Exogenous Transforming Growth Factor-ß1 and Its Helminth-Derived Mimic Attenuate the Heart's Inflammatory Response to Ischemic Injury and Reduce Mature Scar Size.

Coronary reperfusion after acute ST-elevation myocardial infarction (STEMI) is standard therapy to salvage ischemic heart muscle. However, subsequent inflammatory responses within the infarct lead to further loss of viable myocardium. Transforming growth factor (TGF)-ß1 is a potent anti-inflammatory cytokine released in response to tissue injury. The aim of this study was to investigate the protective effects of TGF-ß1 after MI. In patients with STEMI, there was a significant correlation (P = 0.003) between higher circulating TGF-ß1 levels at 24 hours after MI and a reduction in infarct size after 3 months, suggesting a protective role of early increase in circulating TGF-ß1. A mouse model of cardiac ischemia reperfusion was used to demonstrate multiple benefits of exogenous TGF-ß1 delivered in the acute phase. It led to a significantly smaller infarct size (30% reduction, P = 0.025), reduced inflammatory infiltrate (28% reduction, P = 0.015), lower intracardiac expression of inflammatory cytokines IL-1ß and chemokine (C-C motif) ligand 2 (>50% reduction, P = 0.038 and 0.0004, respectively) at 24 hours, and reduced scar size at 4 weeks (21% reduction, P = 0.015) after reperfusion. Furthermore, a low-fibrogenic mimic of TGF-ß1, secreted by the helminth parasite Heligmosomoides polygyrus, had an almost identical protective effect on injured mouse hearts. Finally, genetic studies indicated that this benefit was mediated by TGF-ß signaling in the vascular endothelium.

Implementation of Video Blood Pressure Visits in the Veterans Health Administration.

Introduction: Almost half of veterans (44.6%) seen in the U.S. Department of Veterans Affairs outpatient setting are diagnosed with hypertension (HTN). Because of the widespread nature of HTN, use of virtual visits has the potential to improve blood pressure (BP) management. This evaluation assessed the effectiveness of video blood pressure visits (VBPVs) in the management of HTN in veterans enrolled in Veterans Health Administration primary care. Methods: The program was implemented within the existing veteran-centered medical home. VBPVs are scheduled where the nurse observes veterans taking their BP and provides teaching or counseling. A national training curriculum was delivered to local nurse champions through Microsoft Teams. We analyzed improvement in BP over a 2-year period. We also captured actions taken by nurses during the VBPV by searching the electronic notes. Ratings of training and comments were summarized using feedback forms completed after training. Results: In total, 81,476 veterans participated in VBPVs over 2 years. Of those, 44,682 veterans had an existing ICD-10 code related to HTN. Of the 18,078 veterans who had a pre- and post-VBPV BP, the average change to systolic measurement was -10.6 mm Hg (range -82 to 78). Average change to diastolic measurement was -4.61 mm Hg (range -59 to 55). Most interventions addressed medication management (77%). Nurses' evaluations of the program were positive. Conclusions: Video visits provide reliable and convenient veteran-centered care. Such visits enable care when unanticipated interruptions occur such as the coronavirus disease 2019 pandemic. In addition to medication management, nurse-led interventions such as counseling on lifestyle changes can be effective in HTN management.

Care4AD: A Technology-Driven Platform for Care Coordination and Management: Acceptability Study in Dementia.

INTRODUCTION: The technology-driven solution can reduce the caregiving burden; however, the needs of dementia caregiving are unique, and attitudes towards adopting technology from the perspectives of all the stakeholders involved in dementia caregiving are unclear. This study aims to assess the acceptability and feasibility of a technology-driven platform to facilitate care coordination platform, Care4AD, from the end-user perspective. METHODS: Care4AD includes three components: (1) Care4AD app: the app is used by caregivers to coordinate care, monitor physical activity, and schedule reminders; (2) Care4AD tablet: a smart tablet is used by the care recipient to display scheduled reminders; and (3) Care4AD tags: a series of wireless sensor tags attached to various objects of daily care to facilitate monitoring instrumental activities of daily living (IADL) and adherence to scheduled tasks. Stakeholders in caregiving, including 11 experts in dementia care (age: 53.3 ± 8, 73% female), 10 individuals with dementia (IWD) (age: 76.1 ± 7.3, 50% female), and 14 caregivers (age: 66.9 ± 10.6, 75% female) were interviewed to determine perceived ease of use, attitude towards use, and perceived usefulness, based on the technology acceptance model (TAM) questionnaire. Additionally, we assessed technology anxiety and concerns with data sharing by caregivers and IWD. The interviews were conducted through videoconferencing or in-person meetings. The interview was composed of open-ended questions, a demonstration of the proposed Care4AD platform, and a survey based on TAM. RESULTS: Compared to the neutral response, stakeholders showed significantly higher acceptance (70-100% satisfied to highly satisfied, p < 0.05) for all components of the TAM. Among IWD, age (r = -0.68, p = 0.03) and for caregivers the perceived ease of use (r = 0.73, p < 0.01) were significant predictors of attitude towards using the technology. Interestingly, neither concerns about data sharing nor educational level were limiting factors in the acceptability of the system in our sample. CONCLUSION: Overall, the results support a high perception of usefulness, ease of use, and attitude towards using Care4AD. The key barriers to adopting such technology are the age of IWD and the caregiver's perception of ease of use. Future studies are warranted to explore the effectiveness of such a platform to reduce caregiver stress and improve the quality of life and independence of IWD.

Machine Learning-Based Aggression Detection in Children with ADHD Using Sensor-Based Physical Activity Monitoring.

Aggression in children is highly prevalent and can have devastating consequences, yet there is currently no objective method to track its frequency in daily life. This study aims to investigate the use of wearable-sensor-derived physical activity data and machine learning to objectively identify physical-aggressive incidents in children. Participants (n = 39) aged 7 to 16 years, with and without ADHD, wore a waist-worn activity monitor (ActiGraph, GT3X+) for up to one week, three times over 12 months, while demographic, anthropometric, and clinical data were collected. Machine learning techniques, specifically random forest, were used to analyze patterns that identify physical-aggressive incident with 1-min time resolution. A total of 119 aggression episodes, lasting 7.3 ± 13.1 min for a total of 872 1-min epochs including 132 physical aggression epochs, were collected. The model achieved high precision (80.2%), accuracy (82.0%), recall (85.0%), F1 score (82.4%), and area under the curve (89.3%) to distinguish physical aggression epochs. The sensor-derived feature of vector magnitude (faster triaxial acceleration) was the second contributing feature in the model, and significantly distinguished aggression and non-aggression epochs. If validated in larger samples, this model could provide a practical and efficient solution for remotely detecting and managing aggressive incidents in children.

Association of mental health diagnosis with race and all-cause mortality after a cancer diagnosis: Large-scale analysis of electronic health record data.

BACKGROUND: Disparity in mental health care among cancer patients remains understudied. METHODS: A large, retrospective, single tertiary-care institution cohort study was conducted based on deidentified electronic health record data of 54,852 adult cancer patients without prior mental health diagnosis (MHD) diagnosed at the University of California, San Francisco between January 2012 and September 2019. The exposure of interest was early-onset MHD with or without psychotropic medication (PM) within 12 months of cancer diagnosis and primary outcome was all-cause mortality. RESULTS: There were 8.2% of patients who received a new MHD at a median of 197 days (interquartile range, 61-553) after incident cancer diagnosis; 31.0% received a PM prescription; and 3.7% a mental health-related visit (MHRV). There were 62.6% of patients who were non-Hispanic White (NHW), 10.8% were Asian, 9.8% were Hispanic, and 3.8% were Black. Compared with NHWs, minority cancer patients had reduced adjusted odds of MHDs, PM prescriptions, and MHRVs, particularly for generalized anxiety (Asian odds ratio [OR], 0.66, 95% CI, 0.55-0.78; Black OR, 0.60, 95% CI, 0.45-0.79; Hispanic OR, 0.72, 95% CI, 0.61-0.85) and selective serotonin-reuptake inhibitors (Asian OR, 0.43, 95% CI, 0.37-0.50; Black OR, 0.51, 95% CI, 0.40-0.61; Hispanic OR, 0.79, 95% CI, 0.70-0.89). New early MHD with PM was associated with elevated all-cause mortality (12-24 months: hazard ratio [HR], 1.43, 95% CI, 1.25-1.64) that waned by 24 to 36 months (HR, 1.18, 95% CI, 0.95-1.45). CONCLUSIONS: New mental health diagnosis with PM was a marker of early mortality among cancer patients. Minority cancer patients were less likely to receive documentation of MHDs or treatment, which may represent missed opportunities to identify and treat cancer-related mental health conditions.

Rapid fall in circulating non-classical monocytes in ST elevation myocardial infarction patients correlates with cardiac injury.

Myocardial infarction leads to a rapid innate immune response that is ultimately required for repair of damaged heart tissue. We therefore examined circulating monocyte dynamics immediately after reperfusion of the culprit coronary vessel in STEMI patients to determine whether this correlated with level of cardiac injury. A mouse model of cardiac ischemia/reperfusion injury was subsequently used to establish the degree of monocyte margination to the coronary vasculature that could potentially contribute to the drop in circulating monocytes. We retrospectively analyzed blood samples from 51 STEMI patients to assess the number of non-classical (NC), classical, and intermediate monocytes immediately following primary percutaneous coronary intervention. Classical and intermediate monocytes showed minimal change. On the other hand, circulating numbers of NC monocytes fell by approximately 50% at 90 minutes post-reperfusion. This rapid decrease in NC monocytes was greatest in patients with the largest infarct size (P < .05) and correlated inversely with left ventricular function (r = 0.41, P = .04). The early fall in NC monocytes post-reperfusion was confirmed in a second prospective study of 13 STEMI patients. Furthermore, in a mouse cardiac ischemia model, there was significant monocyte adhesion to coronary vessel endothelium at 2 hours post-reperfusion pointing to a specific and rapid vessel margination response to cardiac injury. In conclusion, rapid depletion of NC monocytes from the circulation in STEMI patients following coronary artery reperfusion correlates with the level of acute cardiac injury and involves rapid margination to the coronary vasculature.

Loss of Endothelial Endoglin Promotes High-Output Heart Failure Through Peripheral Arteriovenous Shunting Driven by VEGF Signaling.

RATIONALE: ENG (endoglin) is a coreceptor for BMP (bone morphogenetic protein) 9/10 and is strongly expressed in endothelial cells. Mutations in ENG lead to the inherited vascular disorder hereditary hemorrhagic telangiectasia characterized by local telangiectases and larger arteriovenous malformations (AVMs); but how ENG functions to regulate the adult vasculature is not understood. OBJECTIVE: The goal of the work was to determine how ENG maintains vessel caliber in adult life to prevent AVM formation and thereby protect heart function. METHODS AND RESULTS: Genetic depletion of endothelial Eng in adult mice led to a significant reduction in mean aortic blood pressure. There was no evidence of hemorrhage, anemia, or AVMs in major organs to explain the reduced aortic pressure. However, large AVMs developed in the peripheral vasculature intimately associated with the pelvic cartilaginous symphysis-a noncapsulated cartilage with a naturally high endogenous expression of VEGF (vascular endothelial growth factor). The increased blood flow through these peripheral AVMs explained the drop in aortic blood pressure and led to increased cardiac preload, and high stroke volumes, ultimately resulting in high-output heart failure. Development of pelvic AVMs in this region of high VEGF expression occurred because loss of ENG in endothelial cells leads to increased sensitivity to VEGF and a hyperproliferative response. Development of AVMs and associated progression to high-output heart failure in the absence of endothelial ENG was attenuated by targeting VEGF signaling with an anti-VEGFR2 (VEGF receptor 2) antibody. CONCLUSIONS: ENG promotes the normal balance of VEGF signaling in quiescent endothelial cells to maintain vessel caliber-an essential function in conditions of increased VEGF expression such as local hypoxia or inflammation. In the absence of endothelial ENG, increased sensitivity to VEGF drives abnormal endothelial proliferation in local regions of high VEGF expression, leading to AVM formation and a rapid injurious impact on heart function.

Guillotine Transmetatarsal Amputations With Staged Closure Promote Early Ambulation and Limb Salvage in Patients With Advanced Chronic Limb-Threatening Ischemia.

PURPOSE: Transmetatarsal amputation (TMA) with primary closure has long been an option for limb salvage in patients with advanced chronic limb-threatening ischemia (CLTI) with extensive tissue loss of the forefoot. However, TMA healing and closure techniques are challenging, specifically in high-risk patients. Guillotine transmetatarsal amputations (gTMA) with staged closure may provide an alternative treatment in this population. We report long-term outcomes of such technique. MATERIALS AND METHODS: A single-center retrospective cohort study of CLTI patients undergoing gTMA between 2017 and 2020 was performed. Limb salvage, wound healing, and survival rates were quantified using Kaplan-Meier (KM) analysis. Multivariate regression was used to identify the effect of patient characteristics on the outcomes. RESULTS: Forty-four gTMA procedures were reviewed. Median follow-up was 381 (interquartile range [IQR], 212-539.75) days. After gTMA, 87.8% (n=36) of the patients were able to ambulate after a median interval of 2 (IQR, 1-3) days. Eventual coverage was achieved in a personalized and staged approach by using a combination of skin substitutes (88.6%, n=39) ± split thickness skin grafts (STSG, 61.4%, n=27). KM estimates for limb salvage, wound healing, and survival were 84.1%, 54.5%, and 88.6% at 1 year and 81.8%, 63.8%, and 84.1% at 2 years. Wound healing was significantly associated with STSG application (p=0.002, OR=16.5, 95% CI 2.87-94.81). CONCLUSION: gTMA resulted in high limb salvage rates during long-term follow-up in CLTI patients. Adjunctive STSG placement may enhance wound healing at the gTMA site, thus leading to expedited wound closure. Surgeons may consider gTMA as an alternative to reduce limb loss in CLTI patients at high risk of major amputation. CLINICAL IMPACT: Currently, the clinical presentation of CLTI is becoming more complex to deal with due to the increasing comorbidities as the society becomes older. The data shown in this article means for clinicians that when facing diffused forefoot gangrene and extensive tissue loss, limb preservation could still be considered instead of major amputation. Guillotine transmetatarsal amputations in the setting of an aggressive multidisciplinary group, can be healed by the responsibly utilization of dermal substitutes and skin grafts leading to the preservation of the extremity, allowing mobility, avoiding of sarcopenia, and decreasing frailty. This will equate to maintenance of independent living and preservation of lifespan.

Evaluation of Motor and Cognitive Performance in People with Parkinson's Disease Using Instrumented Trail-Making Test.

INTRODUCTION: Parkinson's disease (PD) progressively impairs motor and cognitive performance. The current tools to detect decline in motor and cognitive functioning are often impractical for busy clinics and home settings. To address the gap, we designed an instrumented trail-making task (iTMT) based on a wearable sensor (worn on the shin) with interactive game-based software installed on a tablet. The iTMT test includes reaching to 5 indexed circles, a combination of numbers (1-3) and letters (A&B) randomly positioned inside target circles, in a sequential order, which virtually appears on a screen kept in front of the participants, by rotating one's ankle joint while standing and holding a chair for safety. By measuring time to complete iTMT task (iTMT time), iTMT enables quantifying cognitive-motor performance. PURPOSE: This study's objective is to examine the feasibility of iTMT to detect early cognitive-motor decline in PDs. METHOD: Three groups of volunteers, including 14 cognitively normal (CN) older adults, 14 PDs, and 11 mild cognitive impaireds (MCI), were recruited. Participants completed MoCA, 20 m walking test, and 3 trials of iTMT. RESULTS: All participants enabled to complete iTMT with <3 min, indicating high feasibility. The average iTMT time for CN-Older, PD, and MCI participants were 20.9 ± 0.9 s, 32.3 ± 2.4 s, and 40.9 ± 4.5 s, respectively. After adjusting for age and education level, pairwise comparison suggested large effect sizes for iTMT between CN-older versus PD (Cohen's d = 1.7, p = 0.024) and CN-older versus MCI (d = 1.57, p < 0.01). Significant correlations were observed when comparing iTMT time with the gait speed (r = -0.4, p = 0.011) and MoCA score (r = -0.56, p < 0.01). CONCLUSION: This study demonstrated the feasibility and early results supporting the potential application of iTMT to determine cognitive-motor and distinguishing individuals with MCI and PD from CN-older adults. Future studies are warranted to test the ability of iTMT to track its subtle changes over time.

Digital Biomarkers of Cognitive Frailty: The Value of Detailed Gait Assessment Beyond Gait Speed.

BACKGROUND: Cognitive frailty (CF), defined as the simultaneous presence of cognitive impairment and physical frailty, is a clinical symptom in early-stage dementia with promise in assessing the risk of dementia. The purpose of this study was to use wearables to determine the most sensitive digital gait biomarkers to identify CF. METHODS: Of 121 older adults (age = 78.9 ± 8.2 years, body mass index = 26.6 ± 5.5 kg/m2) who were evaluated with a comprehensive neurological exam and the Fried frailty criteria, 41 participants (34%) were identified with CF and 80 participants (66%) were identified without CF. Gait performance of participants was assessed under single task (walking without cognitive distraction) and dual task (walking while counting backward from a random number) using a validated wearable platform. Participants walked at habitual speed over a distance of 10 m. A validated algorithm was used to determine steady-state walking. Gait parameters of interest include steady-state gait speed, stride length, gait cycle time, double support, and gait unsteadiness. In addition, speed and stride length were normalized by height. RESULTS: Our results suggest that compared to the group without CF, the CF group had deteriorated gait performances in both single-task and dual-task walking (Cohen's effect size d = 0.42-0.97, p < 0.050). The largest effect size was observed in normalized dual-task gait speed (d = 0.97, p < 0.001). The use of dual-task gait speed improved the area under the curve (AUC) to distinguish CF cases to 0.76 from 0.73 observed for the single-task gait speed. Adding both single-task and dual-task gait speeds did not noticeably change AUC. However, when additional gait parameters such as gait unsteadiness, stride length, and double support were included in the model, AUC was improved to 0.87. CONCLUSIONS: This study suggests that gait performances measured by wearable sensors are potential digital biomarkers of CF among older adults. Dual-task gait and other detailed gait metrics provide value for identifying CF above gait speed alone. Future studies need to examine the potential benefits of gait performances for early diagnosis of CF and/or tracking its severity over time.

Harnessing Digital Health to Objectively Assess Functional Performance in Veterans with Chronic Obstructive Pulmonary Disease.

INTRODUCTION: An early detection of impaired functional performance is critical to enhance symptom management for patients with chronic obstructive pulmonary disease (COPD). However, conventional functional measures based on walking assessments are often impractical for small clinics where the available space to administrate gait-based test is limited. This study examined the feasibility and effectiveness of an upper-extremity frailty meter (FM) in identifying digital measures of functional performance and assessing frailty in COPD patients. METHODS: Forty-eight patients with COPD (age = 68.8 ± 8.5 years, body mass index [BMI] = 28.7 ± 5.8 kg/m2) and 49 controls (age = 70.0 ± 3.0 years, BMI = 28.7 ± 6.1 kg/m2) were recruited. All participants performed a 20-s repetitive elbow flexion-extension test using a wrist-worn FM sensor. Functional performance was quantified by FM metrics, including speed (slowness), range of motion (rigidity), power (weakness), flexion and extension time (slowness), as well as speed and power reduction (exhaustion). Conventional functional measures, including timed-up-and-go test, gait and balance tests, and 5 repetition sit-to-stand test, were also performed. RESULTS: Compared to controls, COPD patients exhibited deteriorated performances in all conventional functional assessments (d = 0.64-1.26, p < 0.010) and all FM metrics (d = 0.45-1.54, p < 0.050). FM metrics had significant agreements with conventional assessment tools (|r| = 0.35-0.55, p ≤ 0.001). FM metrics efficiently identified COPD patients with pre-frailty and frailty (d = 0.82-2.12, p < 0.050). CONCLUSION: This study proposes the feasibility of using a 20-s repetitive elbow flexion-extension test and wrist-worn sensor-derived frailty metrics as an alternative and practical solution to evaluate functional performance in COPD patients. Its simplicity and low risk for test administration may also facilitate its application for remote patient monitoring. Furthermore, in settings where the administration of walking test is impractical, for example, when ventilator support is needed or space is limited, FM may be used as an alternative solution. Future studies are encouraged to use the FM to quantitatively monitor the progressive decline in functional performance and quantify outcomes of rehabilitation interventions.

Principles of pediatric lupus nephritis in a prospective contemporary multi-center cohort.

Lupus nephritis (LN) is a life-threatening manifestation of systemic lupus erythematosus (SLE) and is more common in children than adults. The epidemiology and management of childhood-onset SLE (cSLE) have changed over time, prompting the need to reassess expected outcomes. The purpose of this study is to use the Childhood Arthritis and Rheumatology Research Alliance (CARRA) prospective registry to validate historical principles of LN in a contemporary, real-world cohort. After an extensive literature review, six principles of LN in cSLE were identified. The CARRA registry was queried to evaluate these principles in determining the rate of LN in cSLE, median time from cSLE diagnosis to LN, short-term renal outcomes, and frequency of rituximab as an induction therapy. Of the 677 cSLE patients in the CARRA registry, 32% had documented LN. Decline in kidney function was more common in Black cSLE patients than non-Black patients (p = 0.04). Black race was associated with worse short-term renal outcomes. In short-term follow up, most children with LN had unchanged or improved kidney function, and end stage kidney disease (ESKD) was rare. Ongoing follow-up of cSLE patients in the CARRA registry will be necessary to evaluate long-term outcomes to inform risk, management, and prognosis of LN in cSLE.

Toward Remote Assessment of Physical Frailty Using Sensor-based Sit-to-stand Test.

BACKGROUND: Traditional physical frailty (PF) screening tools are resource intensive and unsuitable for remote assessment. In this study, we used five times sit-to-stand test (5×STS) with wearable sensors to determine PF and three key frailty phenotypes (slowness, weakness, and exhaustion) objectively. MATERIALS AND METHODS: Older adults (n = 102, age: 76.54 ± 7.72 y, 72% women) performed 5×STS while wearing sensors attached to the trunk and bilateral thigh and shank. Duration of 5×STS was recorded using a stopwatch. Seventeen sensor-derived variables were analyzed to determine the ability of 5×STS to distinguish PF, slowness, weakness, and exhaustion. Binary logistic regression was used, and its area under curve was calculated. RESULTS: A strong correlation was observed between sensor-based and manually-recorded 5xSTS durations (r = 0.93, P < 0.0001). Sensor-derived variables indicators of slowness (5×STS duration, hip angular velocity range, and knee angular velocity range), weakness (hip power range and knee power range), and exhaustion (coefficient of variation (CV) of hip angular velocity range, CV of vertical velocity range, and CV of vertical power range) were different between the robust group and prefrail/frail group (P < 0.05) with medium to large effect sizes (Cohen's d = 0.50-1.09). The results suggested that sensor-derived variables enable identifying PF, slowness, weakness, and exhaustion with an area under curve of 0.861, 0.865, 0.720, and 0.723, respectively. CONCLUSIONS: Our study suggests that sensor-based 5×STS can provide digital biomarkers of PF, slowness, weakness, and exhaustion. The simplicity, ease of administration in front of a camera, and safety of 5xSTS may facilitate a remote assessment of PF, slowness, weakness, and exhaustion via telemedicine.

Digital Biomarkers of Physical Frailty and Frailty Phenotypes Using Sensor-Based Physical Activity and Machine Learning.

Remote monitoring of physical frailty is important to personalize care for slowing down the frailty process and/or for the healthy recovery of older adults following acute or chronic stressors. Taking the Fried frailty criteria as a reference to determine physical frailty and frailty phenotypes (slowness, weakness, exhaustion, inactivity), this study aimed to explore the benefit of machine learning to determine the least number of digital biomarkers of physical frailty measurable from a pendant sensor during activities of daily living. Two hundred and fifty-nine older adults were classified into robust or pre-frail/frail groups based on the physical frailty assessments by the Fried frailty criteria. All participants wore a pendant sensor at the sternum level for 48 h. Of seventeen sensor-derived features extracted from a pendant sensor, fourteen significant features were used for machine learning based on logistic regression modeling and a recursive feature elimination technique incorporating bootstrapping. The combination of percentage time standing, percentage time walking, walking cadence, and longest walking bout were identified as optimal digital biomarkers of physical frailty and frailty phenotypes. These findings suggest that a combination of sensor-measured exhaustion, inactivity, and speed have potential to screen and monitor people for physical frailty and frailty phenotypes.

Digital Biomarker Representing Frailty Phenotypes: The Use of Machine Learning and Sensor-Based Sit-to-Stand Test.

Since conventional screening tools for assessing frailty phenotypes are resource intensive and unsuitable for routine application, efforts are underway to simplify and shorten the frailty screening protocol by using sensor-based technologies. This study explores whether machine learning combined with frailty modeling could determine the least sensor-derived features required to identify physical frailty and three key frailty phenotypes (slowness, weakness, and exhaustion). Older participants (n = 102, age = 76.54 ± 7.72 years) were fitted with five wearable sensors and completed a five times sit-to-stand test. Seventeen sensor-derived features were extracted and used for optimal feature selection based on a machine learning technique combined with frailty modeling. Mean of hip angular velocity range (indicator of slowness), mean of vertical power range (indicator of weakness), and coefficient of variation of vertical power range (indicator of exhaustion) were selected as the optimal features. A frailty model with the three optimal features had an area under the curve of 85.20%, a sensitivity of 82.70%, and a specificity of 71.09%. This study suggests that the three sensor-derived features could be used as digital biomarkers of physical frailty and phenotypes of slowness, weakness, and exhaustion. Our findings could facilitate future design of low-cost sensor-based technologies for remote physical frailty assessments via telemedicine.

Decrease in Mobility during the COVID-19 Pandemic and Its Association with Increase in Depression among Older Adults: A Longitudinal Remote Mobility Monitoring Using a Wearable Sensor.

BACKGROUND: Social isolation during COVID-19 may negatively impact older adults' wellbeing. To assess its impact, we measured changes in physical activity and sleep among community-dwelling older adults, from pre-to post-pandemic declaration. METHOD: Physical activity and sleep in older adults (n = 10, age = 77.3 ± 1.9 years, female = 40%) were remotely assessed within 3-month pre-to 6-month post-pandemic declaration using a pendant-wearable system. Depression was assessed pre-and post-pandemic declaration using the Center for Epidemiologic Studies Depression scale and was compared with 48 h continuous physical activity monitoring data before and during pandemic. RESULTS: Compared to pre-pandemic, post-pandemic time spent in standing declined by 32.7% (Cohen's d = 0.78, p < 0.01), walking by 52.2% (d = 1.1, p < 0.01), step-counts by 55.1% (d = 1.0, p = 0.016), and postural transitions by 44.6% (d = 0.82, p = 0.017) with increase in sitting duration by 20.5% (d = 0.5, p = 0.049). Depression symptoms increased by 150% (d = 0.8, p = 0.046). Interestingly, increase in depression was significantly correlated with unbroken-prolong sitting bout (ρ = 0.677, p = 0.032), cadence (ρ = -0.70, p = 0.024), and sleep duration (ρ = -0.72, p = 0.019). CONCLUSION: This is one of the early longitudinal studies highlighting adverse effect of the pandemic on objectively assessed physical activity and sleep in older adults. Our observations showed need for timely intervention to mitigate hard to reverse consequences of decreased physical activity such as depression.

Signal to Noise Ratio as a Cross-Platform Metric for Intraoperative Fluorescence Imaging.

Real-time molecular imaging to guide curative cancer surgeries is critical to ensure removal of all tumor cells; however, visualization of microscopic tumor foci remains challenging. Wide variation in both imager instrumentation and molecular labeling agents demands a common metric conveying the ability of a system to identify tumor cells. Microscopic disease, comprised of a small number of tumor cells, has a signal on par with the background, making the use of signal (or tumor) to background ratio inapplicable in this critical regime. Therefore, a metric that incorporates the ability to subtract out background, evaluating the signal itself relative to the sources of uncertainty, or noise is required. Here we introduce the signal to noise ratio (SNR) to characterize the ultimate sensitivity of an imaging system and optimize factors such as pixel size. Variation in the background (noise) is due to electronic sources, optical sources, and spatial sources (heterogeneity in tumor marker expression, fluorophore binding, and diffusion). Here, we investigate the impact of these noise sources and ways to limit its effect on SNR. We use empirical tumor and noise measurements to procedurally generate tumor images and run a Monte Carlo simulation of microscopic disease imaging to optimize parameters such as pixel size.

Evaluating the impact of axillary dissection on recurrence-free survival by extent of nodal disease in invasive lobular carcinoma of the breast.

PURPOSE: Clinical trials have shown that axillary lymph node dissection (ALND) can be avoided for many breast cancer patients with limited nodal involvement. However, whether its omission is safe for those with invasive lobular carcinoma (ILC) is still questioned. We sought to evaluate the impact of ALND on recurrence-free survival (RFS) by extent of nodal disease in patients with ILC. METHODS: We performed a retrospective, cross-sectional analysis of ILC patients treated between 1990 and 2019 at our institution. Patients underwent either breast conservation surgery (BCS) or mastectomy. We used univariate and multivariate statistics in Stata 14.2 to evaluate associations between extent of axillary surgery and time to recurrence stratified by nodal burden. RESULTS: Of 520 cases, 387 (78.4%) were node negative, 74 (14.9%) had 1-2 positive nodes, and 59 (11.4%) had three or more positive nodes. Most patients (93.3%) had hormone receptor-positive disease, and 94.8% had low or intermediate-grade tumors. The rate of ALND significantly decreased over time (p < 0.002). Using a multivariate model, there was no significant difference in RFS estimates based on receipt of ALND (HR = 0.53, 95% CI 0.17-1.64, p = 0.27), which also held true for patients with 1-2 positive nodes using a test of interaction (HR = 0.91, 95% CI 0.12-6.76, p = 0.92). CONCLUSIONS: These findings support the safety of omitting ALND in selected patients with ILC. Further studies of axillary management in ILC and imaging tools to predict nodal involvement and therapeutic response are warranted.

Inflammageing in the cardiovascular system: mechanisms, emerging targets, and novel therapeutic strategies.

In the elderly population, pathological inflammation has been associated with ageing-associated diseases. The term 'inflammageing', which was used for the first time by Franceschi and co-workers in 2000, is associated with the chronic, low-grade, subclinical inflammatory processes coupled to biological ageing. The source of these inflammatory processes is debated. The senescence-associated secretory phenotype (SASP) has been proposed as the main origin of inflammageing. The SASP is characterised by the release of inflammatory cytokines, elevated activation of the NLRP3 inflammasome, altered regulation of acetylcholine (ACh) nicotinic receptors, and abnormal NAD+ metabolism. Therefore, SASP may be 'druggable' by small molecule therapeutics targeting those emerging molecular targets. It has been shown that inflammageing is a hallmark of various cardiovascular diseases, including atherosclerosis, hypertension, and adverse cardiac remodelling. Therefore, the pathomechanism involving SASP activation via the NLRP3 inflammasome; modulation of NLRP3 via α7 nicotinic ACh receptors; and modulation by senolytics targeting other proteins have gained a lot of interest within cardiovascular research and drug development communities. In this review, which offers a unique view from both clinical and preclinical target-based drug discovery perspectives, we have focused on cardiovascular inflammageing and its molecular mechanisms. We have outlined the mechanistic links between inflammageing, SASP, interleukin (IL)-1ß, NLRP3 inflammasome, nicotinic ACh receptors, and molecular targets of senolytic drugs in the context of cardiovascular diseases. We have addressed the 'druggability' of NLRP3 and nicotinic α7 receptors by small molecules, as these proteins represent novel and exciting targets for therapeutic interventions targeting inflammageing in the cardiovascular system and beyond.

PERK/eIF2α signaling inhibits HIF-induced gene expression during the unfolded protein response via YB1-dependent regulation of HIF1α translation.

HIF1α (hypoxia inducible factor 1α) is the central regulator of the cellular response to low oxygen and its activity is deregulated in multiple human pathologies. Consequently, given the importance of HIF signaling in disease, there is considerable interest in developing strategies to modulate HIF1α activity and down-stream signaling events. In the present study we find that under hypoxic conditions, activation of the PERK branch of the unfolded protein response (UPR) can suppress the levels and activity of HIF1α by preventing efficient HIF1α translation. Activation of PERK inhibits de novo HIF1α protein synthesis by preventing the RNA-binding protein, YB-1, from interacting with the HIF1α mRNA 5'UTR. Our data indicate that activation of the UPR can sensitise tumor cells to hypoxic stress, indicating that chemical activation of the UPR could be a strategy to target hypoxic malignant cancer cells.