Association Between Depression Symptoms and Disability Outcomes in Older Adults at Risk of Mobility Decline.

Objective: To assess the association between depression symptoms and physical functioning and participation in daily life over 2 years in older adults at risk of mobility decline. Design: A secondary analysis of 2-year observational data from the Boston Rehabilitative Impairment Study of the Elderly. Setting: Nine primary care clinics within a single health care system. Participants: Participants (N=432; mean age ± SD, 76.6±7.0y; range, 65-96y; 67.7% women) were community-dwelling adults (>65y) at risk of mobility decline. Interventions: Not applicable. Main Outcome Measures: Secondary data analyses of the Late Life Function and Disability Instrument (primary outcome), Short Physical Performance Battery (secondary outcome), and Patient Health Questionnaire-9 (PHQ-9) (predictor). Measures were administered at baseline, 12 months, and 24 months. Participants completed a self-report survey asking about 16 medical comorbidities, and demographic information was collected at baseline. Results: Participants had an average ± SD PHQ-9 score of 1.3±3.1, ranging from 0 to 24 at baseline. Twenty-nine percent of participants reported a history of depression. Greater depression symptoms were associated with lower physical functioning (unstandardized beta [B]=-0.14, SE=0.05, P=.011) and restricted participation (frequency subscale: B=-0.21, SE=0.11, P=.001; limitation subscale: B=-0.45, SE=0.04, P<.001) cross-sectionally over 2 years. PHQ-9 was not significantly associated with the rate of change in Late Life Function and Disability Instrument score over 2 years. Conclusions: Treating depression in primary care may be an important strategy for reducing the burden of functional limitations and participation restrictions at any 1 time. Further research is needed on treatment models to cotarget depression and physical functioning among at-risk older adults.

Feasibility and Preliminary Efficacy of Virtual Rehabilitation for Middle and Older Aged Veterans With Mobility Limitations: A Pilot Study.

Objective: To evaluate the feasibility and preliminary efficacy of the transition of an outpatient center-based rehabilitation program for middle and older aged Veterans with mobility limitations to a tele-health platform. Design: Non-randomized non-controlled pilot study including 10 treatment sessions over 8 weeks and assessments at baseline, 8, 16, and 24 weeks. Setting: VA Boston Healthcare System ambulatory care between August 2020 and March 2021. Participants: Veterans aged 50 years and older (n=178) were contacted via letter to participate, and 21 enrolled in the study. Intervention: Participants had virtual intervention sessions with a physical therapist who addressed impairments linked to mobility decline and a coaching program promoting exercise adherence. Main Outcome Measures: Ambulatory Measure for Post-Acute Care (AM-PAC), Phone-FITT, and Self-Efficacy for Exercise (SEE) scale. Results: Completers (n=14, mean age 74.9 years, 86% men) averaged 9.8 out of 10 visits. Changes in the Ambulatory Measure for Post-Acute Care (AM-PAC) exceeded clinically meaningful change after 8 and 24 weeks of treatment, at 4.1 units and 4.3 units respectively. Statistically significant improvements from baseline in AM-PAC and Phone-FITT were observed after 8 weeks of treatment and at 24 weeks. No significant changes were observed in exercise self-efficacy. Conclusions: In this group of veterans, telerehab was feasible and demonstrated preliminary efficacy in both mobility and physical activity, thus justifying further investigation in a larger scale clinical trial.

The role of unit cohesion and perceived resilience in substance use disorder.

Soldiers have high rates of substance use disorders (SUD), often in the aftermath of stressors experienced during military deployments. There are several factors that protect against SUD. For example, individual factors like perceived resilience and group factors such as unit cohesion may make someone less likely to abuse substances. However, there is little research on the differential influence of these resilience factors on SUD over and above deployment stressors. In this study, we examined the relative effects of perceived resilience, unit cohesion, and deployment stressors on SUD in a sample of 21,449 active duty and reserve soldiers from the U.S. Army (primarily White and male, mean age = 28.66, SD = 7.41) using structural equation modeling. We found that unit cohesion (ß = -.17) and perceived resilience (ß = -.16) had negative effects on SUD over and above deployment stressors. The study findings clarify research on resilience to SUD and have implications for addressing substance use in the military, specifically regarding the importance of building unit cohesion.

Ultrasound-mediated delivery of doxorubicin to the brain results in immune modulation and improved responses to PD-1 blockade in gliomas.

Given the marginal penetration of most drugs across the blood-brain barrier, the efficacy of various agents remains limited for glioblastoma (GBM). Here we employ low-intensity pulsed ultrasound (LIPU) and intravenously administered microbubbles (MB) to open the blood-brain barrier and increase the concentration of liposomal doxorubicin and PD-1 blocking antibodies (aPD-1). We report results on a cohort of 4 GBM patients and preclinical models treated with this approach. LIPU/MB increases the concentration of doxorubicin by 2-fold and 3.9-fold in the human and murine brains two days after sonication, respectively. Similarly, LIPU/MB-mediated blood-brain barrier disruption leads to a 6-fold and a 2-fold increase in aPD-1 concentrations in murine brains and peritumoral brain regions from GBM patients treated with pembrolizumab, respectively. Doxorubicin and aPD-1 delivered with LIPU/MB upregulate major histocompatibility complex (MHC) class I and II in tumor cells. Increased brain concentrations of doxorubicin achieved by LIPU/MB elicit IFN-γ and MHC class I expression in microglia and macrophages. Doxorubicin and aPD-1 delivered with LIPU/MB results in the long-term survival of most glioma-bearing mice, which rely on myeloid cells and lymphocytes for their efficacy. Overall, this translational study supports the utility of LIPU/MB to potentiate the antitumoral activities of doxorubicin and aPD-1 for GBM.

Associations of humor, morale, and unit cohesion on posttraumatic stress disorder symptoms.

Military personnel experience many stressors during deployments that can lead to symptoms of posttraumatic stress disorder (PTSD). However, not all military personnel who are exposed to deployment stressors develop PTSD symptoms. Recent research has explored factors that contribute to military personnel resilience, a multifaceted and multidetermined construct, as a means to mitigate and prevent PTSD symptoms. Much of this research has focused on the effects of individual-level factors (e.g., use of coping strategies like humor, the morale of individual unit members), with some research focusing on unit-level factors (e.g., the cohesiveness of a unit). However, there is little research exploring how these factors relate to each other in mitigating or reducing PTSD symptoms. In this study, we examined the association between deployment stressors, perceived unit cohesion, morale, humor, and PTSD symptoms in a sample of 20,901 active-duty military personnel using structural equation modeling. Results indicated that perceived unit cohesion, humor, and morale were positively associated with each other and negatively associated with PTSD symptoms over and above the effect of deployment stressors. These findings highlight the influence of resilience factors on PTSD symptoms beyond their substantial overlap and have implications for future research as well as the potential development of interventions for military personnel.

Comprehensive safety assessment of serendipity berry sweet protein produced from Komagataella phaffii.

Serendipity berry plant (Dioscoreophyllum cumminsii (Stapf) Diels) is the source of a naturally sweet protein referred to as monellin. The safety of serendipity berry sweet protein (SBSP) containing single polypeptide monellin (MON) expressed in Komagataella phaffii (formerly Pichia pastoris) and produced via precision fermentation was examined comprehensively through assessments of in vitro and in silico protein digestion, in silico allergenicity, in vitro genotoxicity (reverse mutation and mammalian micronucleus assays), and 14-day and 90-day oral (dietary) toxicity studies in rats. There was no indication of allergenicity for SBSP in the in silico analyses. Results from both in vitro and in silico protein digestibility assessments indicated that SBSP is digested upon ingestion and would therefore be unlikely to pose a toxigenic or allergenic risk to consumers. SBSP was non-genotoxic in in vitro assays and showed no adverse effects in the 14-day or 90-day toxicity studies up to the highest dose tested. The 90-day toxicity study supports a NOAEL for SBSP of 1954 mg/kg bw/day, which corresponds to a NOAEL for MON of 408 mg/kg bw/day.

Pangenome reconstruction in rats enhances genotype-phenotype mapping and novel variant discovery.

The HXB/BXH family of recombinant inbred rat strains is a unique genetic resource that has been extensively phenotyped over 25 years, resulting in a vast dataset of quantitative molecular and physiological phenotypes. We built a pangenome graph from 10x Genomics Linked-Read data for 31 recombinant inbred rats to study genetic variation and association mapping. The pangenome includes 0.2Gb of sequence that is not present the reference mRatBN7.2, confirming the capture of substantial additional variation. We validated variants in challenging regions, including complex structural variants resolving into multiple haplotypes. Phenome-wide association analysis of validated SNPs uncovered variants associated with glucose/insulin levels and hippocampal gene expression. We propose an interaction between Pirl1l1, chromogranin expression, TNF-α levels, and insulin regulation. This study demonstrates the utility of linked-read pangenomes for comprehensive variant detection and mapping phenotypic diversity in a widely used rat genetic reference panel.

The Effectiveness of Dance Interventions on Psychological and Cognitive Health Outcomes Compared with Other Forms of Physical Activity: A Systematic Review with Meta-analysis.

BACKGROUND: Physical activity is known to improve psychological and cognitive outcomes. Learning dance sequences may challenge cognition, partnered or group dance may benefit social interactions, and the artistic aspect may improve psychological wellbeing. Dance is an equally effective form of physical activity compared with other structured physical activities to improve physical health, but it is unclear how effective dance could be for psychological and cognitive outcome measures. OBJECTIVE: To systematically review the literature on the effectiveness of structured dance interventions, compared with structured exercise programmes, on psychological and cognitive outcomes across the lifespan. METHODS: Eight databases were searched from earliest records to July 2022. Studies investigating a dance intervention lasting ≥ 4 weeks, including psychological and/or cognitive health outcomes, and having a structured exercise comparison group were included. Screening and data extraction were performed by two independent reviewers at all stages. All reviewer disagreements were resolved by the primary author. Where appropriate, meta-analysis was performed, or an effect size estimate generated. RESULTS: Of 21,737 records identified, 27 studies met the inclusion criteria. Total sample size of included studies was 1392 (944 females, 418 males, 30 unreported). Dance was equally as effective as other physical activity interventions in improving quality of life for people with Parkinson's disease [mean difference 3.09; 95% confidence interval (CI) - 2.13 to 8.30; p = 0.25], reducing anxiety (standardised mean difference 2.26; 95% CI - 2.37 to 6.90; p = 0.34), and improving depressive symptoms (standardised mean difference 0.78; 95% CI - 0.92 to 2.48; p = 0.37). Preliminary evidence found dance to be superior to other physical activity interventions to improve motivation, aspects of memory, and social cognition and to reduce distress. Preliminary evidence found dance to be inferior to other physical activity interventions to improve stress, self-efficacy and language fluency. CONCLUSION: Undertaking structured dance of any genre is generally equally and occasionally more effective than other types of structured exercise for improving a range of psychological and cognitive outcomes. TRIAL REGISTRATION: PROSPERO: CRD42018099637.

Depression and Anxiety in Long-Term Care Residents During the COVID-19 Pandemic: The Influence of Telehealth Availability, Cognitive Status, and Trauma History.

OBJECTIVES: The present study investigates the impact of disrupted mental health services during the COVID-19 pandemic on depression and anxiety symptoms in long-term care (LTC) residents. METHODS: The study examined clinical data from 5,645 residents who received at least two psychological services in a long-term care (LTC) or assisted living (AL) setting between March 2019 and March 2021. A series of multiple regressions were run to explore the effects of the COVID-19 shutdown on depression and anxiety symptoms while examining the effects of COVID-19-related facility closure and facility telehealth capabilities. Follow-up regression analyses explored the impact of cognitive impairment and positive trauma history on depression and anxiety symptoms. RESULTS: Post-COVID levels of anxiety and depression were higher for residents with higher levels of pre-COVID anxiety and depression. The interaction between facility closure and availability of telehealth services and trauma history predicted self-report anxiety symptoms. Clinician-observed anxiety symptoms were predicted by cognitive impairment. Residents with a history of trauma had an increase in self-reported anxiety symptoms. CONCLUSIONS: Telehealth appeared to mitigate anxiety during the pandemic for residents with higher pre-COVID anxiety. CLINICAL IMPLICATIONS: For those individuals with severe anxiety, results suggest the importance of ensuring that mental health services are available to mitigate symptoms via telehealth when infection control disrupts the usual delivery of treatment.

Classical Ballet for Women Aged Over 50 Years: Investigating Balance, Strength, and Range of Motion.

Background: Regular exercise can mitigate the loss of strength, balance, and flexibility that contribute to age-related decline in physical function and mobility. However, traditional exercise interventions often report poor adherence rates. There is growing interest in classical ballet as an enjoyable exercise modality for adults in middle to late age. Classical ballet requires muscular strength, coordination, and flexibility. The current study investigated a classical ballet intervention on the balance, physical function, and range of motion of women aged over 50 years. Methods: Twenty-two healthy female participants (aged 56.2 (4.5) years (mean (SD)) completed a 10-week ballet intervention. Results: This single-arm study showed significant improvements (p<.05) in lower limb strength (measured by 5 times sit-to-stand and forward leap) and high adherence rates (95% adherence for participants who completed the intervention). No adverse events were reported. Improvements in balance were reported in the left leg only (as measured by center of pressure ellipse area in the parallel retiré condition). Conclusions: These results allude to the positive effects of ballet training on strength and balance in adults aged 50 years and over. High adherence rates suggest that ballet training was enjoyed and may thus be a long-term exercise modality for this population. Although this study was a single-arm design, it suggests promising results for future research wishing to evaluate the effectiveness of classical ballet training using randomized controlled trial designs.

Trends in Chiropractic Care and Physical Rehabilitation Use Among Adults with Low Back Pain in the United States, 2002 to 2018.

BACKGROUND: While nonpharmacologic treatments are increasingly endorsed as first-line therapy for low back pain (LBP) in clinical practice guidelines, it is unclear if use of these treatments is increasing or equitable. OBJECTIVE: Examine national trends in chiropractic care and physical rehabilitation (occupational/physical therapy (OT/PT)) use among adults with LBP. DESIGN/SETTING: Serial cross-sectional analysis of the National Health Interview Survey, 2002 to 2018. PARTICIPANTS: 146,087 adults reporting LBP in prior 3 months. METHODS: We evaluated the association of survey year with chiropractic care or OT/PT use in prior 12 months. Logistic regression with multilevel linear splines was used to determine if chiropractic care or OT/PT use increased after the introduction of clinical guidelines. We also examined trends in use by age, sex, race, and ethnicity. When trends were similar over time, we present differences by these demographic characteristics as unadjusted ORs using data from all respondents. RESULTS: Between 2002 and 2018, less than one-third of adults with LBP reported use of either chiropractic care or OT/PT. Rates did not change until 2016 when uptake increased with the introduction of clinical guidelines (2016-2018 vs 2002-2015, OR = 1.15; 95% CI: 1.10-1.19). Trends did not differ significantly by sex, race, or ethnicity (p for interactions > 0.05). Racial and ethnic disparities in chiropractic care or OT/PT use were identified and persisted over time. For example, compared to non-Hispanic adults, either chiropractic care or OT/PT use was lower among Hispanic adults (combined OR = 0.62, 95% CI: 0.65-0.73). By contrast, compared to White adults, Black adults had similar OT/PT use (OR = 0.98; 95% CI: 0.94-1.03) but lower for chiropractic care use (OR = 0.50; 95% CI: 0.47-0.53). CONCLUSIONS: Although use of chiropractic care or OT/PT for LBP increased after the introduction of clinical guidelines in 2016, only about a third of US adults with LBP reported using these services between 2016 and 2018 and disparities in use have not improved.

Defining Clinically Meaningful Cut Points for Leg Power Impairment Using Physical Performance in Older Adults: A Secondary Analysis From Boston RISE.

OBJECTIVE: To identify clinically meaningful thresholds of leg power impairment identified by the stair climb power test (SCPT). DESIGN: Cross-sectional analysis using the baseline data from an observational cohort study. SETTING: The Boston Rehabilitative Impairment Study of the Elderly. PARTICIPANTS: Community-dwelling older adults (N=413). MAIN OUTCOME MEASURES: SCPT and the Short Physical Performance Battery (SPPB). RESULTS: Using the receiver operating characteristic curves and Youden's J statistics, the optimal threshold for the SCPT associated with mobility limitation as defined by an SPPB score ≤9 was 3.07 Watts/kg for men with a sensitivity of 74%, a specificity of 73% and, an area under the curve (AUC) value of 0.78. For women, the optimal threshold was 2.59 Watts/kg with a sensitivity of 83%, a specificity of 69%, and an AUC value of 0.81. The classification and regression tree sensitivity analysis demonstrated similar thresholds, 2.88 Watts/kg and 2.53 Watts/kg for men and women, respectively. CONCLUSIONS: The study identified clinically meaningful thresholds of impairment for the SCPT for mobility limited older primary care patients. These thresholds may be used to inform rehabilitation care to improve functional mobility of older adults and should be validated in larger more representative clinical trials.

Magnetically controlled cyclic microscale deformation of in vitro cancer invasion models.

Mechanical cues play an important role in the metastatic cascade of cancer. Three-dimensional (3D) tissue matrices with tunable stiffness have been extensively used as model systems of the tumor microenvironment for physiologically relevant studies. Tumor-associated cells actively deform these matrices, providing mechanical cues to other cancer cells residing in the tissue. Mimicking such dynamic deformation in the surrounding tumor matrix may help clarify the effect of local strain on cancer cell invasion. Remotely controlled microscale magnetic actuation of such 3D in vitro systems is a promising approach, offering a non-invasive means for in situ interrogation. Here, we investigate the influence of cyclic deformation on tumor spheroids embedded in matrices, continuously exerted for days by cell-sized anisotropic magnetic probes, referred to as µRods. Particle velocimetry analysis revealed the spatial extent of matrix deformation produced in response to a magnetic field, which was found to be on the order of 200 µm, resembling strain fields reported to originate from contracting cells. Intracellular calcium influx was observed in response to cyclic actuation, as well as an influence on cancer cell invasion from 3D spheroids, as compared to unactuated controls. Furthermore, RNA sequencing revealed subtle upregulation of certain genes associated with migration and stress, such as induced through mechanical deformation, for spheroids exposed to actuation vs. controls. Localized actuation at one side of a tumor spheroid tended to result in anisotropic invasion toward the µRods causing the deformation. In summary, our approach offers a strategy to test and control the influence of non-invasive micromechanical cues on cancer cell invasion and metastasis.

Veteran's Attitudes and Knowledge of End-of-Life Care: A Pilot Study Using a Mixed Methods Approach.

Veterans make up a quarter of the deaths in the United States (US). However, little is known about their knowledge and preferences about end-of-life care and pain management. Given this, we were interested in how veterans' military experiences impact their end-of-life experiences and attitudes. Our exploratory study addressed the knowledge and perceptions of hospice and pain management at the end of life. The quantitative aspect was a survey using descriptive statistics that used a small (n = 14) subgroup from a randomly selected sample in the continental US. A small population-based sample (N = 123) used a blended sampling frame of randomly selected validated cell phone and landline numbers. The qualitative aspect examined eight targeted interviews of urban dwelling older veterans over age 60 residing in Northeast Ohio to get a deeper understanding of their knowledge and attitudes toward end-of-life care. Our findings suggest that veterans did not understand the difference between hospice and palliative care and expressed concerns regarding pain medication use at the end of life. Future research examining the concept of stoicism at the end of life among veterans and educational interventions are needed.

Association of potato consumption with calcified atherosclerotic plaques in the coronary arteries: The NHLBI Family Heart Study.

BACKGROUND AND AIMS: While the association of potato consumption with risk factors for coronary artery disease has been inconsistent, no data are available in the literature on the influence of potato consumption on subclinical disease. Thus, we sought to examine whether baked/mashed potato consumption is associated with calcified atherosclerotic plaques in the coronary arteries. METHODS AND RESULTS: In a cross-sectional design, we studied 2208 participants of the NHLBI Family Heart Study. These subjects were selected based on their elevated cardiovascular disease risk compared to the general population. Potato consumption was assessed by a semi-quantitative food frequency questionnaire. We defined prevalent CAC using an Agatston score of at least 100 and fitted generalized estimating equations to calculate prevalence odds ratios of CAC. Mean age at initial clinic visit was 58.2 years and 55% were female. Median consumption of potatoes was 2-4/week. There was no statistically significant association between frequency of potato consumption and prevalent CAC: odds ratios (95% CI) for CAC were 1.0 (reference), 0.85 (0.56-1.30), 0.85 (0.58-1.26), and 0.95 (0.60-1.53) among subjects reporting potato consumption of <1/week, 1/week, 2-4/week, and 5+/week, respectively (p for linear trend 0.83), adjusting for age, sex, BMI, smoking, exercise, diabetes, hypertension, total calories, prevalent coronary heart disease, income, education, and daily red meat intake. CONCLUSIONS: We found no significant association between baked/mashed potato consumption and CAC in older adults. STUDY REGISTRATION NUMBER: NCT00005136. Study registration date: 5/25/2000.

Evaluating the effect of upper-body morbidity on quality of life following primary breast cancer treatment: a systematic review and meta-analysis.

PURPOSE: Improvements in breast cancer management continue to increase survival and life expectancy after treatment. Yet the adverse effects of treatment may persist long term, threatening physical, psychological, and social wellbeing, leading to impaired quality of life (QOL). Upper-body morbidity (UBM) such as pain, lymphoedema, restricted shoulder range of motion (ROM), and impaired function are widely reported after breast cancer treatment, but evidence demonstrating its impact on QOL is inconsistent. Therefore, the aim of the study was to conduct a systematic review and meta-analysis evaluating the effect of UBM on QOL following primary breast cancer treatment. METHODS: The study was prospectively registered on PROSPERO (CRD42020203445). CINAHL, Embase, Emcare, PsycInfo, PubMed/Medline, and SPORTDiscus databases were searched for studies reporting QOL in individuals with and without UBM following primary breast cancer treatment. Primary analysis determined the standardised mean difference (SMD) in physical, psychological, and social wellbeing scores between UBM + /UBM - groups. Secondary analyses identified differences in QOL scores between groups, according to questionnaire. RESULTS: Fifty-eight studies were included, with 39 conducive to meta-analysis. Types of UBM included pain, lymphoedema, restricted shoulder ROM, impaired upper-body function, and upper-body symptoms. UBM + groups reported poorer physical (SMD = - 0.99; 95%CI = - 1.26, - 0.71; p < 0.00001), psychological (SMD = - 0.43; 95%CI = - 0.60, - 0.27; p < 0.00001), and social wellbeing (SMD = - 0.62; 95%CI = - 0.83, - 0.40; p < 0.00001) than UBM - groups. Secondary analyses according to questionnaire showed that UBM + groups rated their QOL poorer or at equal to, UBM - groups across all domains. CONCLUSIONS: Findings demonstrate the significant, negative impact of UBM on QOL, pervading physical, psychological, and social domains. IMPLICATIONS FOR CANCER SURVIVORS: Efforts to assess and minimise the multidimensional impact of UBM are warranted to mitigate impaired QOL after breast cancer.

Repeated blood-brain barrier opening with an implantable ultrasound device for delivery of albumin-bound paclitaxel in patients with recurrent glioblastoma: a phase 1 trial.

BACKGROUND: Low-intensity pulsed ultrasound with concomitant administration of intravenous microbubbles (LIPU-MB) can be used to open the blood-brain barrier. We aimed to assess the safety and pharmacokinetics of LIPU-MB to enhance the delivery of albumin-bound paclitaxel to the peritumoural brain of patients with recurrent glioblastoma. METHODS: We conducted a dose-escalation phase 1 clinical trial in adults (aged ≥18 years) with recurrent glioblastoma, a tumour diameter of 70 mm or smaller, and a Karnofsky performance status of at least 70. A nine-emitter ultrasound device was implanted into a skull window after tumour resection. LIPU-MB with intravenous albumin-bound paclitaxel infusion was done every 3 weeks for up to six cycles. Six dose levels of albumin-bound paclitaxel (40 mg/m2, 80 mg/m2, 135 mg/m2, 175 mg/m2, 215 mg/m2, and 260 mg/m2) were evaluated. The primary endpoint was dose-limiting toxicity occurring during the first cycle of sonication and albumin-bound paclitaxel chemotherapy. Safety was assessed in all treated patients. Analyses were done in the per-protocol population. Blood-brain barrier opening was investigated by MRI before and after sonication. We also did pharmacokinetic analyses of LIPU-MB in a subgroup of patients from the current study and a subgroup of patients who received carboplatin as part of a similar trial (NCT03744026). This study is registered with ClinicalTrials.gov, NCT04528680, and a phase 2 trial is currently open for accrual. FINDINGS: 17 patients (nine men and eight women) were enrolled between Oct 29, 2020, and Feb 21, 2022. As of data cutoff on Sept 6, 2022, median follow-up was 11·89 months (IQR 11·12-12·78). One patient was treated per dose level of albumin-bound paclitaxel for levels 1 to 5 (40-215 mg/m2), and 12 patients were treated at dose level 6 (260 mg/m2). A total of 68 cycles of LIPU-MB-based blood-brain barrier opening were done (median 3 cycles per patient [range 2-6]). At a dose of 260 mg/m2, encephalopathy (grade 3) occurred in one (8%) of 12 patients during the first cycle (considered a dose-limiting toxicity), and in one other patient during the second cycle (grade 2). In both cases, the toxicity resolved and treatment continued at a lower dose of albumin-bound paclitaxel, with a dose of 175 mg/m2 in the case of the grade 3 encephalopathy, and to 215 mg/m2 in the case of the grade 2 encephalopathy. Grade 2 peripheral neuropathy was observed in one patient during the third cycle of 260 mg/m2 albumin-bound paclitaxel. No progressive neurological deficits attributed to LIPU-MB were observed. LIPU-MB-based blood-brain barrier opening was most commonly associated with immediate yet transient grade 1-2 headache (12 [71%] of 17 patients). The most common grade 3-4 treatment-emergent adverse events were neutropenia (eight [47%]), leukopenia (five [29%]), and hypertension (five [29%]). No treatment-related deaths occurred during the study. Imaging analysis showed blood-brain barrier opening in the brain regions targeted by LIPU-MB, which diminished over the first 1 h after sonication. Pharmacokinetic analyses showed that LIPU-MB led to increases in the mean brain parenchymal concentrations of albumin-bound paclitaxel (from 0·037 µM [95% CI 0·022-0·063] in non-sonicated brain to 0·139 µM [0·083-0·232] in sonicated brain [3·7-times increase], p<0·0001) and carboplatin (from 0·991 µM [0·562-1·747] in non-sonicated brain to 5·878 µM [3·462-9·980] µM in sonicated brain [5·9-times increase], p=0·0001). INTERPRETATION: LIPU-MB using a skull-implantable ultrasound device transiently opens the blood-brain barrier allowing for safe, repeated penetration of cytotoxic drugs into the brain. This study has prompted a subsequent phase 2 study combining LIPU-MB with albumin-bound paclitaxel plus carboplatin (NCT04528680), which is ongoing. FUNDING: National Institutes of Health and National Cancer Institute, Moceri Family Foundation, and the Panattoni family.

Effects of the COVID-19 Pandemic on Anxiety Symptoms in Long-Term Care Residents: A Multilevel Growth Curve Analysis.

OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has negatively impacted the mental health functioning of older adults residing in long-term care (LTC) settings. This study examines the impact of the lockdown on anxiety symptoms over time in LTC residents. DESIGN: Secondary data analysis was conducted on clinical data obtained with permission from a large behavioral health company that provides behavioral health services in long-term care (LTC) and assisted living (AL) facilities. SETTING AND PARTICIPANTS: Data were obtained from 1149 adults (mean age 72.37, 70% female) in LTC and AL facilities across the United States who were receiving psychological services 1 year prior, and 1 year after, the COVID-19 pandemic lockdown. METHODS: Changes in anxiety (measured using a clinician rating scale) over time before and after the pandemic were assessed using latent growth curve modeling with psychiatric diagnosis, psychiatric medication, and demographic factors included as covariates. RESULTS: Anxiety severity decreased over time before and after the onset of the COVID-19 pandemic. Although pandemic-level factors such as facility closure and telehealth availability did not affect anxiety over time, individual treatment factors such as obsessive compulsive disorder diagnosis, initial anxiety severity, bipolar disorder diagnosis, and prescriptions for anxiolytic and antipsychotic medications affected the trajectory of anxiety during the pandemic. CONCLUSIONS AND IMPLICATIONS: These results demonstrate that individual covariates such as diagnosis, symptom severity, and medication use impacted the trajectory of anxiety symptoms before and during the COVID-19 pandemic more strongly than pandemic-related circumstances (facility closure, telehealth availability). The impact of the COVID-19 pandemic may be better observed through treatment-relevant variables, rather than pure symptom severity. In preparation for future pandemics or other large-scale disasters potentially impacting service delivery, facilities should continue to prioritize continuity of care or a timely resumption of services attending to individual treatment factors.