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BACKGROUND: Preventing Loss of Independence through Exercise (PLIÉ) is a group program for people living with dementia that combines movements to support daily function with present moment body awareness and social engagement that has been found to have physical, emotional, social, and cognitive benefits. The goal of this study was to develop and refine a PLIÉ remote training program for interdisciplinary Veterans Affairs (VA) nursing home staff members also known as community living center (CLC) staff. METHODS: This pre-implementation study used iterative Plan-Do-Study-Act (PDSA) cycles. The 10-week PDSA cycles occurred from June to September 2021 at 2 VA nursing home sites. Remote training was delivered via Microsoft Teams and included 1-hour live-streamed weekly didactic sessions (nursing staff with PLIÉ instructor) focused on PLIÉ principles and 1-hour weekly live-streamed experiential sessions for staff to apply PLIÉ principles with residents. We administered weekly feedback surveys to iteratively refine the training process. RESULTS: 14 staff members participated (5 recreation therapists, 3 social workers, 2 registered nurses, 2 chaplains, 1 psychologist, and 1 speech pathologist). The experiential sessions were rated as most helpful overall. Key PDSA refinements included: (1) creating 10-minute video recording summaries to support learning, particularly for those unable to attend live training sessions due to clinical schedules; and (2) incorporating self-reflection and goal setting to support staff incorporation of PLIÉ principles into routine care and personal life. These refinements resulted in increased use of PLIÉ principles with the residents from 67 to 89% of the staff participants. 100% of regular attendees (11/11) rated their overall satisfaction with remote training as very good or excellent. CONCLUSIONS: It was feasible to train interdisciplinary CLC staff participants to deliver an integrative group movement program for residents with dementia remotely. PDSA cycles supported refinement of the training process and improved uptake. A larger study of PLIÉ remote CLC staff training is needed to assess outcomes on residents and quality of care.

BACKGROUND: The COVID-19 pandemic and shut down of in-person complementary and integrative (CIH) wellness services at the San Francisco Veterans Affairs Healthcare System (SFVAHCS) required implementation of virtual program delivery. In May 2020, VA in-person group yoga classes pivoted to virtual classes for existing attendees. In October 2020, we partnered with SFVAHCS Integrative Health and the VA Office of Rural Health to formalize the TeleYoga Program to expand yoga access to Veterans in SFVAHCS geographically dispersed area. OBJECTIVE: This pilot study evaluated Veterans experiences and self-reported health outcomes after participating in at-home tele-yoga groups during the COVID-19 pandemic. METHODS: The RE-AIM framework guided program delivery evaluation. Reach was assessed with medical record data. Adoption was assessed by the number of new facilities providing referrals to tele-yoga. Implementation, satisfaction, and patient-reported outcomes, were evaluated through structured interviews with Likert scale and open-ended responses. RESULTS: We offered 4-6 weekly livestreamed classes between October 2020-September 2021. The program reached 70 Veterans, including 40 new participants, with 1208 total unique encounters. Referrals increased from 2 to 6 SFVAHCS facilities. Fourteen participants completed structured interviews. Over half rated highly the convenience and overall experience of tele-yoga classes and reported improvement with pain, stress management, exercise, and flexibility. Open-ended responses indicated opportunities for social connection, maintaining mental health, cultivating resilience, improving function, and managing pain. Suggestions for improvement focused on technological aspects, including audiovisual quality. CONCLUSIONS: During the COVID-19 pandemic, we successfully transitioned and expanded virtual group yoga delivery to Veterans from all geographic locations within SFVAHCS. We attribute this success to existing infrastructure for telehealth and CIH services and a virtual program orientation for new participants. The results of this pilot study suggest in-person group yoga may be successfully implemented virtually, serving as a viable modality that contributes to holistic wellbeing for Veterans.

INTRODUCTION: There are few widely-available, evidence-based options to support quality of life (QOL) for people living with Alzheimers disease and related dementias. METHODS: We performed a randomized, controlled trial with a Waitlist control group to determine whether an online, livestream, mind-body, group movement program (Moving Together, 1 hour, 2 days/week, 12 weeks) improves QOL in people with cognitive impairment (PWCI) or care partners (CPs) and explore mechanisms of action. The primary outcome for both participants was self-reported QOL. Secondary outcomes and potential mediators included mobility, isolation, well-being, cognitive function, and sleep in PWCI and burden, positive emotions, caregiver self-efficacy, stress management, and sleep in CPs. Blinded assessors collected outcome data at baseline, 12, and 24 weeks. We assessed adverse events including falls through monthly check-in surveys and collected qualitative data through evaluation surveys. Intention-to-treat analyses used linear mixed models to compare mean change over time between groups and calculated standardized effect sizes (ESs). RESULTS: Ninety-seven dyads enrolled (PWCI: age 76 ± 11 years, 43% female, 80% non-Hispanic White; CPs: age 66 ± 12 years, 78% female, 71% non-Hispanic White); 15% withdrew before 12 weeks and 22% before 24 weeks. PWCI self-reported significantly better QOL from baseline to 12 weeks in the Moving Together group compared to the Waitlist group (ES = 0.474, p = 0.048) and CPs self-reported improved ability to manage stress (ES = 0.484, p = 0.021). Improvements in participant self-reported QOL were mediated by improvements in their self-reported well-being and CP-reported ability to manage stress. Results were similar when the Waitlist group participated in the program (QOL ES = 0.663, p = 0.006; stress management ES = 0.742, p = 0.002) and were supported by qualitative data. Exploratory analyses suggested possible fall reduction in PWCI. There were no study-related serious adverse events. DISCUSSION: Online programs such as Moving Together offer a scalable strategy for supporting high QOL for PWCI and helping CPs manage stress. TRIAL REGISTRATION: ClinicalTrials.gov NCT04621448. HIGHLIGHTS: The approval of new medications that slow cognitive decline in people living with Alzheimers disease and related disorders (ADRD) has raised hope and excitement. However, these medications do not appear to impact quality of life, which is often considered by patients and care partners to be the most important outcome.In this randomized clinical trial, we found that an evidence-based, online, livestream, mind-body, group movement program significantly and meaningfully improves self-rated quality of life in people with ADRD and helps care partners manage stress. Mediation analyses revealed that the key drivers of improvements in participants quality of life were improvements in their feelings of well-being and care partners ability to manage stress. Exploratory analyses also suggested a 30% reduction in falls.These results are important because they suggest that an online program, which is available now and can be performed by people from the comfort of home or other location of choice, could be recommended as a complement or alternative to new therapies to help maximize quality of life for people living with ADRD and their care partners.

Abstract Construction of minimal metabolic networks (MMNs) contributes both to our understanding of the origins of metabolism and to the efficiency of biotechnological processes by preventing the diversion of flux away from product formation. We have designed MMNs using a novel in silico synthetic biology pipeline that removes genes encoding enzymes and transporters from genome-scale metabolic models. The resulting minimal gene-set still ensures both viability and high growth rates. The composition of these MMNs has defined a new functional class of genes termed Network Efficiency Determinants (NEDs). These genes, whilst not essential, are very rarely eliminated in constructing an MMN, suggesting that it is difficult for metabolism to be re-routed to obviate the need for such genes. Moreover, the removal of NED genes from an MMN significantly reduces its global efficiency. Bioinformatic analyses of the NED genes have revealed that not only do these genes have more genetic interactions than the bulk of metabolic genes but their protein products also show more protein-protein interactions. In yeast, NED genes are predominantly single-copy and are highly conserved across evolutionarily distant organisms. These features confirm the importance of the NED genes to the metabolic network, including why they are so rarely excluded during minimisation.

Abstract Background Preventing Loss of Independence through Exercise (PLIÉ) is a group program for people living with dementia that combines movements to support daily function with present moment body awareness and social engagement that has been found to have physical, emotional, social, and cognitive benefits. The goal of this study was to develop and refine a PLIÉ remote training program for interdisciplinary Veterans Affairs (VA) nursing home staff members also known as community living center (CLC) staff. Methods This pre-implementation study used iterative Plan-Do-Study-Act (PDSA) cycles. The 10-week PDSA cycles occurred from June to September 2021 at 2 VA nursing home sites. Remote training was delivered via Microsoft Teams and included 1-hour live-streamed weekly didactic sessions (nursing staff with PLIÉ instructor) focused on PLIÉ principles and 1-hour weekly live-streamed experiential sessions for staff to apply PLIÉ principles with residents. We administered weekly feedback surveys to iteratively refine the training process. Results 14 staff members participated (5 recreation therapists, 3 social workers, 2 registered nurses, 2 chaplains, 1 psychologist, and 1 speech pathologist). The experiential sessions were rated as most helpful overall. Key PDSA refinements included: (1) creating 10-minute video recording summaries to support learning, particularly for those unable to attend live training sessions due to clinical schedules; and (2) incorporating self-reflection and goal setting to support staff incorporation of PLIÉ principles into routine care and personal life. These refinements resulted in increased use of PLIÉ principles with the residents from 67 to 89% of the staff participants. 100% of regular attendees (11/11) rated their overall satisfaction with remote training as “very good” or “excellent.” Conclusions It was feasible to train interdisciplinary CLC staff participants to deliver an integrative group movement program for residents with dementia remotely. PDSA cycles supported refinement of the training process and improved uptake. A larger study of PLIÉ remote CLC staff training is needed to assess outcomes on residents and quality of care.

Mind-wandering (MW) is a universal cognitive process that is estimated to comprise [approximately] 30% of our everyday thoughts. Despite its prevalence, the functional utility of MW remains a scientific blind spot. The present study sought to investigate whether MW serves a functional role in cognition. Specifically, we investigated whether MW contributes to memory consolidation-like processes, and if age differences in the ability to reactivate episodic memories during MW may contribute to age-related declines in episodic memory. Younger and older adults encoded paired associates, received targeted reactivation cues during an interval filled with a task that promotes MW, and were tested on their memory for the cued and uncued stimuli from the initial encoding task. Thought probes were presented during the retention (MW) interval to assess participants' thought contents. Across four experiments, we compared the effect of different cue modalities (i.e., auditory, visual) on cued recall performance, and examined both correct retrieval RTs as well as accuracy. Across experiments, there was evidence that stimuli that were cued during the MW task were correctly retrieved more quickly than uncued stimuli and that this effect was more robust for younger adults than older adults. Additionally, the more MW a participant reported during the retention interval, the stronger the cuing effect they produced during retrieval. The results from these experiments are interpreted within a retrieval facilitation framework wherein cues serve to reactivate the earlier traces during MW, and this reactivation benefits retrieval speed for cued items compared with uncued items.

Abstract We use the duality between gravitational dynamics and fluids living on dynamical surfaces carrying multiple charges, known as the blackfold approach, to perturbatively construct new asymptotically global (Anti)-de Sitter multi-spinning, non-extremal, multi-charged black holes in theories of higher-dimensional gravity minimally coupled to a dilaton and higher-form gauge fields in spacetime dimensions D ≥ 5, and new asymptotically AdS l × S m black holes in type IIB and eleven-dimensional supergravity. These solutions include the generalisation of the Kerr-Newman solution to (A)dS carrying either electric or string charge, generalisations of black rings to higher-dimensions with 𝕊 p × 𝕊 n+1 horizon topology, static de Sitter solutions carrying arbitrary q-brane charge, as well as various asymptotically AdS l × S m multi-charged and multi-spinning black hole solutions, some of which correspond to novel thermal states in N $$ \mathcal{N} $$ = 4 Super-Yang-Mills theory.

Abstract Background We retrospectively investigate feasibility and safety of whole brain radiotherapy (WBRT) including a simultaneous-integrated boost technique (WBRT-SIB) in a cohort of patients with a very poor prognosis suffering from multiple and/or large brain metastases, unfavorable primary histology, poor performance status and/or symptomatic BMs. Materials and Methods Thirty-five patients with high brain tumor burden, extracranial metastases and low life-expectancy were treated with WBRT-SIB mostly with 35-42 Gy/14 fractions. All metastases were boosted in patients with up to 12 BMs. In patients with > 12 BM, large and/or small metastases in critical brain regions were boosted up to a maximum of 12 SIB volumes. Results The median number of BM was 8 (range 2–45) and the median BM diameter was 12 mm (range 4–90 mm). Fifteen (43%) patients had ≥ 10 BMs and 25 patients presented with a Karnofski index ≤ 80%. Primary tumor histology was NSCLC (n = 13), SCLC (n = 11), breast cancer (n = 7), melanoma (n = 2), other (n = 2). The median iPFS was not reached, and 12- and 18-months iPFS were 75% and 50%, respectively. Overall, seven patients had intracranial progression: two patients within the SIB and WBRT area, one patient only within the SIB region and four patients had new BMs in the WBRT volume alone. The median iPFS for non-SCLC patients was 17 months and the 12- and 18-month iPFS were 56.8% and 28.4%, respectively. There was no significant OS difference between SCLC-group and non-SCLC patients (p = 0.38). Overall, median OS was 8.7 months and 1-year OS was 25%. The treatment was generally well-tolerated with no observed cases of radionecrosis. Conclusion Our WBRT-SIB approach involves a combination of whole brain radiotherapy and a simultaneous integrated boost to specific tumor volumes, and its effectiveness is compared with other treatment modalities in the literature. Further research, including prospective studies with larger patient cohorts, is necessary to validate and refine the findings.

Abstract Extracellular vesicles (EVs) are membrane-enclosed bio-nanoparticles secreted by cells and naturally evolved to transport various bioactive molecules between cells and even organisms. These cellular objects are considered one of the most promising bio-nanovehicles for the delivery of native and exogenous molecular cargo. However, many challenges with state-of-the-art EV-based candidates as drug carriers still exist, including issues with scalability, batch-to-batch reproducibility, and cost-sustainability of the final therapeutic formulation. Microalgal extracellular vesicles, which we named nanoalgosomes, are naturally released by various microalgal species. Here, we evaluate the innate biological properties of nanoalgosomes derived from cultures of the marine microalgae Tetraselmis chuii, using an optimized manufacturing protocol. Our investigation of nanoalgosome biocompatibility in preclinical models includes toxicological analyses, using the invertebrate model organism Caenorhabditis elegans, hematological and immunological evaluations ex vivo and in mice. We evaluate nanoalgosome cellular uptake mechanisms in C. elegans at cellular and subcellular levels, and study their biodistribution in mice with accurate space-time resolution. Further examination highlights the antioxidant and anti-inflammatory bioactivities of nanoalgosomes. This holistic approach to nanoalgosome functional characterization demonstrates that they are biocompatible and innate bioactive effectors with unique bone tropism. These findings suggest that nanoalgosomes have significant potential for future therapeutic applications.

Sex differences in glioblastoma (GBM) incidence and outcome are well recognized, and emerging evidence suggests that these extend to genetic/epigenetic and cellular differences, including immune responses. However, the mechanisms driving immunologic sex differences are not fully understood. Here, we demonstrate that T cells play a critical role in driving GBM sex differences. Male mice exhibited accelerated tumor growth, with decreased frequency and increased exhaustion of CD8+ T cells in the tumor. Furthermore, a higher frequency of progenitor exhausted T cells was found in males, with improved responsiveness to anti-PD-1 treatment. Moreover, increased T-cell exhaustion was observed in male GBM patients. Bone marrow chimera and adoptive transfer models indicated that T cell-mediated tumor control was predominantly regulated in a cell-intrinsic manner, partially mediated by the X chromosome inactivation escape gene Kdm6a. These findings demonstrate that sex-biased predetermined behavior of T cells is critical for inducing sex differences in GBM progression and immunotherapy response.SignificanceImmunotherapies in patients with GBM have been unsuccessful due to a variety of factors, including the highly immunosuppressive tumor microenvironment in GBM. This study demonstrates that sex-biased T-cell behaviors are predominantly intrinsically regulated, further suggesting sex-specific approaches can be leveraged to potentially improve the therapeutic efficacy of immunotherapy in GBM. See related commentary by Alspach, p. 1966. This article is featured in Selected Articles from This Issue, p. 1949.

One of the most robust approaches to the prediction of causal driver genes of complex diseases is to apply reverse engineering methods to infer a gene regulatory network (GRN) from gene expression profiles (GEPs). In this work, we analysed 794 GEPs of 1117 human whole-blood samples from Amyotrophic Lateral Sclerosis (ALS) patients and healthy subjects reported in the GSE112681 dataset. GRNs for ALS and healthy individuals were reconstructed by ARACNe-AP (Algorithm for the Reconstruction of Accurate Cellular Networks - Adaptive Partitioning). In order to examine phenotypic differences in the ALS population surveyed, several datasets were built by arranging GEPs according to sex, spinal or bulbar onset, and survival time. The designed reverse engineering methodology identified a significant number of potential ALS-promoting mechanisms and putative transcriptional biomarkers that were previously unknown. In particular, the characterization of ALS phenotypic networks by pathway enrichment analysis has identified a gender-specific disease signature, namely network activation related to the radiation damage response, reported in the networks of bulbar and female ALS patients. Also, focusing on a smaller interaction network, we selected some hub genes to investigate their inferred pathological and healthy subnetworks. The inferred GRNs revealed the interconnection of the four selected hub genes (TP53, SOD1, ALS2, VDAC3) with p53-mediated pathways, suggesting the potential neurovascular response to ALS neuroinflammation. In addition to being well consistent with literature data, our results provide a novel integrated view of ALS transcriptional regulators, expanding information on the possible mechanisms underlying ALS and also offering important insights for diagnostic purposes and for developing possible therapies for a disease yet incurable.