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Héctor A Velásquez García,1,2 Carolyn C Gotay,1 Christine M Wilson,3 Caroline A Lohrisch,4 Agnes S Lai,2 Kristan J Aronson,5 John J Spinelli1,21School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada; 2Population Oncology, BC Cancer, Vancouver, BC, Canada; 3Screening Mammography Program, BC Cancer, Vancouver, BC, Canada; 4Department of Medical Oncology, BC Cancer, Vancouver, BC, Canada; 5Department of Public Health Sciences and Division of Cancer Care and Epidemiology, Cancer Research Institute, Queen’s University, Kingston, ON, CanadaCorrespondence: Héctor A Velásquez GarcíaPopulation Oncology, BC Cancer, 8 th floor, 686 West Broadway, Vancouver, BC V5Z 1G1, CanadaTel +1604 877 6068Fax +1 604 877 6212Email hector.velasquezgarcia@alumni.ubc.caPurpose: Mammographic density is an important breast cancer risk factor, although it is not clear whether the association differs across breast cancer tumor subtypes. We examined the association between indicators of mammographic density and breast cancer risk by tumor subtype among postmenopausal women by investigating heterogeneity across tumor characteristics.Methods: Mammographic density measures were determined for 477 breast cancer cases and 588 controls, all postmenopausal, in Vancouver, British Columbia, using digitized screening mammograms and Cumulus software. Mammographic dense (DA), non-dense (NDA), and percent dense (PDA) areas were treated as continuous covariates and categorized into quartiles according to the distribution in controls. For cases only, tests for heterogeneity between tumor subtypes were assessed by multinomial logistic regression. Associations between mammographic density and breast cancer risk were modeled for each subtype separately through unconditional logistic regression.Results: Heterogeneity was apparent for the association of PDA with tumor size (p-heterogeneity=0.04). Risk did not differ across the other assessed tumor characteristics (p-heterogeneity values >0.05).Conclusion: These findings do not provide strong evidence that mammographic density parameters differentially affect specific breast cancer tumor characteristics.Keywords: mammographic density, breast cancer, tumor characteristics, heterogeneity, multinomial logistic regression

This study examined the prevalence of primary human immunodeficiency type 1 (HIV-1) drug resistance among recently infected youth in the United States. Of the 55 subjects studied, major mutations conferring HIV drug resistance were present in 10 (18%). Eight (15%) had nonnucleoside reverse-transcriptase inhibitor (NNRTI) mutations, with the majority (6) having the K103N mutation; 2 (4%) had nucleoside reverse-transcriptase inhibitor (NRTI) mutations; and 2 (4%) had protease inhibitor (PI) mutations. Phenotypic drug resistance was present in 12 (22%) subjects: 10 (18%) for NNRTIs, 2 (4%) for NRTIs, and 3 (5.5%) for PIs. The prevalence of primary HIV-1 drug resistance, particularly to NNRTIs, in this group of recently infected youth was high. [ABSTRACT FROM AUTHOR]

Introduction Traditionally, physical therapist (PT) services do not commence until an injury, fall, or health issue has already occurred although there is increasing evidence that preventative programs administered by PTs may decrease the fall risk among elderly individuals. The purpose of this study was to examine billing, reimbursement, and administrative outcomes of the previously established and investigated prevention-based screening and intervention HOP-UP-PT (Home-based Older Persons Upstreaming Prevention-Physical Therapy) program delivered by a physical therapist in the home of older adults after being referred by a community partner. A randomized controlled trial of the HOP-UP-PT program demonstrated an 8-fold reduction in falls for participants at moderate and high fall risk compared to those who did not participate in the program. Methods A prospective observational study was performed to examine administrative and payment outcomes of HOP-UP-PT participation. Participants were referred into the HOP-UP-PT program via a local community center. Physician authorization for physical therapy participation was obtained for each participant as required for payment under United States' Center for Medicare and Medicaid Services (CMS) guidelines. The HOP-UP-PT program is preventative physical therapy delivered in the person's home with five in person visits (approximately one per month) followed by a monthly telehealth visit and a final in-person visit. Interventions included a balance program, home safety recommendations, health coaching, and addressing individual risks of falling or becoming homebound. A retrospective analysis was performed on the administrative and insurance payment data from this study which was then analyzed descriptively. Results Six participants with four different insurances completed the 7-month program (mean age=77 years) in 2021. The physical therapy visits were submitted to the participants' Medicare Part B plan. One participant's physical therapy visits were not submitted for payment as the health system did not have an active agreement with that health insurer. Due to the unclear status of telehealth visits in 2021, these services were not submitted to the insurance company for payment. All other PT visits were paid by the insurance companies. The mean amount paid for the initial evaluation code was $102.83 and the mean payment for the ~15 minute treatment codes was $25.90 per unit. Initial pilot data demonstrated a potential for a 4.2% positive operating margin when considering salary costs and travel. The mean delay from the initial referral into the HOP-UP-PT program until the physician provided written authorization for physical therapy was 69.7 days. Conclusion This study demonstrated initial evidence that payment for prevention-focused outpatient physical therapist services delivered in the home was feasible, however delays and costs in procuring physician authorization was a substantial barrier to prevention-focused physical therapy. A 4.2% operating margin demonstrated that, when efficiently operated, similar programs are likely to be viable. Furthermore, if telehealth services would have been paid, the operating margin was estimated to increase to 32%. Physical therapists are highly qualified to deliver efficient, effective preventative services which has the potential to reduce falls and institutionalization and subsequent healthcare cost savings., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Henry Ford Health System Institutional Review Board and Oakland University Institutional Review Board issued approval Henry Ford: IRB # 13704, Oakland University: FY 2020-199. This study was approved by the Henry Ford Health System Institutional Review Board and the Oakland University Institutional Review Board. 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: This study was funded by the Michigan Health Endowment Fund Healthy Aging Grant in 2018. Financial relationships: Chris Wilson and Sara Arena declare(s) employment from HOP-UP-PT, LLC. Authors CW and SA are co-principals in the commercial organization HOP-UP-PT, LLC. 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, Wilson et al.)

Huntington's disease (HD) is caused by an expansion of CAG trinucleotide repeat in the HTT gene; the exact pathogenesis of HD currently remains unclear. One of the promising directions in the study of HDs is to determine the molecular mechanism underlying the development and role of microRNAs (miRNAs). This study aimed to identify the profile of miRNAs in an HD human cell line model as diagnostic biomarkers for HD. To study HD, the human SH-SY5Y HD cell model is based on the expression of two different forms: pEGFP-Q23 and pEGFP-Q74 of HTT. The expression of Htt protein was confirmed using aggregation assays combined with immunofluorescence and Western blotting methods. miRNA levels were measured in SH-SY5Y neuronal cell model samples stably expressing Q23 and Q74 using the extraction-free HTG EdgeSeq protocol. A total of 2083 miRNAs were detected, and 354 (top 18 miRNAs) miRNAs were significantly differentially expressed (DE) ( p  < 0.05) in Q23 and Q74 cell lines. A majority of the miRNAs were downregulated in the HD cell model. Moreover, we revealed that six DE miRNAs target seven genes ( ATN1, GEMIN4, EFNA5 , CSMD2, CREBBP, ATXN1, and B3GNT ) that play important roles in neurodegenerative disorders and showed significant expression differences in mutant Htt (Q74) when compared to wild-type Htt (Q23) using RT-qPCR ( p  < 0.05 and 0.01). We demonstrated the most important DE miRNA-mRNA profiles, interaction binding sites, and their related pathways in HD using experimental and bioinformatics methods. This will allow the development of novel diagnostic strategies and provide alternative therapeutic routes for treating HD., Competing Interests: The 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Belkozhayev, Niyazova, Kamal, Ivashchenko, Sharipov and Wilson.)

Introduction: Integration of exercise into standard oncology care requires a highly skilled workforce of exercise professionals; however, competency requirements have not kept pace with advancements in the field. Therefore, the aim of this study was to obtain consensus on core competencies required for an exercise professional to be qualified to work with adults undergoing active cancer treatment., Materials and Methods: A three-round modified electronic Delphi process was used. In Round 1, an international group of 64 exercise oncology stakeholders (i.e., exercise oncology professionals (n = 29), clinical referrers (n = 21), and people with lived experience (n = 14)) responded to open-ended prompts eliciting perspectives regarding competencies needed for an exercise oncology professional to work with adults receiving active cancer treatment. Subsequently, only exercise oncology professionals participated, ranking the importance of competencies. In Round 2, professionals received summary feedback, ranked new competencies generated from open-ended responses, and reranked competencies not reaching consensus. In the final round, professionals finalized consensus ranking and rated frequency and mastery level for each., Results: Consensus was reached on 103 core competencies required for exercise professionals to be qualified to deliver care to adults undergoing active cancer treatment. The core competencies represent 10 content areas and reflect the needs of clinical referrers and people with lived experience of receiving cancer treatment., Conclusions: The core competencies identified reflect significant advancements in the field of exercise oncology. Results will underpin the development of education, certification, and employment requirements for exercise oncology professionals, providing a critical step toward achieving routine integration of exercise into standard oncology care., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Sortilin is an important regulator with potential tumour-suppressor function by limiting EGFR signalling. In this study, we undertook a comprehensive expression analysis of sortilin transcript variants and the DNA methylation status of their corresponding promoters in human non-small cell carcinomas (NSCLCs). RNA/DNA was extracted from 81 NSCLC samples and paired normal tissue. mRNA expression was measured by qPCR and DNA methylation determined by pyrosequencing. BigDye-terminator sequencing was used to confirm exon-8 alternative splicing. Results demonstrated that both SORT1A and SORT1B variants were downregulated in lung tumours. The SORT1A/SORT1B expression ratio was higher in tumours compared to normal tissue. SORT1B promoter hypermethylation was detected in lung tumours compared to normal lung (median difference 14%, Mann-Whitney test p = 10 -6 ). Interestingly, SORT1B is hypermethylated in white blood cells, but a small and very consistent drop in methylation (6%, p = 10 -15 ) was observed in the lung cancer cases compared to control subjects. We demonstrate that the SORT1B exon-8 splice variation, reported in sequence databases, is also a feature of SORT1A. The significantly altered quantitative and qualitative characteristics of sortilin mRNA in NSCLC indicate a significant involvement in tumour pathogenesis and may have significant impact for its utility as a predictive marker in lung cancer management.

Multiplexed genetic perturbations are critical for testing functional interactions among coding or non-coding genetic elements. Compared to double-stranded DNA cutting, repressive chromatin formation using CRISPR interference (CRISPRi) avoids genotoxicity and is more effective for perturbing non-coding regulatory elements in pooled assays. However, current CRISPRi pooled screening approaches are limited to targeting one to three genomic sites per cell. We engineer an Acidaminococcus Cas12a (AsCas12a) variant, multiplexed transcriptional interference AsCas12a (multiAsCas12a), that incorporates R1226A, a mutation that stabilizes the ribonucleoprotein-DNA complex via DNA nicking. The multiAsCas12a-KRAB fusion improves CRISPRi activity over DNase-dead AsCas12a-KRAB fusions, often rescuing the activities of lentivirally delivered CRISPR RNAs (crRNA) that are inactive when used with the latter. multiAsCas12a-KRAB supports CRISPRi using 6-plex crRNA arrays in high-throughput pooled screens. Using multiAsCas12a-KRAB, we discover enhancer elements and dissect the combinatorial function of cis-regulatory elements in human cells. These results instantiate a group testing framework for efficiently surveying numerous combinations of chromatin perturbations for biological discovery and engineering., (© 2024. The Author(s).)

Competing Interests: The 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.

Superconducting quantum circuits are a natural platform for quantum simulations of a wide variety of important lattice models describing topological phenomena, spanning condensed matter and high-energy physics. One such model is the bosonic analog of the well-known fermionic Kitaev chain, a 1D tight-binding model with both nearest-neighbor hopping and pairing terms. Despite being fully Hermitian, the bosonic Kitaev chain exhibits a number of striking features associated with non-Hermitian systems, including chiral transport and a dramatic sensitivity to boundary conditions known as the non-Hermitian skin effect. Here, using a multimode superconducting parametric cavity, we implement the bosonic Kitaev chain in synthetic dimensions. The lattice sites are mapped to frequency modes of the cavity, and the in situ tunable complex hopping and pairing terms are created by parametric pumping at the mode-difference and mode-sum frequencies, respectively. We experimentally demonstrate important precursors of nontrivial topology and the non-Hermitian skin effect in the bosonic Kitaev chain, including chiral transport, quadrature wavefunction localization, and sensitivity to boundary conditions. Our experiment is an important first step towards exploring genuine many-body non-Hermitian quantum dynamics., (© 2024. The Author(s).)

Exposure to blast overpressure has been a pervasive feature of combat-related injuries. Studies exploring the neurological correlates of repeated low-level blast exposure in career "breachers" demonstrated higher levels of tumor necrosis factor alpha (TNFα) and interleukin (IL)-6 and decreases in IL-10 within brain-derived extracellular vesicles (BDEVs). The current pilot study was initiated in partnership with the U.S. Special Operations Command (USSOCOM) to explore whether neuroinflammation is seen within special operators with prior blast exposure. Data were analyzed from 18 service members (SMs), inclusive of 9 blast-exposed special operators with an extensive career history of repeated blast exposures and 9 controls matched by age and duration of service. Neuroinflammation was assessed utilizing positron emission tomography (PET) imaging with [ 18 F]DPA-714. Serum was acquired to assess inflammatory biomarkers within whole serum and BDEVs. The Blast Exposure Threshold Survey (BETS) was acquired to determine blast history. Both self-report and neurocognitive measures were acquired to assess cognition. Similarity-driven Multi-view Linear Reconstruction (SiMLR) was used for joint analysis of acquired data. Analysis of BDEVs indicated significant positive associations with a generalized blast exposure value (GBEV) derived from the BETS. SiMLR-based analyses of neuroimaging demonstrated exposure-related relationships between GBEV, PET-neuroinflammation, cortical thickness, and volume loss within special operators. Affected brain networks included regions associated with memory retrieval and executive functioning, as well as visual and heteromodal processing. Post hoc assessments of cognitive measures failed to demonstrate significant associations with GBEV. This emerging evidence suggests neuroinflammation may be a key feature of the brain response to blast exposure over a career in operational personnel. The common thread of neuroinflammation observed in blast-exposed populations requires further study.

The 1983-1984 mortality event of the long-spined sea urchin Diadema antillarum reduced their population by up to 99% and was accompanied by a phase shift from coral dominated to algal dominated reefs in the Caribbean. Modest rebounds of D. antillarum populations in the Caribbean have been noted, and here we document the impacts of two major hurricanes (2017, Irma and Maria) and the 2022 disease outbreak on populations of D. antillarum found by targeted surveys in the urchin zone at nine fringing reef and three mangrove sites on St. John, USVI. D. antillarum populations at the reef sites had declined by 66% five months after the hurricanes but showed significant recovery just one year later. The impact of recent disease on these populations was much more profound, with all reef populations exhibiting a significant decline (96.4% overall). Fifteen months after the disease was first noted, D. antillarum at reef sites exhibited a modest yet significant recovery (15% pre-disease density). D. antillarum populations in mangrove sites were impacted by the hurricanes but exhibited much higher density than reef sites after the disease outbreak, suggesting that at D. antillarum in some locations may be less vulnerable to disease., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Godard et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The Patient Cloud ePRO app was adopted by the National Cancer Institute National Clinical Trials Network (NCTN) to facilitate capturing electronic patient-reported (ePRO) outcome data, but use has been low. The study objectives were to test whether a patient-targeted ePRO educational resource (ePRO-E) would increase ePRO intent (number of users) and improve data quality (high quality: ≥80% of the required surveys submitted) within an ongoing NCTN study., Methods: The ePRO-E intervention, a patient-targeted educational resource (written material and 6-minute animated YouTube video), was designed to address ePRO barriers. ePRO intent and data quality were compared between 2 groups (N = 69): a historical control group and a prospectively recruited intervention group exposed to ePRO-E. Covariates included technology attitudes, age, sex, education, socioeconomic status, and comorbidity., Results: Intervention group ePRO intent (78.8%) was statistically significantly higher than historical control group intent (47.1%) (P = .03). Patients choosing ePRO versus paper surveys had more positive and higher technology attitudes scores (P = .03). The odds of choosing ePRO were 4.7 times higher (95% Confidence Interval [CI] = 1.2 to 17.8) (P = .02) among intervention group patients and 5.2 times higher (95% CI = 1.3 to 21.6) (P = .02) among patients with high technology attitudes scores, after controlling for covariates. However, the 80% submission rate (percentage submitting ≥80% of required surveys) in the ePRO group (30.6%) was statistically significantly lower than in the paper group (57.9%) (P = .05)., Conclusions: ePRO-E exposure increased ePRO intent. High technology attitudes scores were associated with ePRO selection. Since the ePRO survey submission rate was low, additional strategies are needed to promote high-quality data submission., (© The Author(s) 2024. Published by Oxford University Press.)

Introduction Technology literacy is the ability to comfortably understand, use, and navigate digital devices. It is considered a "super social determinant of health", and yet 39% of adults aged 65+ report not using a smartphone, and 25% of seniors still lack internet access. The purpose of this study was to examine the applicability of a physical therapist-delivered clinical assessment tool related to technological literacy and to identify relationships between technology utilization and perceptions related to sociodemographic factors in community-dwelling older adults. Methods A prospective mixed-methods observational-descriptive study where physical therapists (PTs) administered a newly designed technology literacy algorithm to older adults and evaluated the results of the algorithm. A convenience sample of 30 participants aged 65 and older was evaluated for their technology literacy. The exclusion criteria were if the person had a vision deficit, lived in a nursing home or extended care facility, was unable to fluently read and understand the English language, or was not willing to have an in-home visit by a licensed PT. After informed consent was obtained, the participant completed a Past Experience with Technology Questionnaire assessing participant confidence with technology usage and a demographic questionnaire. A PT data collector visited participants' homes and administered a novel technology literacy algorithm. The PTs also provided subjective feedback after patient visits as to their perceptions of the algorithm. Inferential statistics were performed for key variables, including a Kruskal-Wallis test being utilized for variables with three or more levels and a two-sample Wilcoxon test being utilized for variables with two levels. The binary results were evaluated with chi-squared tests. Trends in distribution and measures of central tendency were analyzed for demographic data. Statistical significance was set at P<0.05 with a confidence interval of 95%. Results Participants (n=30) were evenly distributed with regard to age, and 66% of people had a college degree. Most were female, of the white race, and retired. There were statistically significant relationships between older age and decreased comfort level with using the internet (P=0.30) and sending messages (P=0.31), with individuals 80+ years old having a mean confidence of 6.78 out of 10. A statistically significant relationship was also found between higher income and increased confidence in browsing the internet (P = 0.07). Most qualitative data from physical therapist experiences included positive trends such as ease of use, efficiency, and confidence instilled. Constructive feedback included a lack of resources to assist with more advanced technology-related needs and recommendations to refine the algorithm when advanced needs were identified. Conclusion Technology literacy is a vital component of accessing health and medical care and maximizing the quality of that care, especially in the older adult population. The tools created may assist clinicians with identifying and addressing issues related to technology in older adults. This may help a patient navigate health issues that require the use of technology in their home. This study provided evidence that a PT-administered algorithm may be feasible to address technology literacy issues in the homes of older adults., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2023, Wilson et al.)

Prioritizing patient values-who/what matters most-is central to palliative care and critical to treatment decision making. Yet which factors are most important to family caregivers in these decisions remains understudied. Using data from a U.S. national survey of cancer caregivers (N = 1661), we examined differences in factors considered very important by caregivers when partnering with patients in cancer treatment decision making by cancer stage and caregiver sociodemographics. Fifteen factors were rated on a 4-point Likert-scale from 'very unimportant' to 'very important.' Descriptive statistics were used to characterize caregiver factors and tabulate proportions of importance for each. Generalized linear mixed effect modeling was used to examine the importance of factors by cancer stage, and chi-square analyses were performed to determine associations between caregiver sociodemographics and the five most commonly endorsed factors: quality of life (69%), physical well-being (68%), length of life (66%), emotional well-being (63%), and opinions/feelings of oncology team (59%). Significant associations (all p 's < 0.05) of small magnitude were found between the most endorsed factors and caregiver age, race, gender, and ethnicity, most especially 'opinions/feelings of the oncology team'. Future work is needed to determine the best timing and approach for eliciting and effectively incorporating caregiver values and preferences into shared treatment decision making.

Introduction: Studies showing associations between inflammation in suicide are typically cross-sectional. Present study investigated how cytokine levels track with suicidal ideation and severity longitudinally., Methods: Veterans with a diagnosis of major depressive disorder (MDD) with or without suicide attempt history (MDD/SA n  = 38, MDD/NS n  = 41) and non-psychiatric non-attempter controls (HC n  = 33) were recruited, MDD/SA and HC groups were followed longitudinally at 3 months and 6 months. Blood plasma was collected and processed using Luminex Immunology Multiplex technology., Results: Significant differences in depression severity (BDI) and suicidal ideation severity (SSI) were observed across all groups at study entry, wherein MDD/SA group had the highest scores followed by MDD/NS and HC, respectively. Cytokines IL-1β, IL-4, TNF-α, IFN-γ, and IL-6 were examined at study entry and longitudinally, with IL6 levels differing significantly across the groups ( p  = 0.0123) at study entry. Significant differences in changes in cytokine levels between depressed attempters and the control group were detected for IL-6 (interaction F 1,91.77  = 5.58, p  = 0.0203) and TNF-α ( F 1,101.73  = 4.69, p  = 0.0327). However, only depressed attempters showed a significant change, in IL-6 and TNF-α levels, decreasing over time [IL-6: b  = -0.04, 95% CI = (-0.08, -0.01), p  = 0.0245 and TNF-α: b  = -0.02, 95% CI = (-0.04, -0.01), p  = 0.0196]. Although IL-6 levels were not predictive of suicidal ideation presence [OR = 1.34, 95% CI = (0.77, 2.33), p  = 0.3067], IL-6 levels were significantly associated with suicidal ideation severity ( b  = 0.19, p  = 0.0422)., Discussion: IL-6 was not associated with presence of suicidal ideation. IL-6 however, was associated with severity of ideation, suggesting that IL-6 may be useful in clinical practice, as an objective marker of heightened suicide risk., Competing Interests: The 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 Sun, Wilson, Alter, Ge, Hazlett, Goodman, Yehuda, Galfalvy and Haghighi.)

Introduction The high prevalence of falls, lack of stability and balance, and general physical deconditioning are concerning issues for longevity and quality of life for adults aged 65 years and older. Although supervised delivery of the Otago Exercise Program (OEP) has demonstrated evidence of effectiveness in reducing fall risk of older adults, opportunities for ongoing unsupervised exercise performance are warranted. An option to facilitate exercise and performance of health behaviors may be via a social robot. The purpose of this study was to examine feasibility and initial outcomes of a robot-delivered fall prevention exercise program for community-dwelling older adults. Methods Five participants aged 65 years and older were recruited to receive robot-delivered modified OEP and walking program three times per week for four weeks. Outcomes of demographics, self-reported performance measures (Modified Falls Self-Efficacy Scale, Activities-specific Balance Confidence, and Almere Model assessing various constructs of acceptance of use of robotic technology), and physical performance measures (Timed Up and Go Test, Short Physical Performance Battery, Balance Tracking System [BTrackS] center of pressure sway) were collected. Data were analyzed descriptively and examined for trends in change. Measures of central tendency and distribution were used according to the distribution of the data. Results The mean age of the participants was 75 years (range: 66-83 years; four females and one male). The range of participant exercise session completion was 7-12 (mode=11, n=3). Constructs on the Almere Model that started and remained positive were Attitudes Toward Technology and Perceived Enjoyment with the robot. Anxiety improved from 3.80 to 4.68, while Social Presence of the robot improved from 2.80 to 3.56. The construct of Trust was somewhat negative among participants upon commencing the program and did not substantially change over time. Two participants improved their confidence on the Activities-specific Balance Confidence scale by more than 10%, while all participants showed some improvement in confidence in their balance. Mixed results were found with the Modified Falls Self-Efficacy Scale. Mean gait speed for the participants improved by 0.76 seconds over 3 meters. Improvement was also demonstrated for the Short Physical Performance Battery, with two participants improving scores by 2-3 points out of 12. No appreciable changes were found with the Timed Up and Go test and the BTrackS assessment. Conclusion Using a robot-led exercise program is an accessible and feasible way to deliver exercise to community-dwelling older adults in the home, but some technical constraints remain. Outcomes suggest that a four-week program is sufficient to elicit some positive trends in health outcomes and has the potential to reduce fall risk., Competing Interests: Authors C.W., L.B., and S.A. have a declared potential conflict of interest. C.W. and S.A. are co-principals in the company HOP-UP-PT, LLC. C.W., L.B., and S.A. are board members of the HOP-UP Foundation, a 501c3 nonprofit charity. A conflict of interest compliance plan has been filed with the Oakland University Institutional Review Board. The procedures and protocols for this study were reviewed and approved by the Institutional Review Board at Oakland university (#FY2022-206), and written informed consent was obtained for all research participants., (Copyright © 2023, Wilson et al.)

Abstract Traumatic brain injury (TBI) continues to be a major cause of death and disability worldwide. This study assessed the effectiveness of non-invasive vagus nerve stimulation (nVNS) in reducing brain lesion volume and improving neurobehavioral performance in a rat model of TBI. Animals were randomized into three experimental groups: (1) TBI with sham stimulation treatment (Control), (2) TBI treated with five lower doses (2-min) nVNS, and (3) TBI treated with five higher doses (2 × 2-min) nVNS. We used the gammaCore nVNS device to deliver stimulations. Magnetic resonance imaging studies were performed 1 and 7 days post-injury to confirm lesion volume. We observed smaller brain lesion volume in the lower dose nVNS group compared with the control group on days 1 and 7. The lesion volume for the higher dose nVNS group was significantly smaller than either the lower dose nVNS or the control groups on days 1 and 7 post-injury. The apparent diffusion coefficient differences between the ipsilateral and contralateral hemispheres on day 1 were significantly smaller for the higher dose (2 × 2 min) nVNS group than for the control group. Voxel-based morphometry analysis revealed an increase in the ipsilateral cortical volume in the control group caused by tissue deformation and swelling. On day 1, these abnormal volume changes were 13% and 55% smaller in the lower dose and higher dose nVNS groups, respectively, compared with the control group. By day 7, nVNS dampened cortical volume loss by 35% and 89% in the lower dose and higher dose nVNS groups, respectively, compared with the control group. Rotarod, beam walking, and anxiety performances were significantly improved in the higher-dose nVNS group on day 1 compared with the control group. The anxiety indices were also improved on day 7 post-injury compared with the control and the lower-dose nVNS groups. In conclusion, the higher dose nVNS (five 2 × 2-min stimulations) reduced brain lesion volume to a level that further refined the role of nVNS therapy for the acute treatment of TBI. Should nVNS prove effective in additional pre-clinical TBI models and later in clinical settings, it would have an enormous impact on the clinical practice of TBI in both civilian and military settings, as it can easily be adopted into routine clinical practice.

Introduction: Dirofilariasis, including heartworm disease, is a major emergent veterinary parasitic infection and a human zoonosis. Currently, experimental infections of cats and dogs are used in veterinary heartworm preclinical drug research., Methods: As a refined alternative in vivo heartworm preventative drug screen, we assessed lymphopenic mouse strains with ablation of the interleukin-2/7 common gamma chain (γc) as susceptible to the larval development phase of Dirofilaria immitis ., Results: Non-obese diabetic (NOD) severe combined immunodeficiency (SCID)γc -/- (NSG and NXG) and recombination-activating gene (RAG)2 -/- γc -/- mouse strains yielded viable D. immitis larvae at 2-4 weeks post-infection, including the use of different batches of D. immitis infectious larvae, different D. immitis isolates, and at different laboratories. Mice did not display any clinical signs associated with infection for up to 4 weeks. Developing larvae were found in subcutaneous and muscle fascia tissues, which is the natural site of this stage of heartworm in dogs. Compared with in vitro- propagated larvae at day 14, in vivo- derived larvae had completed the L4 molt, were significantly larger, and contained expanded Wolbachia endobacteria titres. We established an ex vivo L4 paralytic screening system whereby assays with moxidectin or levamisole highlighted discrepancies in relative drug sensitivities in comparison with in vitro- reared L4 D. immitis . We demonstrated effective depletion of Wolbachia by 70%-90% in D. immitis L4 following 2- to 7-day oral in vivo exposures of NSG- or NXG-infected mice with doxycycline or the rapid-acting investigational drug, AWZ1066S. We validated NSG and NXG D. immitis mouse models as a filaricide screen by in vivo treatments with single injections of moxidectin, which mediated a 60%-88% reduction in L4 larvae at 14-28 days., Discussion: Future adoption of these mouse models will benefit end-user laboratories conducting research and development of novel heartworm preventatives via increased access, rapid turnaround, and reduced costs and may simultaneously decrease the need for experimental cat or dog use., Competing Interests: CF, UD, AMan, SM, and JM are employed by TRS Laboratories Inc. FG is employed by Eisai Global Health. 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 Marriott, Dagley, Hegde, Steven, Fricks, DiCosty, Mansour, Campbell, Wilson, Gusovsky, Ward, Hong, O'Neill, Moorhead, McCall, McCall, Taylor and Turner.)

The evidence to support the benefits of exercise for people living with and beyond cancer is robust. Still, exercise oncology interventions in the United States are only eligible for coverage by third-party payers within the restrictions of cancer rehabilitation settings. Without expanded coverage, access will remain highly inequitable, tending toward the most well-resourced. This article describes the pathway to third-party coverage for 3 programs that address a chronic disease and utilize exercise professionals: the Diabetes Prevention Program, Supervised Exercise Training for Peripheral Artery Disease, and Cancer Rehabilitation. Lessons learned will be applied toward expanding third-party coverage for exercise oncology programming., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Lung cancer is a global health problem affecting millions of people each year. Non-small cell lung cancer (NSCLC) is the most common form of lung cancer with various conventional treatment available in the clinic. Application of these treatments alone often results in high rates of cancer reoccurrence and metastasis. In addition, they can cause damage to healthy tissues, resulting in many adverse effects. Nanotechnology has emerged as a modality for the treatment of cancer. When used in combination with nanoparticles, it is possible to improve the pharmacokinetic and pharmacodynamic profiles of pre-existing drugs used in cancer treatment. Nanoparticles have physiochemical properties such as small size which allowing passage through challenging areas of the body, and large surface area allows for higher doses of drugs to be brought to the tumor site. Nanoparticles can be functionalized which involves modifying the surface chemistry of the particles and allows for the conjugation of ligands (small molecules, antibodies, and peptides). Ligands can be chosen for their ability to target components that are specific to or are upregulated in cancer cells, such as targeting receptors on the tumor surface that are highly expressed in the cancer. This ability to precisely target the tumor can improve the efficacy of drugs and decrease toxic side effects. This review will discuss approaches used for targeting drugs to tumors using nanoparticles, provide examples of how this has been applied in the clinic and highlight future prospects for this technology., Competing Interests: The 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 Holder, Ferguson, Oliveira, Lodeiro, Trim, Byrne, Bertolo and Wilson.)

Background The purpose of this study was to determine if the use of evidence-based cognitive and cardiovascular screening prior to initiating a prevention-focused exercise program that utilizes a physical therapist (PT) direct consumer access referral model is safe. Methods A retrospective descriptive analysis of data from a prior randomized controlled trial (RCT) was performed. Two data sets emerged: Group S was screened for study inclusion but not enrolled, and Group E was enrolled and participated in preventative exercise. Participant outcomes of cognitive screenings (Mini-Cog, Trail Making Test-Part B) and cardiovascular screening (American College of Sports Medicine Exercise Pre-participation Health Screening) were extracted. Descriptive statistics were generated for demographic and outcome variables and inferential statistics were analyzed (p < 0.05). Results Records from 70 individuals (Group S) and 144 individuals (Group E) were available for analysis. Overall, 18.6% (n = 13) in Group S were not enrolled due to medical instability or potential safety considerations. The need for medical clearance prior to initiating an exercise program was identified and then clearance was obtained for 40% (n = 58) of the participants in Group E. No adverse events related to program participation were reported. Conclusions A PT-led program utilizing direct access referrals from senior centers offers a safe option for older adults to participate in individualized preventative exercise programming., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2023, Arena et al.)

Despite the progress in the comprehension of LC progression, risk, immunologic control, and treatment choices, it is still the primary cause of cancer-related death. LC cells possess a very low and heterogeneous antigenicity, which allows them to passively evade the anticancer defense of the immune system by educating cytotoxic lymphocytes (CTLs), tumor-infiltrating lymphocytes (TILs), regulatory T cells (Treg), immune checkpoint inhibitors (ICIs), and myeloid-derived suppressor cells (MDSCs). Though ICIs are an important candidate in first-line therapy, consolidation therapy, adjuvant therapy, and other combination therapies involving traditional therapies, the need for new predictive immunotherapy biomarkers remains. Furthermore, ICI-induced resistance after an initial response makes it vital to seek and exploit new targets to benefit greatly from immunotherapy. As ICIs, tumor mutation burden (TMB), and microsatellite instability (MSI) are not ideal LC predictive markers, a multi-parameter analysis of the immune system considering tumor, stroma, and beyond can be the future-oriented predictive marker. The optimal patient selection with a proper adjuvant agent in immunotherapy approaches needs to be still revised. Here, we summarize advances in LC immunotherapy approaches with their clinical and preclinical trials considering cancer models and vaccines and the potential of employing immunology to predict immunotherapy effectiveness in cancer patients and address the viewpoints on future directions. We conclude that the field of lung cancer therapeutics can benefit from the use of combination strategies but with comprehension of their limitations and improvements.

Introduction Traditionally, physical therapy has adopted a tertiary approach to preventative care. However, recent trends in fall-related injuries and deaths among older individuals suggest a dire need for earlier intervention. The Home-based Older Persons Upstreaming Prevention Physical Therapy (HOP-UP-PT) program has been developed to improve the health and overall function of community-dwelling older adults at risk of functional decline. As demand continually rises for HOP-UP-PT services, online training modules have been developed to safely and efficiently provide HOP-UP-PT competency to physical therapists. The purpose of this study was to examine self-reported experiences and perceptions of physical therapists after completing an asynchronous training program to deliver HOP-UP-PT. Methods After securing Oakland University IRB approval, a qualitative study using a sample of convenience used two structured focus group interviews. Inclusion criteria required participants to be licensed physical therapists (PTs) in the state of Michigan providing at least 20 hours of direct patient care per week. Participants completed eight 30-minute training modules, each with a corresponding quiz. Upon completion, PTs attended one of two video conference focus groups. Data was analyzed using the constant comparative method to develop themes and concepts based on responses about the training modules and the overall HOP-UP-PT program. Results Twelve PTs with a median age of 31-40 years participated. Analysis of two focus group sessions identified three concepts (Novel Approach to Physical Therapy Care, Integration of a Preventative Approach into Clinical Practice, and Knowledge Translation) and ten themes (Addressing an Unmet Need, Establishing a Working Relationship with Community Centers, Applicability to Various Settings, Shifting the Mindset to a Prevention-focused Paradigm, Applicability to Physical Therapists that Care for Older Adults, Patient Engagement and Prevention, Value for the Professional, Importance of Availability of Options in a Learning Platform, Ongoing Availability of Program Resources and Tools, and Clinical Application Practice). Conclusion PTs identified the HOP-UP-PT program as a novel, clinically applicable, and adding value to the profession. Furthermore, its upstream focus aligns with the growing role of preventative care by PTs; however, as HOP-UP-PT is not a traditional approach, additional training and clinical support materials may facilitate adoption and clinical application. HOP-UP-PT uses a preventative approach to clinical practice, but efforts to translate knowledge to PT are an important consideration. Additionally, the study identified a need for refinement and modifications to the existing HOP-UP-PT training modules., Competing Interests: Breana Knust, Aaron Krueger, Erica Wilson and Allison Zornow completed this study as a component of their graduation from the Oakland University Doctor of Physical Therapy program., (Copyright © 2022, Wilson et al.)

Current imaging approaches used to monitor tumor progression can lack the ability to distinguish true progression from pseudoprogression. Simultaneous metabolic 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) positron emission tomography (PET) and magnetic resonance imaging (MRI) offers new opportunities to overcome this challenge by refining tumor identification and monitoring therapeutic responses to cancer immunotherapy. In the current work, spatial and quantitative analysis of tumor burden were performed using simultaneous [ 18 F]FDG-PET/MRI to monitor therapeutic responses to a novel silicified cancer cell immunotherapy in a mouse model of disseminated serous epithelial ovarian cancer. Tumor progression was validated by bioluminescence imaging of luciferase expressing tumor cells, flow cytometric analysis of immune cells in the tumor microenvironment, and histopathology. While PET demonstrated the presence of metabolically active cancer cells through [ 18 F]FDG uptake, MRI confirmed cancer-related accumulation of ascites and tissue anatomy. This approach provides complementary information on disease status without a confounding signal from treatment-induced inflammation. This work provides a possible roadmap to facilitate accurate monitoring of therapeutic responses to cancer immunotherapies.

Continuous revision of the histologic and stage-wise classification of lung cancer by the World Health Organization (WHO) provides the foundation for therapeutic advances by promoting molecular targeted and immunotherapies and ensuring accurate diagnosis. Cancer epidemiologic data provide helpful information for cancer prevention, diagnosis, and management, supporting health-care interventions. Global cancer mortality projections from 2016 to 2060 show that cancer will overtake ischemic heart diseases (IHD) as the leading cause of death (18.9 million) immediately after 2030, surpassing non-small cell lung cancer (NSCLC), which accounts for 85 percent of lung cancers. The clinical stage at the diagnosis is the main prognostic factor in NSCLC therapies. Advanced early diagnostic methods are essential as the initial stages of cancer show reduced mortality compared to the advanced stages. Sophisticated approaches to proper histological classification and NSCLC management have improved clinical efficiency. Although immune checkpoint inhibitors (ICIs) and targeted molecular therapies have refined the therapeutic management of late-stage NSCLC, the specificity and sensitivity of cancer biomarkers should be improved by focusing on prospective studies, followed by their use as therapeutic tools. The liquid biopsy candidates such as circulating tumor cells (CTCs), circulating cell-free tumor DNA (cfDNA), tumor educated platelets (TEP), and extracellular vesicles (EVs) possess cancer-derived biomolecules and aid in tracing: driver mutations leading to cancer, acquired resistance caused by various generations of therapeutic agents, refractory disease, prognosis, and surveillance., Competing Interests: The authors declare that there are no conflict of interests., (© 2022 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.)

Introduction: Safe aging in place (SAIP) is when an older adult can successfully and comfortably remain in their home despite increasing barriers, including falls. Various physical, medical, psychological, and psychosocial factors may individually or cumulatively impact an older adult's ability to safely age in place. Physiotherapists should assess not only items traditionally considered within their scope of practice but should select efficient and effective outcome measures to quantify other domains of health. A comprehensive geriatric assessment (CGA) is an evidence-based clinical assessment which identifies medical, psychosocial, and functional limitations of an older person. The CGA is useful to dictate individualized exercise/intervention prescription to address identified areas of increased risk., Purpose and Importance to Practice: The purpose of this Masterclass is to describe key screening, assessments, and interventions to facilitate SAIP and to provide overviews of currently available programming and care delivery models applicable to physiotherapist practice. There are a wide variety of outcome measures and interventions that vary in depth, validity, and reliability. Measures selected for inclusion in this Masterclass were chosen based upon their clinical utility with respect to time and resource constraints and ease of administration during a comprehensive assessment for SAIP in community-dwelling older adults. Measures recommended for assessing physical function were the Short Physical Performance Battery, the Timed-Up-and-Go, the 30 second chair rise test, and the Four Test Balance Scale. Additionally, measures from the heath domain (e.g., Functional Comorbidity Index) and the environmental domain (e.g., Home FAST) are recommended. Relative to interventions, the Otago Exercise Program, motivational interviewing, home modifications, and leveraging technology are recommended. Partnerships with community-facing organizations facilitate utilization of resources for sustainable SAIP. The Home-based Older Person Upstreaming Prevention Physical Therapy (HOP-UP-PT) program is one approach led by physiotherapists framed in the screening, assessments, and interventions discussed in this Masterclass with strong scientific grounding., Conclusion: Programs integrating both community and healthcare approaches have the strongest evidence for their utility; however, implementation for these preventative approaches are lagging behind the increased need due to the substantial population growth of those over 65 years., (© 2022. The Author(s).)

Plasminogen (Plg) activation to the serine protease plasmin (Pla) plays a key role in regulating wound healing and fibrotic responses, particularly when bound to cell surface receptors. Our previous work suggested that mesothelial cells bind Plg at the cell surface, though no Plg receptors were described for these cells. Since mesothelial cells contribute to injury responses, including cellular differentiation to a mesenchymal-like phenotype and extracellular matrix remodeling, we hypothesized that Plg binding would promote these responses. Here, we confirm that Plg binds to both pleural and peritoneal mesothelial cells via the lysine-binding domain present in Plg, and we demonstrate the presence of three Plg receptors on the mesothelial cell surface: α-Enolase, Annexin A2, and Plg-R KT . We further show that bound-Plg is activated to Pla on the cell surface and that activation is blocked by an inhibitor of urokinase plasminogen activator or by the presence of animal-derived FBS. Lastly, we demonstrate that Plg promotes mesothelial cell invasion through a type I collagen matrix but does not promote cellular differentiation or proliferation. These data demonstrate for the first time that mesothelial cells bind and activate Plg at the cell surface and that active Pla is involved in mesothelial cell invasion without cell differentiation.

Background: Tumor-infiltrating lymphocytes (TIL) confer a survival benefit among patients with ovarian cancer; however, little work has been conducted in racially diverse cohorts., Methods: The current study investigated racial differences in the tumor immune landscape and survival of age- and stage-matched non-Hispanic Black and non-Hispanic White women with high-grade serous ovarian carcinoma (HGSOC) enrolled in two population-based studies (n = 121 in each racial group). We measured TILs (CD3+), cytotoxic T cells (CD3+CD8+), regulatory T cells (CD3+FoxP3+), myeloid cells (CD11b+), and neutrophils (CD11b+CD15+) via multiplex immunofluorescence. Multivariable Cox proportional hazard regression was used to estimate the association between immune cell abundance and survival overall and by race., Results: Overall, higher levels of TILs, cytotoxic T cells, myeloid cells, and neutrophils were associated with better survival in the intratumoral and peritumoral region, irrespective of tissue compartment (tumor, stroma). Improved survival was noted for T-regulatory cells in the peritumoral region and in the stroma of the intratumoral region, but no association for intratumoral T-regulatory cells. Despite similar abundance of immune cells across racial groups, associations with survival among non-Hispanic White women were consistent with the overall findings, but among non-Hispanic Black women, most associations were attenuated and not statistically significant., Conclusions: Our results add to the existing evidence that a robust immune infiltrate confers a survival advantage among women with HGSOC; however, non-Hispanic Black women may not experience the same survival benefit as non-Hispanic White women with HGSOC., Impact: This study contributes to our understanding of the immunoepidemiology of HGSOC in diverse populations., (©2022 American Association for Cancer Research.)

Summary: Spatially resolved transcriptomics promises to increase our understanding of the tumor microenvironment and improve cancer prognosis and therapies. Nonetheless, analytical methods to explore associations between the spatial heterogeneity of the tumor and clinical data are not available. Hence, we have developed spatialGE, a software that provides visualizations and quantification of the tumor microenvironment heterogeneity through gene expression surfaces, spatial heterogeneity statistics that can be compared against clinical information, spot-level cell deconvolution and spatially informed clustering, all using a new data object to store data and resulting analyses simultaneously., Availability and Implementation: The R package and tutorial/vignette are available at https://github.com/FridleyLab/spatialGE. A script to reproduce the analyses in this manuscript is available in Supplementary information. The Thrane study data included in spatialGE was made available from the public available from the website https://www.spatialresearch.org/resources-published-datasets/doi-10-1158-0008-5472-can-18-0747/., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Plants use complex gene regulatory mechanisms to overcome diverse environmental challenges. For instance, cold stress induces rapid and massive transcriptome changes via alternative splicing (AS) to confer cold tolerance in plants. In mammals, mounting evidence suggests chromatin structure can regulate co-transcriptional AS. Recent evidence also supports co-transcriptional regulation of AS in plants, but how dynamic changes in DNA methylation and the chromatin structure influence the AS process upon cold stress remains poorly understood. In this study, we used the DNA methylation inhibitor 5-Aza-2'-Deoxycytidine (5-aza-dC) to investigate the role of stochastic variations in DNA methylation and nucleosome occupancy in modulating cold-induced AS, in Arabidopsis thaliana (Arabidopsis). Our results demonstrate that 5-aza-dC derived stochastic hypomethylation modulates nucleosome occupancy and AS profiles of genes implicated in RNA metabolism, plant hormone signal transduction, and of cold-related genes in response to cold stress. We also demonstrate that cold-induced remodelling of DNA methylation regulates genes involved in amino acid metabolism. Collectively, we demonstrate that sudden changes in DNA methylation via drug treatment can influence nucleosome occupancy levels and modulate AS in a temperature-dependent manner to regulate plant metabolism and physiological stress adaptation.

An alarming rate of injurious falls among older adults warrants proactive measures to reduce falls and fall risk. The purpose of this article was to examine and synthesize the literature as it relates to programmatic components and clinical outcomes of individualized fall prevention programs on community-dwelling older adults. A literature search of four databases was performed using search strategies and terms unique to each database. Title, abstract, and full article reviews were performed to assure inclusion and exclusion criteria were met. Data were analyzed for type of study, program providers, interventions and strategies used to deliver the program, assessments used, and statistically significant outcomes. Queries resulted in 410 articles and 32 met all inclusion criteria (19 controlled trials and 13 quasi-experimental). Physical therapists were part of the provider team in 23 (72%) studies and the only provider in 10 (31%). There was substantial heterogeneity in procedures and outcome measures. Most common procedures were balance assessments (n=30), individualized balance exercises (n=29), cognition (n=21), home and vision assessments (n=16), specific educational modules (n=15), referrals to other providers/community programs (n=8), and motivational interviewing (n=7). Frequency of falls improved for eight of 13 (61.5%) controlled trials and four of five (80%) quasi-experimental studies. Balance and function improved in six of 11 (54.5%) controlled trials and in each of the six (100%) quasi-experimental studies. Strength improved in three of seven (43%) controlled trials and four of five (75%) quasi-experimental studies. While many programs improved falls and balance of older adults, there was no conclusive evidence as to which assessments and interventions were optimal to deliver as individualized fall prevention programming. The skill of a physical therapist and measures of fall frequency, balance, and function were common among the majority of studies reviewed. Despite the variability among programs, there is emerging evidence that individualized, multimodal fall prevention programs may improve fall risk of community-dwelling older adults and convenient access to these programs should be emphasized., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2022, Boright et al.)

Motivation: A gradient boosting decision tree (GBDT) is a powerful ensemble machine-learning method that has the potential to accelerate biomarker discovery from high-dimensional molecular data. Recent algorithmic advances, such as extreme gradient boosting (XGB) and light gradient boosting (LGB), have rendered the GBDT training more efficient, scalable and accurate. However, these modern techniques have not yet been widely adopted in discovering biomarkers for censored survival outcomes, which are key clinical outcomes or endpoints in cancer studies., Results: In this paper, we present a new R package 'Xsurv' as an integrated solution that applies two modern GBDT training frameworks namely, XGB and LGB, for the modeling of right-censored survival outcomes. Based on our simulations, we benchmark the new approaches against traditional methods including the stepwise Cox regression model and the original gradient boosting function implemented in the package 'gbm'. We also demonstrate the application of Xsurv in analyzing a melanoma methylation dataset. Together, these results suggest that Xsurv is a useful and computationally viable tool for screening a large number of prognostic candidate biomarkers, which may facilitate future translational and clinical research., Availability and Implementation: 'Xsurv' is freely available as an R package at: https://github.com/topycyao/Xsurv., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

There are different modalities of intercellular communication governed by cellular homeostasis. In this review, we will explore one of these forms of communication called extracellular vesicles (EVs). These vesicles are released by all cells in the body and are heterogeneous in nature. The primary function of EVs is to share information through their cargo consisting of proteins, lipids and nucleic acids (mRNA, miRNA, dsDNA etc.) with other cells, which have a direct consequence on their microenvironment. We will focus on the role of EVs of mesenchymal stem cells (MSCs) in the nervous system and how these participate in intercellular communication to maintain physiological function and provide neuroprotection. However, deregulation of this same communication system could play a role in several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, multiple sclerosis, prion disease and Huntington's disease. The release of EVs from a cell provides crucial information to what is happening inside the cell and thus could be used in diagnostics and therapy. We will discuss and explore new avenues for the clinical applications of using engineered MSC-EVs and their potential therapeutic benefit in treating neurodegenerative diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Summary: Multiplex immunofluorescence (mIF) staining combined with quantitative digital image analysis is a novel and increasingly used technique that allows for the characterization of the tumor immune microenvironment (TIME). Generally, mIF data is used to examine the abundance of immune cells in the TIME; however, this does not capture spatial patterns of immune cells throughout the TIME, a metric increasingly recognized as important for prognosis. To address this gap, we developed an R package spatialTIME that enables spatial analysis of mIF data, as well as the iTIME web application that provides a robust but simplified user interface for describing both abundance and spatial architecture of the TIME. The spatialTIME package calculates univariate and bivariate spatial statistics (e.g. Ripley's K, Besag's L, Macron's M and G or nearest neighbor distance) and creates publication quality plots for spatial organization of the cells in each tissue sample. The iTIME web application allows users to statistically compare the abundance measures with patient clinical features along with visualization of the TIME for one tissue sample at a time., Availability and Implementation: spatialTIME is implemented in R and can be downloaded from GitHub (https://github.com/FridleyLab/spatialTIME) or CRAN. An extensive vignette for using spatialTIME can also be found at https://cran.r-project.org/web/packages/spatialTIME/index.html. iTIME is implemented within a R Shiny application and can be accessed online (http://itime.moffitt.org/), with code available on GitHub (https://github.com/FridleyLab/iTIME)., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2021. Published by Oxford University Press.)

Background: Reduced falls and fall risks have been observed among older adults referred to the HOP-UP-PT (Home-based Older Persons Upstreaming Prevention-Physical Therapy) program. The purpose of this study was to describe outcomes of HOP-UP-PT program participants and then to compare these outcomes to non-participants., Methods: Six Michigan senior centers referred adults ≥65 years who were at-risk for functional decline or falls. 144 participants (n = 72 per group) were randomized to either the experimental group (EG) or the control group (CG). Physical therapists (PTs) delivered physical, environmental, and health interventions to the EG over nine encounters (six in-person, three telerehabilitation) spanning seven months. The CG participants were told to continue their usual physical activity routines during the same time frame. Baseline and re-assessments were conducted at 0-, 3-, and 7-months in both groups. Descriptions and comparisons from each assessment encounter were analyzed., Results: Participants ages were: EG = 76.6 (7.0) years and CG = 77.2 (8.2). Baseline measures were not significantly different apart from the Short Physical Performance Battery (SPPB) which favored the EG (P = 0.02). While no significant differences were identified in the survey outcomes or home environment assessments, significant differences in favor of the EG were identified in common fall risk indicators including the Timed Up and Go (P = 0.04), Four Test Balance Scale (P = 0.01), and the modified SPPB (P = 0.02) at the 3-month assessment visit. However, these differences were not sustained at the 7-month assessment as, notably, both groups demonstrated positive improvements in the Four Test Balance Score and SPPB. For individuals at a moderate/high fall risk at baseline, 47.8% of CG reported falling at seven months; whereas, only 6.3% of EG participants meeting the same criteria reported a fall after HOP-UP-PT participation., Conclusions: A prevention-focused multimodal program provided by PTs in older adults' homes proved beneficial and those with the highest fall risk demonstrated a significant decrease in falls. A collaboration between PTs and community senior centers resulted in upstreaming care delivery that may reduce both the financial and personal burdens associated with falls in an older adult population., Trial Registration: This study was retrospective registered at Clinical Trials.gov , TRN: NCT04814459 on 24/03/2021., (© 2021. The Author(s).)