluster and base rate were defined, and greater hospital complexity was recognized, compared to previous years. Three hospitals were added to the program, for a total of 68., Conclusions: This experience shows that it is possible to sustain a public health financing policy that achieves greater efficiency and equity in the health system, based on the existence of robust institutions that continuously develop and improve., Competing Interests: Conflicto de intereses. Ninguno declarado por los autores.

Meta-analysis of genome-wide association study data has implicated PDE4B in the pathogenesis of Alzheimer's disease (AD), the leading cause of senile dementia. PDE4B encodes one of four subtypes of cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase-4 (PDE4A-D). To interrogate the involvement of PDE4B in the manifestation of AD-related phenotypes, the effects of a hypomorphic mutation (Pde4b Y358C ) that decreases PDE4B's cAMP hydrolytic activity were evaluated in the App NL-G-F knock-in mouse model of AD using the Barnes maze test of spatial memory, 14 C-2-deoxyglucose autoradiography, thioflavin-S staining of β-amyloid (Aβ) plaques, and inflammatory marker assay and transcriptomic analysis (RNA sequencing) of cerebral cortical tissue. At 12 months of age, App NL-G-F mice exhibited spatial memory and brain metabolism deficits, which were prevented by the hypomorphic PDE4B in App NL-G-F /Pde4b Y358C mice, without a decrease in Aβ plaque burden. RNA sequencing revealed that, among the 531 transcripts differentially expressed in App NL-G-F versus wild-type mice, only 13 transcripts from four genes - Ide, Btaf1, Padi2, and C1qb - were differentially expressed in App NL-G-F /Pde4b Y358C versus App NL-G-F mice, identifying their potential involvement in the protective effect of hypomorphic PDE4B. Our data demonstrate that spatial memory and cerebral glucose metabolism deficits exhibited by 12-month-old App NL-G-F mice are prevented by targeted inhibition of PDE4B. To our knowledge, this is the first demonstration of a protective effect of PDE4B subtype-specific inhibition in a preclinical model of AD. It thus identifies PDE4B as a key regulator of disease manifestation in the App NL-G-F model and a promising therapeutic target for AD., (© 2024. The Author(s).)

While the impact of spirituality as it relates to quality of life post-liver transplant (LT) has been studied, there are limited data showing how religious affiliation impacts objective measures such as survival. The aim of the study is to investigate whether LT recipients who identified as having a religious affiliation had better clinical outcomes when compared to LT recipients who did not. Religious affiliation is obtained as part of general demographic information for patients within our institution (options of "choose not to disclose" and "no religious affiliation" are available). Subjects in this retrospective cohort study which conformed with the Declarations of Helsinki and Istanbul were separated into cohorts: LT recipients who self-reported religious affiliation and LT recipients who did not. All LT recipients between March 2007 and September 2018 who had available information regarding their reported religion were included. Excluded patients included those who received a multi-organ transplant, underwent re-transplantation, received a partial liver graft, and identified as agnostic. Outcomes included 30-day readmission, death, and the composite outcome of re-transplantation/death. In an unadjusted analysis of 378 patients, there were no statistically significant differences between the two groups for 30-day readmission (OR=1.15, P=0.71), death (HR=0.63, P=0.19), or re-transplantation/death (HR=0.90, P=0.75). In multivariable analysis, adjusting for age at transplant and hospital admittance status when called for transplant, results were similar. We found no statistically significant difference in the outcomes measured between patients with and without self-reported religious affiliation. Further studies into the role of participation in religious activity and the impact of engagement with a religious community should be conducted in the future., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Review Board of Mayo Clinic issued approval 22-006393. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Prier et al.)

Purpose: We investigated the effectiveness of a highly individualized morphosyntactic intervention using the SHAPE CODING™ system delivered at different dosages., Method: Eight children with developmental language disorder aged 8;0-10;10 (years;months) received 10 hr of explicit individualized intervention for morphosyntax delivered in 30-min individual sessions once per week for 20 weeks. Following at least four baseline probe tests, two grammatical targets per session received explicit instruction until they reached criterion (90%), when the next target was introduced. To control for session length and teaching episode density, either both targets received 20 teaching episodes per session or one target received 10 teaching episodes and the other 30. Maintenance testing of completed targets was also carried out., Results: Scores on probe tests post-intervention were significantly higher than during the baseline phase ( d = 1.6) with no change during the baseline or maintenance phases. However, progress during the intervention phase was highly significant. One participant showed significantly faster progress with intervention, while one (with the lowest attention score) made little progress. When considering progress relative to cumulative intervention sessions, progress was faster with 30 teaching episodes per session and slower with 10. However, when cumulative teaching episodes were used as the predictor, all three within-session dosages showed very similar rates of progress, with the odds of a correct response increasing by 3.9% for each teaching episode. The targets that were achieved required an average of 40-60 teaching episodes., Conclusions: With the exception of one participant, the individualized intervention was highly effective and efficient. Thus, the individualized target identification process and intervention method merit further research in a larger group of children. The cumulative number of teaching episodes per target provided across sessions appeared to be key. Thus, clinicians should aim for high teaching episode rates, particularly if the number of sessions is constrained. Otherwise, intervention scheduling can be flexible., Supplemental Material: https://doi.org/10.23641/asha.25996168.

Wet granulation, a particle size enlargement process, can significantly enhance the critical quality attributes of powders and improve the ability to form tablets in pharmaceutical manufacturing. In this study, a mechanistic-based population balance model is applied to twin screw wet granulation. This model incorporated a recently developed breakage kernel specifically designed for twin screw granulation, along with nucleation, layering, and consolidation. Calibration and validation were performed on Hydrochlorothiazide and Acetaminophen formulations, which exhibit different particle size and wettability characteristics. Utilizing a compartmental experimental dataset, a comprehensive global sensitivity analysis identified critical inputs impacting quality attributes. The study revealed that the nucleation rate process model, effectively represented particle size distributions for both formulations. Adjustments to nucleation and breakage rate parameters, influenced by material properties and screw configuration, improved the model's accuracy. A model-driven workflow was proposed, offering step-by-step guidelines and facilitating PBM model usage, providing essential details for future active pharmaceutical ingredient (API) formulations., 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 © 2024. Published by Elsevier B.V.)

Given the pathological role of Tau aggregation in Alzheimer's disease (AD), our laboratory previously developed the novel Tau aggregation inhibitor peptide, RI-AG03. As Tau aggregates accumulate intracellularly, it is essential that the peptide can traverse the cell membrane. Here we examine the cellular uptake and intracellular trafficking of RI-AG03, in both a free and liposome-conjugated form. We also characterize the impact of adding the cell-penetrating peptide (CPP) sequences, polyarginine (polyR) or transactivator of transcription (TAT), to RI-AG03. Our data show that liposome conjugation of CPP containing RI-AG03 peptides, with either the polyR or TAT sequence, increased cellular liposome association three-fold. Inhibition of macropinocytosis modestly reduced the uptake of unconjugated and RI-AG03-polyR-linked liposomes, while having no effect on RI-AG03-TAT-conjugated liposome uptake. Further supporting macropinocytosis-mediated internalization, a 'fair' co-localisation of the free and liposome-conjugated RI-AG03-polyR peptide with macropinosomes and lysosomes was observed. Interestingly, we also demonstrate that RI-AG03-polyR detaches from liposomes following cellular uptake, thereby largely evading organellar entrapment. Collectively, our data indicate that direct membrane penetration and macropinocytosis are key routes for the internalization of liposomes conjugated with CPP containing RI-AG03. Our study also demonstrates that peptide-liposomes are suitable nanocarriers for the cellular delivery of RI-AG03, furthering their potential use in targeting Tau pathology in AD., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Eating disorders (EDs) are serious, often chronic, conditions associated with pronounced morbidity, mortality, and dysfunction increasingly affecting young people worldwide. Illness progression, stages and recovery trajectories of EDs are still poorly characterised. The STORY study dynamically and longitudinally assesses young people with different EDs (restricting; bingeing/bulimic presentations) and illness durations (earlier; later stages) compared to healthy controls. Remote measurement technology (RMT) with active and passive sensing is used to advance understanding of the heterogeneity of earlier and more progressed clinical presentations and predictors of recovery or relapse., Methods: STORY follows 720 young people aged 16-25 with EDs and 120 healthy controls for 12 months. Online self-report questionnaires regularly assess ED symptoms, psychiatric comorbidities, quality of life, and socioeconomic environment. Additional ongoing monitoring using multi-parametric RMT via smartphones and wearable smart rings ('Ōura ring') unobtrusively measures individuals' daily behaviour and physiology (e.g., Bluetooth connections, sleep, autonomic arousal). A subgroup of participants completes additional in-person cognitive and neuroimaging assessments at study-baseline and after 12 months., Discussion: By leveraging these large-scale longitudinal data from participants across ED diagnoses and illness durations, the STORY study seeks to elucidate potential biopsychosocial predictors of outcome, their interplay with developmental and socioemotional changes, and barriers and facilitators of recovery. STORY holds the promise of providing actionable findings that can be translated into clinical practice by informing the development of both early intervention and personalised treatment that is tailored to illness stage and individual circumstances, ultimately disrupting the long-term burden of EDs on individuals and their families., (© 2024. The Author(s).)

Emotion is closely associated with language, but we know very little about how children express emotion in their own writing. We used a large-scale, cross-sectional, and data-driven approach to investigate emotional expression via writing in children of different ages, and whether it varies for boys and girls. We first used a lexicon-based bag-of-words approach to identify emotional content in a large corpus of stories (N>100,000) written by 7- to 13-year-old children. Generalized Additive Models were then used to model changes in sentiment across age and gender. Two other machine learning approaches (BERT and TextBlob) validated and extended these analyses, converging on the finding that positive sentiments in children's writing decrease with age. These findings echo reports from previous studies showing a decrease in mood and an increased use of negative emotion words with age. We also found that stories by girls contained more positive sentiments than stories by boys. Our study shows the utility of large-scale data-driven approaches to reveal the content and nature of children's writing. Future experimental work should build on these observations to understand the likely complex relationships between written language and emotion, and how these change over development., (© 2024 The Authors. Cognitive Science published by Wiley Periodicals LLC on behalf of Cognitive Science Society (CSS).)

Introduction: Successful mentorship programs in academic medicine correlate with increased achievement in scholarly activities, leadership, and academic advancement for faculty members, as well as reduced burnout. Despite these benefits, the traditional mentorship model may be underutilized due to challenges of time constraints and alignment in goals. Furthermore, women and underrepresented in medicine (UriM) physicians are less likely to have mentorship, perpetuating the gap in the diversity of academic faculty in leadership and career advancement. To address this, we created an innovative mentorship model for busy academic faculty physicians using a virtual academic asynchronous mentoring video platform.  Methods: A series of videos were created by interviewing 10 identified mentors (four male, six female) from various medical specialties at a national academic institution. The mentors included nine physician faculty with the academic rank of Associate Professor or full Professor and one Research Administrator. Key learning points shared by mentors included topics on academic advancement, mentorship development, leadership development, and research resources., Results: Between March 2020 and September 2023, the Virtual Academic Asynchronous Mentoring (VAAM) Video Series garnered 182 unique viewers, received 2,107 visits, and accumulated 1,871 total minutes of viewing time. All viewers were surveyed, with an 11% survey response rate received. Fifty-two percent of survey respondents reported that the video content was excellent and 43% reported very good. Seventy-six percent of respondents thought the video series had the potential to enhance their professional development and academic productivity., Conclusion: The VAAM Video Platform offers a novel approach to academic mentoring for faculty physicians which eliminates limitations of traditional mentorship models in a convenient and cost-effective way. VAAM offers an egalitarian starting point for all junior faculty who have not yet established a mentoring relationship to seek information and resources on academic advancement and career development., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Yin et al.)

Background: Germline genetic testing is recommended for men with metastatic or high-risk prostate cancer to inform treatment and risk management for other cancers and inform genetic testing in at-risk relatives. However, relatively few patients with prostate cancer undergo genetic testing. Given the low rate of testing and increasing demands on genetic service providers, strategies are needed that reduce barriers to testing while conserving genetic counseling resources. The primary goal of this study was to determine whether a proactive and streamlined "traceback" approach could yield increased genetic testing participation among prostate cancer survivors., Methods: We randomized 107 survivors of metastatic and high-risk prostate cancer to streamlined testing (ST) versus enhanced usual care (EUC). ST participants were proactively provided with print genetic education materials and the option to proceed to genetic testing without pre-test genetic counseling. EUC participants were sent a letter from their physician advising them of their eligibility for genetic testing and recommending they schedule genetic counseling. The primary outcome was genetic testing participation. Secondary outcomes were distress, knowledge, decision satisfaction, and regret., Results: In the ST group, 41.5% of participants completed genetic testing compared with 27.8% in the EUC group. After adjusting for education and marital status, the odds of testing were more than twice as high for the ST group as for the EUC group (odds ratio, 2.57; 95% CI, 1.05-6.29). The groups did not differ on any of the psychosocial outcomes at the 3-month follow-up., Conclusions: Proactive outreach paired with streamlined genetic testing delivery may be a safe, effective, and resource-efficient approach to facilitate traceback genetic testing in prostate cancer survivors.

Purpose: Intensity-modulated radiation therapy (IMRT) with brachytherapy boost for unfavorable prostate cancer has been shown to improve biochemical relapse-free survival compared to IMRT alone. Stereotactic body radiation therapy (SBRT) is a less-invasive alternative to brachytherapy. Early outcomes utilizing SBRT boost suggest low rates of high-grade toxicity with a maintained patient-reported quality of life. Here, we report the 5-year progression-free survival (PFS) and prostate cancer-specific survival (PCSS) of patients treated with IMRT plus SBRT boost., Materials and Methods: Between 2008 and 2020, 255 patients with unfavorable prostate cancer were treated with robotic SBRT (19.5 Gy in three fractions) followed by fiducial-guided IMRT (45-50.4 Gy) according to an institutional protocol. For the first year, the patient's PSA level was monitored every 3 months, biannually for 2 years, and annually thereafter. Failure was defined as nadir + 2 ng/mL or a rising PSA with imaging suggestive of recurrence. Detection of recurrence also included digital rectal examination and imaging studies, such as MRI, CT, PET/CT, and/or bone scans. PFS and PCSS were calculated using the Kaplan-Meier method., Results: The median follow-up period was 71 months. According to the NCCN risk classification, 5% (13/255) of the patients had favorable intermediate-risk disease, 23% (57/255) had unfavorable intermediate-risk disease, 40% (102/255) had high-risk disease, and 32% (83/255) had very high-risk disease. Androgen deprivation therapy was administered to 80% (204/255) of the patients. Elective pelvic lymph node IMRT was performed in 28 (10%) patients. The PFS for all patients at 5 years was 81% (favorable intermediate risk, 91%; unfavorable intermediate risk, 89%; high-risk, 78%; and very-high risk, 72%). The PCSS for all patients at 5 years was 97% (favorable intermediate risk, 100%; unfavorable intermediate risk, 100%; high risk, 100%; and very high risk, 89%)., Conclusion: The incidence of failure following IMRT plus SBRT for unfavorable prostate cancer remains low at 5 years., Competing Interests: We would like to disclose that SC, the principal investigator for this study is a clinical consultant for Accuray. The remaining authors 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., (Copyright © 2023 Carrasquilla, Sholklapper, Pepin, Hodgins, Lei, Rashid, Danner, Zwart, Bolanos, Ayoob, Yung, Aghdam, Collins, Suy, Kumar, Hankins, Kowalczyk, Dawson and Collins.)

This work presents a granule size prediction approach applicable to diverse formulations containing new active pharmaceutical ingredients (APIs) in continuous twin-screw wet granulation. The approach consists of a surrogate selection method to identify similar materials with new APIs and a T-shaped partial least squares (T-PLS) model for granule size prediction across varying formulations and process conditions. We devised a surrogate material selection method, employing a combination of linear pre-processing and nonlinear classification algorithms, which effectively identified suitable surrogates for new materials. Using only material properties obtained through four characterization methods, our approach demonstrated its predictive prowess. The selected surrogate methods were seamlessly integrated with our developed T-PLS model, which was meticulously validated for high-dose formulations involving three new APIs. When surrogating new APIs based on Gaussian process classification, we achieved the lowest prediction errors, signifying the method's robustness. The predicted d-values were within the range of uncertainty bounds for all cases, except for d90 of API C. Notably, the approach offers a direct and efficient solution for early-phase formulation and process development, considerably reducing the need for extensive experimental work. By relying on just four material characterization methods, it streamlines the research process while maintaining a high degree of accuracy., 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 © 2023 Elsevier B.V. All rights reserved.)

Introduction: This study evaluated patient preference of physician attire both before and after the coronavirus disease 2019 (COVID-19) global pandemic began. The primary outcome was patient preference of physician attire in 2017 compared to 2022 survey cohorts. Methods: An observational cross-sectional study performed at a single-site academic institution in the United States using patient survey materials. In total, 339 patients were included in the study, 161 from 2017 and 178 from 2022. Key Points: There was a statistically significant decrease in patient preference for formal attire in the clinical settings of primary care, hospital, and overall. Male patient preference for formal attire declined in primary care, emergency room, and overall; whereas female patient preference for formal attire declined in the hospital setting. For all genders, the odds ratio was statistically significantly lower in the settings of primary care clinic, hospital, and overall clinical settings. Conclusions: Patient preference for physicians wearing formal attire has decreased significantly since the COVID-19 global pandemic began., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

We argue that solutions-based research must avoid treating climate change as a merely technical problem, recognizing instead that it is symptomatic of the history of European and North American colonialism. It must therefore be addressed by decolonizing the research process and transforming relations between scientific expertise and the knowledge systems of Indigenous Peoples and of local communities. Partnership across diverse knowledge systems can be a path to transformative change only if those systems are respected in their entirety, as indivisible cultural wholes of knowledge, practices, values, and worldviews. This argument grounds our specific recommendations for governance at the local, national, and international scales. As concrete mechanisms to guide collaboration across knowledge systems, we propose a set of instruments based on the principles of consent, intellectual and cultural autonomy, and justice. We recommend these instruments as tools to ensure that collaborations across knowledge systems embody just partnerships in support of a decolonial transformation of relations between human communities and between humanity and the more-than-human world., (© 2023. The Author(s).)

Objective: The purpose of this scoping review is to identify the main theoretical frameworks being used to explain dual-task performance deficits in people with post-stroke aphasia, to identify the domains of function being measured and the assessments being used, to highlight current interventions to improve dual-task performance, and to identify the gaps in the current body of literature on dual tasking and aphasia., Introduction: Post-stroke aphasia can lead to challenges across all activities of daily living. However, little is known about how a stroke and co-occurring language impairment may affect the allocation of cognitive resources, particularly in dual-task conditions. This vital information will allow researchers and clinicians to develop more effective interventions to combat the effects of the infarct., Inclusion Criteria: To be considered in the review, articles must be written in English, include individuals at least 6 months post stroke, include adults with aphasia (with data presented separately from other populations), and include measures of dual-task performance., Methods: This review will be conducted in line with the JBI methodology for scoping reviews. A search of Linguistics and Language Behavior Abstracts, PsycINFO, Communication Mass Media Complete, PubMed, CINAHL Plus, ScienceDirect, and the Cochrane Library will be undertaken to identify publications on the topic. Results will be restricted to sources that meet the inclusion/exclusion criteria. Data will be extracted from included papers by up to 3 independent reviewers using a data extraction tool developed by the reviewers. The results will be presented as a narrative summary, accompanied by charted results, as appropriate., Review Registration: Open Science Framework https://osf.io/2yx76., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 JBI.)

Nonnutritive sweeteners (NNSs) and low-calorie sweeteners (LCSs) are commonly used as sugar substitutes. Many popular media Web sites caution against the use of these sweeteners because of their potential adverse effects such as inflammation; however, there are limited supporting data. A Medline search of articles published between 2010 and 2020 was conducted, resulting in 833 articles, of which 12 relevant studies were included in this review. Acute adverse effects associated with the consumption of NNSs and LCSs are rare. A few studies cite reports of acute adverse effects, including mild gastrointestinal disturbance, headaches, lightheadedness, hypersensitivity reactions, impaired spatial orientation, depression, and pain. Little scientific evidence has been reported in the literature since 2010 to support these warning statements to consumers about acute adverse effects to NNSs and LCSs.

Autism spectrum disorders are more common in males, and have a substantial genetic component. Chromosomal 16p11.2 deletions in particular carry strong genetic risk for autism, yet their neurobiological impact is poorly characterised, particularly at the integrated systems level. Here we show that mice reproducing this deletion (16p11.2 DEL mice) have reduced GABAergic interneuron gene expression (decreased parvalbumin mRNA in orbitofrontal cortex, and male-specific decreases in Gad67 mRNA in parietal and insular cortex and medial septum). Metabolic activity was increased in medial septum, and in its efferent targets: mammillary body and (males only) subiculum. Functional connectivity was altered between orbitofrontal, insular and auditory cortex, and between septum and hippocampus/subiculum. Consistent with this circuit dysfunction, 16p11.2 DEL mice showed reduced prepulse inhibition, but enhanced performance in the continuous performance test of attentional ability. Level 1 autistic individuals show similarly heightened performance in the equivalent human test, also associated with parietal, insular-orbitofrontal and septo-subicular dysfunction. The data implicate cortical and septal GABAergic dysfunction, and resulting connectivity changes, as the cause of pre-attentional and attentional changes in autism., (© 2023. The Author(s).)

Nonprofit organizations, providing psychotherapy services in community-based settings, are often faced with the tensions inherent in both ensuring quality services while limiting program costs. The same is true in private and public health care settings, where services regularly navigate cost reductions and budget cuts. At the Ububele Educational and Psychotherapy Trust, an nonprofit organization in South Africa, reflective supervision is seen as a critical component for effective, ethically sound, and culturally sensitive intervention despite competition for financial resources. This article will provide an overview of the organization's reflective supervision model, motivating for the need to prioritize reflective supervision for frontline staff. It also provides a case example, to demonstrate the value of reflective supervision for promoting practitioner reflexivity and preventing practitioner burnout in a highly traumatized environment. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Human mucosal-associated invariant T (MAIT) cells are characterized by their expression of an invariant TCR α chain Vα7.2-Jα33/Jα20/Jα12 paired with a restricted TCR β chain. MAIT cells recognize microbial peptides presented by the highly conserved MHC class I-like molecule MR1 and bridge the innate and acquired immune systems to mediate augmented immune responses. Upon activation, MAIT cells rapidly proliferate, produce a variety of cytokines and cytotoxic molecules, and trigger efficient antitumor immunity. Administration of a representative MAIT cell ligand 5-OP-RU effectively activates MAIT cells and enhances their antitumor capacity. In this review, we introduce MAIT cell biology and their importance in antitumor immunity, summarize the current development of peripheral blood mononuclear cell-derived and stem cell-derived MAIT cell products for cancer treatment, and discuss the potential of genetic engineering of MAIT cells for off-the-shelf cancer immunotherapy., Competing Interests: Declaration of interests Y.-R.L. and L.Y. are inventors on patents relating to this article filed by UCLA. L.Y. is a scientific adviser to AlzChem and Amberstone Biosciences, and a co-founder, stockholder, and advisory board member of Appia Bio. None of the declared companies contributed to or directed any of the research reported in this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Our aim was to identify self-reported stressors and coping mechanisms during the 2020-2021 application cycle by dermatology residency applicants. We hypothesized that coronavirus disease 2019 (COVID-19) would be the most reported stressor., Methods: During the 2020-2021 application season, the Mayo Clinic Florida Dermatology residency program sent a supplemental application to each applicant requesting that they describe a challenging life situation and how they handled it. Comparisons of self-reported stressors and self-expressed coping mechanisms according to sex, race, and geographic region were performed., Results: The most common stressors reported were academic (18.4%), family crisis (17.7%), and COVID-19 (10.5%). The most frequent coping mechanisms expressed were perseverance (22.3%), seeking community (13.7%), and resilience (11.5%). The coping mechanism of diligence was observed more often in females than in males (2.8% vs 0.0%, P = 0.045). First in medicine was more often observed in Black or African American students (12.5% vs 0%, P = 0.001), immigrant experience was more often observed in Black or African American and Hispanic students (16.7% and 11.8% vs 3.1%, P = 0.021), and natural disaster was reported more often in Hispanic students (26.5% vs 0.5%, P < 0.001) as compared with White applicants. By geography, applicants in the northeastern United States were more likely to report the COVID-19 pandemic as a stressor (19.5%, P = 0.049), and the natural disaster stressor was more often reported by applicants from outside the continental United States (45.5%, P < 0.001)., Conclusions: Stressors reported by dermatology applicants in the 2020-2021 cycle included academic, family crisis, and the COVID-19 pandemic. The type of stressor reported varied by race/ethnicity and geographic location of the applicant.

Attempts to link human development and biodiversity conservation goals remain a constant feature of policy and practice related to protected areas (PAs). Underlying these approaches are narratives that simplify assumptions, shaping how interventions are designed and implemented. We examine evidence for five key narratives: 1) conservation is pro-poor; 2) poverty reduction benefits conservation; 3) compensation neutralises costs of conservation; 4) local participation is good for conservation; 5) secure tenure rights for local communities support effective conservation. Through a mixed-method synthesis combining a review of 100 peer-reviewed papers and 25 expert interviews, we examined if and how each narrative is supported or countered by the evidence. The first three narratives are particularly problematic. PAs can reduce material poverty, but exclusion brings substantial local costs to wellbeing, often felt by the poorest. Poverty reduction will not inevitably deliver on conservation goals and trade-offs are common. Compensation (for damage due to human wildlife conflict, or for opportunity costs), is rarely sufficient or commensurate with costs to wellbeing and experienced injustices. There is more support for narratives 4 and 5 on participation and secure tenure rights, highlighting the importance of redistributing power towards Indigenous Peoples and Local Communities in successful conservation. In light of the proposed expansion of PAs under the post-2020 Global Biodiversity Framework, we outline implications of our review for the enhancement and implementation of global targets in order to proactively integrate social equity into conservation and the accountability of conservation actors., Competing Interests: Research ethics statementEthical approval was granted by the Departmental Research Ethics Committee of University College London’s Anthropology Department.Consent for publication statementThe authors declare that research participants’ informed consent to publication of findings – including photos, videos and any personal or identifiable information – was secured prior to publication.Conflicts of interest statementThe co-author Elisa Morgera is an Editorial Board Member of this journal the article is published in, UCL Open: Environment, and the article went through the journals standard open peer review processes – all open peer review reports can be read freely online by following the DOI link of this article https://doi.org/10.14324/111.444/ucloe.000050. All other authors declare no conflicts of interest.The co-author Elisa Morgera is an Editorial Board Member of this journal the article is published in, UCL Open: Environment, and the article went through the journals standard open peer review processes – all open peer review reports can be read freely online by following the DOI link of this article https://doi.org/10.14324/111.444/ucloe.000050. All other authors declare no conflicts of interest., (© 2022 The Authors.)

Background and Purpose: Physical therapists (PTs) require specialized education and training to increase the capacity and competence of the dementia care workforce. Four areas of critical dementia workforce education and training gaps that apply to the physical therapy profession have been identified, including recruitment/retention, financing and cost of training, interprofessional education, and translation/implementation of effective dementia care. A critical step in developing effective training programs and educational curricula is to understand PTs' and PT students' experiences and views on working with people with dementia (PwD). Therefore, the purpose of this scoping review was to examine the extent and types of evidence that explore the experiences and views of PTs and PT students on the provision of physical therapy services to PwD., Methods: The Cochrane Database of Systematic Reviews, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsychINFO, ERIC, PEDro, Web of Science, and Medline databases and sources of gray literature were searched for sources of evidence that met the inclusion criteria of the review protocol. The literature was mapped according to author, participant role, setting, publication type, study design, study aim, key findings, and dementia workforce training gaps addressed., Results and Discussion: A total of 552 sources of evidence were screened for eligibility, and 16 studies were selected for inclusion. Twelve studies included PTs as participants, and 5 included PT students. Included sources explored PTs' experiences, behaviors, knowledge, attitudes, and confidence in working with PwD and the influence of educational, organizational, and other factors on these domains. Challenges to and strategies for delivering effective care to PwD were examined in multiple sources. The 4 areas of critical dementia workforce education and training gaps were each addressed by at least 1 of the included studies., Conclusions: The current body of literature identifies several gaps in both research and education that need to be addressed before our profession is truly prepared to effectively manage this challenging population of patients with specialized needs., Competing Interests: There are no conflicts of interest or funding sources to disclose by any authors. The authors declare no conflicts of interest., (Copyright © 2022 APTA Geriatrics, An Academy of the American Physical Therapy Association.)

The solvent-mediated crystal morphologies of the α and β polymorphic forms of l-glutamic acid are presented. This work applies a digital mechanistically based workflow that encompasses calculation of the crystal lattice energy and its constituent intermolecular synthons, their interaction energies, and their key role in understanding and predicting crystal morphology as well as assessing the surface chemistry, topology, and solvent binding on crystal habit growth surfaces. Through a comparison between the contrasting morphologies of the conformational polymorphs of l-glutamic acid, this approach highlights how the interfacial chemistry of organic crystalline materials and their inherent anisotropic interactions with their solvation environments direct their crystal habit with potential impact on their further downstream processing behavior., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

2p16.3 deletion, involving NEUREXIN1 (NRXN1) heterozygous deletion, substantially increases the risk of developing autism and other neurodevelopmental disorders. We have a poor understanding of how NRXN1 heterozygosity impacts on brain function and cognition to increase the risk of developing the disorder. Here we characterize the impact of Nrxn1α heterozygosity on cerebral metabolism, in mice, using 14 C-2-deoxyglucose imaging. We also assess performance in an olfactory-based discrimination and reversal learning (OB-DaRL) task and locomotor activity. We use decision tree classifiers to test the predictive relationship between cerebral metabolism and Nrxn1α genotype. Our data show that Nrxn1α heterozygosity induces prefrontal cortex (medial prelimbic cortex, mPrL) hypometabolism and a contrasting dorsal raphé nucleus (DRN) hypermetabolism. Metabolism in these regions allows for the predictive classification of Nrxn1α genotype. Consistent with reduced mPrL glucose utilization, prefrontal cortex insulin receptor signaling is decreased in Nrxn1α +/- mice. Behaviorally, Nrxn1α +/- mice show enhanced learning of a novel discrimination, impaired reversal learning and an increased latency to make correct choices. In addition, male Nrxn1α +/- mice show hyperlocomotor activity. Correlative analysis suggests that mPrL hypometabolism contributes to the enhanced novel odor discrimination seen in Nrxn1α +/- mice, while DRN hypermetabolism contributes to their increased latency in making correct choices. The data show that Nrxn1α heterozygosity impacts on prefrontal cortex and serotonin system function, which contribute to the cognitive alterations seen in these animals. The data suggest that Nrxn1α +/- mice provide a translational model for the cognitive and behavioral alterations seen in autism and other neurodevelopmental disorders associated with 2p16.3 deletion. LAY SUMMARY: Deletion of the chromosomal region 2p16.3, involving reduced NEUREXIN1 gene expression, dramatically increases the risk of developing autism. Here, we show that reduced Neurexin1α expression, in mice, impacts on the prefrontal cortex and impairs cognitive flexibility. The data suggest that 2p16.3 deletion increases the risk of developing autism by impacting on the prefrontal cortex. Mice with the deletion are a useful model for testing new drugs to treat the cognitive flexibility problems experienced by people with autism., (© 2022 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

Glaucoma is a common eye disorder and an irreversible cause of blindness worldwide. There are several treatment options for this condition, with the traditional first-line treatment being ophthalmologic drops. Although administered topically, it is associated with inadvertent systemic absorption leading to a potential for both local and systemic side effects. We discuss the case of a 71-year-old male who presented with a complaint of recurring episodes of distressing sensations including lightheadedness, dyspnea, chest pressure, and faintness. His past medical history included congestive heart failure, hypertension, hyperlipidemia, Barrett's esophagus, and glaucoma. Upon a thorough review of the patient's medications, it was discovered that he had recently been started on timolol ophthalmic drops. The patient then noted that his symptoms had begun after he started using the eye drops. After we recommended that the patient hold the use of the eye drops, these episodes stopped. When prescribing topical ophthalmologic drops, providers must educate patients on common systemic side effects of such drugs., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Haga et al.)

Background: The Alzheimer's disease (AD)-associated amyloid-beta protein precursor (AβPP) can be cleaved by β-site AβPP cleaving enzyme 1 (BACE1) and the γ-secretase complex to yield neurotoxic amyloid-β (Aβ) peptides. However, AβPP can also be cleaved in a 'non-amyloidogenic' manner either by α-secretase to produce soluble AβPP alpha (sAβPPα) (a fragment with neuroprotective/neurogenic functions) or through alternative BACE1-mediated 'beta prime' activity yielding soluble AβPP beta prime (sAβPPβ')., Objective: To determine whether sAβPPα depletion, as opposed to Aβ peptide accumulation, contributes to cytotoxicity in AD-relevant SH-SY5Y neuroblastoma cell models., Methods: AβPP proteolysis was characterized by immunoblotting in mock-, wild-type AβPP (wtAβPP)-, BACE1-, and Swedish mutant AβPP (SweAβPP)-transfected cells. AβPP beta prime cleavage was confirmed through secretase inhibitor studies and C-terminal fragment analysis. The roles of sAβPPα and sAβPPβ' in cell viability were confirmed by overexpression studies., Results: Despite producing enhanced Aβ peptide levels, wtAβPP- and SweAβPP-transfected cells did not exhibit reduced viability whereas BACE1-transfected cells did. sAβPPα generation in SH-SY5Y-BACE1 cells was virtually ablated in lieu of BACE1-mediated sAβPPβ' production. sAβPPα overexpression in SH-SY5Y-BACE1 cells restored viability whereas sAβPPβ' overexpression decreased viability further. The anti-AβPP 6E10 antibody was shown to cross-react with sAβPPβ'., Conclusion: sAβPPα depletion and/or sAβPPβ' accumulation, but not elevated Aβ peptide levels, represent the cytotoxic mechanism following BACE1 overexpression in SH-SY5Y cells. These data support the novel concept that competitive sAβPPα depletion by BACE1 beta prime activity might contribute to AD. The cross-reactivity of 6E10 with AβPPβ'also questions whether previous studies assessing sAβPPα as a biomarker using this antibody should be revisited.

Background and Purpose: Falls are a leading cause of morbidity, mortality, loss of independence, and significant functional decline in aging populations. Effective interventions aimed at reducing the risk of falls, and preventing associated disability and functional decline, are needed to promote the health and wellness of older adults. Recent literature has found that an Otago-based exercise program (OBEP), which incorporates strengthening, balance, and walking, may not only decrease falls and fall risk among community-dwelling older adults but may also be effective among older adults residing in assisted living facilities (ALFs). The purpose of this study is to expand upon current research by comparing the outcomes of an OBEP and traditional physical therapy (TPT) in decreasing falls and the risk of falls among older adults living in an ALF. The authors hypothesized that traditional physical therapy would reduce fall risk and the number of falls in older adults residing in ALFs more than an OBEP., Methods: This study conducted a 2-group retrospective chart review of 59 older adults living in an ALF from January 2013 to October 2018 who received either TPT (n = 29) or the OBEP (n = 30). Participants were a mean of 87 years old and were classified at risk for falls by the Tinetti Performance-Oriented Mobility Assessment (POMA). Primary variables included the number of falls prior to intervention, during intervention, and 1 year following intervention, as well as pre- and posttreatment Tinetti POMA scores. Efficacy was examined using multiple linear regression analysis., Results and Discussion: Both groups achieved reduced falls and increased POMA scores. Group assignment did not significantly predict performance in key outcome measures, namely the number of falls (P = .199) and Tinetti POMA scores (P = .063) following treatment., Conclusions: These findings indicated that both an OBEP and tpt may be effective interventions for reducing falls and fall risk in the ALF setting., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 APTA Geriatrics, An Academy of the American Physical Therapy Association.)

Job security can never be taken for granted, especially in times of rapid, widespread and unexpected social and economic change. These changes can force workers to transition to new jobs. This may be because new technologies emerge or production is moved abroad. Perhaps it is a global crisis, such as COVID-19, which shutters industries and displaces labor en masse. Regardless of the impetus, people are faced with the challenge of moving between jobs to find new work. Successful transitions typically occur when workers leverage their existing skills in the new occupation. Here, we propose a novel method to measure the similarity between occupations using their underlying skills. We then build a recommender system for identifying optimal transition pathways between occupations using job advertisements (ads) data and a longitudinal household survey. Our results show that not only can we accurately predict occupational transitions (Accuracy = 76%), but we account for the asymmetric difficulties of moving between jobs (it is easier to move in one direction than the other). We also build an early warning indicator for new technology adoption (showcasing Artificial Intelligence), a major driver of rising job transitions. By using real-time data, our systems can respond to labor demand shifts as they occur (such as those caused by COVID-19). They can be leveraged by policy-makers, educators, and job seekers who are forced to confront the often distressing challenges of finding new jobs., Competing Interests: For six months during the course of the study ND was a paid employee of the commercial firm Faethm AI. ND is no longer an employee of this company. There are no patents, products in development or marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Cognitive deficits profoundly impact on the quality of life of patients with schizophrenia. Alterations in brain derived neurotrophic factor (BDNF) signalling, which regulates synaptic function through the activation of full-length tropomyosin-related kinase B receptors (TrkB-FL), are implicated in the aetiology of schizophrenia, as is N-methyl-D-aspartate receptor (NMDA-R) hypofunction. However, whether NMDA-R hypofunction contributes to the disrupted BDNF signalling seen in patients remains unknown., Aims: The purpose of this study was to characterise BDNF signalling and function in a preclinical rodent model relevant to schizophrenia induced by prolonged NMDA-R hypofunction., Methods: Using the subchronic phencyclidine (PCP) model, we performed electrophysiology approaches, molecular characterisation and behavioural analysis., Results: The data showed that prolonged NMDA-R antagonism, induced by subchronic PCP treatment, impairs long-term potentiation (LTP) and the facilitatory effect of BDNF upon LTP in the medial prefrontal cortex (PFC) of adult mice. Additionally, TrkB-FL receptor expression is decreased in the PFC of these animals. By contrast, these changes were not present in the hippocampus of PCP-treated mice. Moreover, BDNF levels were not altered in the hippocampus or PFC of PCP-treated mice. Interestingly, these observations are paralleled by impaired performance in PFC-dependent cognitive tests in mice treated with PCP., Conclusions: Overall, these data suggest that NMDA-R hypofunction induces dysfunctional BDNF signalling in the PFC, but not in the hippocampus, which may contribute to the PFC-dependent cognitive deficits seen in the subchronic PCP model. Additionally, these data suggest that targeting BDNF signalling may be a mechanism to improve PFC-dependent cognitive dysfunction in schizophrenia.

Skilled reading is characterized by rapid recognition of morphologically complex words. Evidence suggests that adult readers segment complex words into their constituent morphemes during visual word recognition, and that this extends to items that have only a surface morphological structure (e.g., corner), a process termed 'morpho-orthographic segmentation'. It is not yet known how and when this mechanism is established over the course of reading development, although data from English-speaking children suggest that it may be a relatively late-acquired milestone. The purpose of this study was to examine for the first time the mechanisms driving morphological processing across late childhood and adolescence. A cross-sectional sample of 204 children and adolescents from South-East England, ranging in age from 9 to 18 years (M age = 13.74 years, SD = 2.68; 110 female), completed a visual masked prime lexical decision task using three sets of prime-target pairs: morphological (e.g., teacher - TEACH), pseudomorphological (sharing an apparent morphological relationship in the absence of a semantic relationship, e.g., corner - CORN), and form (sharing an orthographic relationship only, e.g., window - WIND). Linear mixed effects models revealed both morphological and pseudomorphological priming in the absence of form priming, with priming magnitude increasing in line with age, and stronger evidence of morpho-orthographic segmentation emerging in line with word reading efficiency. Our findings reveal advances in the reading system during adolescence which may reflect accumulated exposure to regularities in the writing system, facilitating rapid access to meaning from print., (Copyright © 2021. Published by Elsevier B.V.)

Background: Omission of axillary lymph node dissection (ALND) is accepted for patients with one or two positive sentinel nodes, and studies are focusing on clinically node-positive patients who have been downstaged with neoadjuvant chemotherapy (NAC). Evidence is lacking for patients with positive nodes who undergo surgery upfront. These patients are assumed to have a higher burden of nodal disease such that ALND remains the standard of care., Methods: Patients who underwent ALND for breast cancer between 2010 and 2019 at the authors' institution were retrospectively identified. Those with clinical N1 disease were included in the study. Patients who received NAC and those who had surgery for sentinel node positive disease or axillary recurrence were excluded. Clinical and pathologic factors associated with nodal stage were evaluated., Results: Of 111 patients who met the inclusion criteria, 61.3% had a palpable node on exam, and 41.4% ultimately had pN1 disease. Most of the tumors were estrogen receptor (ER)-positive (91.5%), and 21.7% of the tumors were invasive lobular cancers. Lobular histology, tumor size, and metastasis size were associated with higher nodal stage. In the multivariable analysis, the patients with nodal metastasis larger than 10 mm had significantly lower odds of having pN1 disease (odds ratio 0.12; 95% confidence interval 0.02-0.69; p = 0.02). In a subset analysis of patients with palpable nodes, tumor size and histology remained significantly associated with nodal stage., Conclusion: More than 40% of breast cancer patients with clinically positive nodes had minimal nodal disease (pN1) at surgery. Additionally, palpable nodes on exam did not predict higher nodal stage. A subset of patients with clinically positive nodes may be identified who can potentially be spared the morbidity of ALND.

Objective: This study aimed to review the association between timeliness to completion of a discharge summary to 30-day readmission to the hospital., Methods: This was a retrospective chart review of 109 patients discharged from Mayo Clinic Hospital., Results: Twenty-four of these patients were readmitted within 30 days. The time to completion of discharge summary was categorized for these readmissions to <72 hours: 15 (20%), between 72 hours and 7 days: 2 (11.1%), and >7 days: 7 (43.7%). There was no statistical significance for readmission for discharge summaries completed between 72 hours and 7 days compared with <72 hours ( P = 0.44). There was statistical significance correlating readmission within 30 days to the discharge summary completed >7 days compared with <72 hours ( P = 0.04)., Conclusions: This study found that discharge summaries completed >7 days have an increased association with 30-day readmission rate.

Ruddy shelduck migrate from wintering grounds in lowland India and Myanmar to breeding grounds in central China and Mongolia, sustaining flight over the Himalayas, where oxygen availability is greatly reduced. We compared phenotypes of the pectoralis muscle and the ventricle of the heart from ruddy shelduck and common shelduck (a closely related low-altitude congener) that were raised in common conditions at sea level, predicting that oxidative capacity would be greater in ruddy shelduck to support high-altitude migration. Fibre-type composition of the pectoralis and the maximal activity of eight enzymes involved in mitochondrial energy metabolism in the pectoralis and heart, were compared between species. Few differences distinguished ruddy shelduck from common shelduck in the flight muscle, with the exception that ruddy shelduck had higher activities of complex II and higher ratios of complex IV (cytochrome c oxidase) and complex II when expressed relative to citrate synthase activity. There were no species differences in fibre-type composition, so these changes in enzyme activity may reflect an evolved modification in the functional properties of muscle mitochondria, potentially influencing mitochondrial respiratory capacity and/or oxygen affinity. Ruddy shelduck also had higher lactate dehydrogenase activity concurrent with lower pyruvate kinase and hexokinase activity in the left ventricle, which likely reflects an increased capacity for lactate oxidation by the heart. We conclude that changes in pathways of mitochondrial energy metabolism in the muscle and heart may contribute to the ability of ruddy shelduck to fly at high altitude.

There is evidence that sensitive responsiveness is manifested differently in varying cultural contexts. This exploratory study examines a sample of 50 South African mothers in the context of a socioeconomically deprived Township, and investigates differences between the Ainsworth sensitivity scale (that does not specify particular manifestations of sensitivity) and the Maternal Behavior Q-sort (MBQ) mini, that assesses a more specified array of behaviors. Results showed a significant but modest association between the two measures, and maternal education was related to the MBQ-mini but not the Ainsworth scores. This pattern of results appears to be due to the higher salience of social games and verbal teaching in the MBQ-mini than in the Ainsworth scale. Such behaviors are less common in South African parenting, where more physical forms of responsiveness seem more typical. A local "South African" sort was developed to capture culture-specific manifestations of sensitivity.

Background: Fast gait speed is being increasingly recognized as an important clinical tool in older adults. However, the underlying muscular and functional contributors to fast gait speed performance remain poorly understood., Aim: We sought to determine predictors of fast gait speed in older adults. We hypothesized that lower-extremity skeletal muscle size and quality would be strong predictors., Methods: Ninety community-dwelling older adults (33 men, 57 women; mean ± SD age = 74 ± 6 years) participated. B-mode ultrasonography was used to capture images of the vastus lateralis, rectus femoris, and gastrocnemius in the transverse plane. Each participant performed 30-second chair stand, heel-rise, functional reach, and grip strength tests. Fast gait speed was measured using the NIH Toolbox 4-Meter Walk Test. ImageJ software was used to quantify cross-sectional area (CSA), subcutaneous tissue thickness, and echo intensity. Two separate stepwise regression analyses were performed, one using muscle morphology variables as independent variables, and another including the functional outcomes., Results: The ultrasound variables exhibited weak-to-moderate correlations with fast gait speed (|r| range = 0.168-0.416). The initial regression analysis indicated that the combination of medial gastrocnemius CSA and subcutaneous tissue thickness explained 22.8% of the variance in fast gait speed. The secondary analysis indicated that 30-second chair stand, heel-rise, and grip strength performance explained 45.5% of the variance., Conclusion: While medial gastrocnemius morphology is important, measures of upper and lower-extremity muscle function are better predictors of fast gait speed. These results highlight a dissociation between skeletal muscle morphology and fast gait speed.

Background: In metastatic castration-resistant prostate cancer (mCRPC), assessing treatment response and bone lesions with technetium-99m is limited by image resolution and subjectivity. We evaluated bone scan lesion area (BSLA), a quantitative imaging assessment of response in patients with mCRPC receiving radium-223 alone or in combination with androgen receptor pathway inhibitors (abiraterone/prednisone or enzalutamide)., Patients and Methods: This randomized, non-comparative phase IIa three-arm trial (NCT02034552) evaluated technetium-99m-based BSLA response rate (RR), safety, radiologic progression-free survival (rPFS), and time to first symptomatic skeletal event (SSE) in men with mCRPC and bone metastases receiving radium-223 with/without abiraterone/prednisone or enzalutamide. The primary endpoint was week 24 BSLA RR., Results: Overall, 63 patients received treatment (abiraterone/prednisone combination, n = 22; enzalutamide combination, n = 22; radium-223 monotherapy, n = 19). Median treatment duration (first to last dose of any study treatment) was 12 months (abiraterone/prednisone combination), 10 months (enzalutamide combination), and 3 months (radium-223 monotherapy). Week 24 BSLA RR was 58% [80% confidence interval (CI) 41% to 74%; one-sided P < 0.0001; 11/19 patients] with abiraterone/prednisone combination, 50% (32% to 68%; one-sided P < 0.0001; 8/16 patients) with enzalutamide combination, and 22% (10% to 40%; one-sided P = 0.0109; 4/18 patients) with radium-223 monotherapy. Median rPFS was not evaluable for combination arms and 4 months (80% CI 4 to 12) for monotherapy. SSEs were reported in 32% of patients; median time to first SSE was not estimable. Fatigue and back pain were the most commonly reported treatment-emergent adverse events (TEAEs); more patients receiving combination therapy than monotherapy had TEAEs. Fractures were reported in 18% receiving abiraterone/prednisone, 32% receiving enzalutamide, and 11% receiving radium-223 monotherapy. Fracture rates were lower in patients taking bone health agents versus not taking bone health agents at baseline., Conclusions: Technetium-99m imaging BSLA may offer objective, quantifiable assessment of isotope uptake changes, and potentially treatment response, in patients with mCRPC and bone metastases treated with radium-223 alone or in combination with abiraterone/prednisone or enzalutamide. In this largely treatment-naive population, BSLA RR was numerically lower with radium-223 monotherapy versus combination therapy, indicating a limited role as first-line treatment. Use of radium-223 should follow evidence-based treatment guidelines and the licensed indication., Competing Interests: Disclosure DPP has received honoraria from Advanced Accelerator Applications, Amgen, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis Oncology, Eli Lilly, Exelixis, Incyte, Janssen, Pfizer, Pharmacyclics, Roche, Seattle Genetics, and UroGen; and has received research grants/funding from Advanced Accelerator Applications, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Clovis Oncology, Eli Lilly, Endocyte, Genentech, Innocrin, MedImmune, Merck, Novartis, Pfizer, Progenics, Roche, Sanofi Aventis, and Seattle Genetics. UNV has received honoraria, has acted as an advisor/consultant, and has received research grants/funding from Bayer, Sanofi Inc., Exelixis, Bristol-Myers Squibb, Pfizer, and EMD Serono Inc. CSH has acted as an advisor/consultant for Aptevo, Asana, Astellas, AstraZeneca, Bayer, Blue Earth Diagnostics, Churchill Pharma, Clovis Oncology, Dendreon, Endocyte, Ferring, Hinova Pharma, Janssen, Myriad Genetics, Orion Corporation, and Pfizer; has received research grants/funding from Aptevo, Bayer, Aragon Pharma, Astellas, AstraZeneca, Dendreon, Genentech, Hoffman-La Roche, Medivation, Sanofi, and Pfizer; and has received travel, accommodation, and expenses from Bayer, Blue Earth Diagnostics, Clovis Oncology, Ferring, Genentech, Hinova, Janssen, Myriad Genetics, Orion Corporation, and Pfizer. CA has acted as a speaker bureau/expert testimony for Sanofi. NAD has acted as a speaker bureau/expert testimony for Astellas/Pfizer and Janssen. BAM has received honoraria, travel, and accommodation expenses, and acted as an advisor/consultant for Astellas, Amgen, Bayer, Janssen, and Pfizer; and has received grants/funding from Astellas, Bayer, Janssen, and Pfizer. DIQ has received research grants/funding from Seattle Genetics, MSD, and Novartis; has acted as an advisor/consultant for Astellas, AstraZeneca, Bayer, BMS, Dendreon, Exelixis, Roche, Janssen, MSD, Novartis, Pfizer, and Sanofi; and has received travel, accommodation, and expenses from Pfizer, MSD, AstraZeneca, BMS, and Roche. OS reports grand and/or fees from Advanced Accelerator Applications, Astellas, AstraZeneca, Bayer, Bellicum, Blue Earth Diagnostics, Inc., Bristol-Myers Squibb, Celgene, Constellation, Dendreon, EMD Serono, Innocrin, Invitae, Johnson & Johnson, Merck, Myovant, Pfizer, Sanofi, and SOTIO. VJW, JS, and LT are employees of Bayer HealthCare Pharmaceuticals. All other authors have declared no conflicts of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Alzheimer's disease (AD) is the leading form of dementia but lacks curative treatments. Current understanding of AD aetiology attributes the development of the disease to the misfolding of two proteins; amyloid-β (Aβ) and hyperphosphorylated tau, with their pathological accumulation leading to concomitant oxidative stress, neuroinflammation, and neuronal death. These processes are regulated at multiple levels to maintain homeostasis and avert disease. However, many of the relevant regulatory proteins appear to be downregulated in the AD-afflicted brain. Enhancement/restoration of these 'protective' proteins, therefore, represents an attractive therapeutic avenue. Gene therapy is a desirable means of achieving this because it is not associated with the side-effects linked to systemic protein administration, and sustained protein expression virtually eliminates compliance issues. The current article represents a focused and succinct review of the better established 'protective' protein targets for gene therapy enhancement/restoration rather than being designed as an exhaustive review incorporating less validated protein subjects. In addition, we will discuss how the risks associated with uncontrolled or irreversible gene expression might be mitigated through combining neuronal-specific promoters, inducible expression systems and localised injections. Whilst many of the gene therapy targets reviewed herein are yet to enter clinical trials, preclinical testing has thus far demonstrated encouraging potential for the gene therapy-based treatment of AD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Few investigations have examined dementia training programs for rehabilitation professionals. To address this, the L everaging E xisting A bilities in D ementia (LEAD) program was developed and examined with a pilot study. LEAD addressed dementia knowledge; the Strength-Based Approach; strategies for communication, recognizing behaviors, and learning techniques; and documentation. Participants completed pre-program, post-program, and three-month follow-up questionnaires assessing confidence, practice patterns, and dementia knowledge. Confidence and use of treatment strategies increased through the three-month follow-up and dementia knowledge significantly increased following training. LEAD positively impacted rehabilitation professionals' knowledge, confidence, and use of evidence-based treatment strategies. Implications of LEAD and future research are discussed.

CATH (https://www.cathdb.info) identifies domains in protein structures from wwPDB and classifies these into evolutionary superfamilies, thereby providing structural and functional annotations. There are two levels: CATH-B, a daily snapshot of the latest domain structures and superfamily assignments, and CATH+, with additional derived data, such as predicted sequence domains, and functionally coherent sequence subsets (Functional Families or FunFams). The latest CATH+ release, version 4.3, significantly increases coverage of structural and sequence data, with an addition of 65,351 fully-classified domains structures (+15%), providing 500 238 structural domains, and 151 million predicted sequence domains (+59%) assigned to 5481 superfamilies. The FunFam generation pipeline has been re-engineered to cope with the increased influx of data. Three times more sequences are captured in FunFams, with a concomitant increase in functional purity, information content and structural coverage. FunFam expansion increases the structural annotations provided for experimental GO terms (+59%). We also present CATH-FunVar web-pages displaying variations in protein sequences and their proximity to known or predicted functional sites. We present two case studies (1) putative cancer drivers and (2) SARS-CoV-2 proteins. Finally, we have improved links to and from CATH including SCOP, InterPro, Aquaria and 2DProt., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

SARS-CoV-2 has a zoonotic origin and was transmitted to humans via an undetermined intermediate host, leading to infections in humans and other mammals. To enter host cells, the viral spike protein (S-protein) binds to its receptor, ACE2, and is then processed by TMPRSS2. Whilst receptor binding contributes to the viral host range, S-protein:ACE2 complexes from other animals have not been investigated widely. To predict infection risks, we modelled S-protein:ACE2 complexes from 215 vertebrate species, calculated changes in the energy of the complex caused by mutations in each species, relative to human ACE2, and correlated these changes with COVID-19 infection data. We also analysed structural interactions to better understand the key residues contributing to affinity. We predict that mutations are more detrimental in ACE2 than TMPRSS2. Finally, we demonstrate phylogenetically that human SARS-CoV-2 strains have been isolated in animals. Our results suggest that SARS-CoV-2 can infect a broad range of mammals, but few fish, birds or reptiles. Susceptible animals could serve as reservoirs of the virus, necessitating careful ongoing animal management and surveillance.