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We built a Streptomyces expression system to discovery bacterial terpenoids. Though genome mining and expression of terpene BGCs, 11 terpene skeletons including 3 new ones, and 18 novel distinct terpenoids were isolated and characterized.

Objectives Social participation is known to enhance well-being. Caregiving responsibilities are more intense when caring for an older adult with than without dementia and may affect caregivers’ ability for social participation. We estimate social participation restrictions among caregivers for older persons with versus without dementia, variation within racial/ethnic group, and the mediating effect of care hours. Methods We use the 2017 National Health and Aging Trends Study (NHATS) and National Study of Caregiving (NSOC) to study family caregivers for older adults. We estimate the prevalence of social participation (e.g., visiting family/friends, religious activities, group/club activities, going out) that were important to the caregiver but missed due to caregiving. We use logistic models to test for differences in restrictions by the older adult’s dementia status overall and within race/ethnic group, adjusting for caregiver and care receiver characteristics. Results One-third of family caregivers for older adults with dementia reported restrictions due to caregiving, double the prevalence among caregivers of an older adult without dementia (33.3% vs 16.0%; p < .001). This doubling gap persisted in adjusted models (odds ratio [OR] = 2.4; p < .01) but mainly for White, non-Hispanic caregivers (OR = 3.2; p < .001). Substantially greater caregiving hours for people with versus without dementia was found (104 vs 60 hr per month), which is responsible for about 21% of the total difference in restrictions (p < .05). Discussion More time spent among caregivers of persons with versus without dementia may be an important factor undermining social participation, but hours only partially explain the gap. Future interventions should consider how to facilitate social participation among caregivers.

This chapter reviews a three-arm clinical trial, which compared the LiFE (Lifestyle-integrated Functional Exercise) program to structured strength and balance exercise and gentle flexibility exercise. Older adults, aged 70 years and above, who had a history of falls were recruited from the community and randomly assigned to one of the three exercise programs. Older adults in the LiFE program successfully integrated strength and balance exercises into their everyday activities. Significant improvements in favor of the LiFE condition were observed for fall rates, static balance, ankle strength, function, and participation. The study shows that the LiFE program is an effective alternative fall prevention program compared to traditional structured strength and balance exercise.

Tetracyclines are a class of antibiotics that exhibited potent activity against a wide range of Gram-positive and Gram-negative bacteria, yet only five members were isolated from actinobacteria, with two of them approved as clinical drugs. In this work, we developed a genome mining strategy using a TetR/MarR-transporter, a pair of common resistance enzymes in tetracycline biosynthesis, as probes to find the potential tetracycline gene clusters in the actinobacteria genome database. Further refinement using the phylogenetic analysis of chain length factors resulted in the discovery of 25 distinct tetracycline gene clusters, which finally resulted in the isolation and characterization of a novel tetracycline, hainancycline (1). Through genetic and biochemical studies, we elucidated the biosynthetic pathway of 1, which involves a complex glycosylation process. Our work discloses nature's huge capacity to generate diverse tetracyclines and expands the chemical diversity of tetracyclines.

Nonribosomal peptide synthetases (NRPSs) are modular enzymes that use a thiotemplate mechanism to assemble the peptide backbones of structurally diverse and biologically active natural products in bacteria and fungi. Unlike these canonical multi-modular NRPSs, single-module NRPS-like enzymes, which lack the key condensation (C) domain, are rare in bacteria, and have been largely unexplored to date. Here, we report the discovery of a gene cluster (gup) encoding a NRPS-like megasynthetase through genome mining. Heterologous expression of the gup cluster led to the production of two unprecedented alkaloids, guanipiperazines A and B. The NRPS-like enzyme activates two l-tyrosine molecules, reduces them to the corresponding amino aldehydes, and forms an unstable imine product. The subsequent enzymatic reduction affords piperazine, which can be morphed by a P450 monooxygenase into a highly strained compound through C–O bond formation. Further intermolecular oxidative coupling forming the C–C or C–O bond is catalyzed by another P450 enzyme. This work reveals the huge potential of NRPS-like biosynthetic gene clusters in the discovery of novel natural products., Genome mining of a NRPS-like gene cluster led to the identification of two novel alkaloids with antimicrobial activity. This work reveals the huge potential of NRPS-like biosynthetic gene clusters in the discovery of novel natural products.

Importance: Frailty is common, detrimental, and costly in later life. Interventions can reduce the risk for frailty. Objective: To assess the feasibility of a frailty prevention intervention. Design: A two-arm, prospective randomized controlled trial with blinded participant allocation and data collection at baseline and 1 wk postintervention by data collectors blinded to participant assignment. Setting: Community. Participants: Thirty community-dwelling, English-speaking, older African-Americans who were classified as prefrail were randomly recruited from a university research subject registry. Intervention: The habit formation treatment was delivered face to face during 12 weekly home-based sessions approximately 45 min in length. Outcomes and Measures: We assessed feasibility as reflected in participant recruitment, retention, session attendance, and program satisfaction. Clinical outcomes included sedentary time and dietary quality (primary) as well as frailty status, physical activity, physical function, depression, quality of life, and anthropometry (secondary). Habit formation (mechanism of change) was assessed in the treatment group only. Results: Twenty women (M age = 73.5 yr) completed the study. The recruitment rate was 69.8%, and we retained 95.2% of participants through the end of the study, with session attendance rates of 98.1% and 88.6% for the treatment and control groups, respectively, and mean acceptability scores of 30.3 and 28.0 for the treatment and control groups, respectively. Changes in primary and secondary clinical outcomes were largely in the expected direction. Conclusions and Relevance: The intervention was feasible to deliver. Although future efficacy studies are needed, our preliminary data suggest the potential of an occupational therapy intervention to reduce frailty risk. What This Article Adds: Although it may be possible to slow or prevent the progression to frailty by modifying existing habits and occupations, few occupational therapy interventions address frailty. Our data provide new and much-needed insights about the potential feasibility of an occupational therapy intervention to reduce frailty risk.

Sordarin (1) is a fungal diterpene glycoside that displays potent antifungal bioactivity through inhibition of elongation factor 2. The structures of sordarin and related compounds feature a highly rearranged tetracyclic diterpene core. In this study, we identified a concise pathway in the biosynthesis of sordarin. A diterpene cyclase (SdnA) generates the 5/8/5 cycloaraneosene framework, which is decorated by a set of P450s that catalyze a series of oxidation reactions, including hydroxylation, desaturation, and C-C bond oxidative cleavage, to give a carboxylate intermediate with a terminal alkene and a cyclopentadiene moiety. A novel Diels-Alderase SdnG catalyzes an intramolecular Diels-Alder (IMDA) reaction on this intermediate to forge the sordarin core structure. Subsequent methyl hydroxylation and glycosylation complete the biosynthesis of sordarin. Our work discloses a new strategy used by nature for the formation of the rearranged diterpene skeleton.

OBJECTIVE: Determine whether race predicts fear of falling (FOF) in older adults with a history of previous fall(s) while controlling for mobility performance, activity of daily living (ADL) independence, age, gender, and education. METHODS: We examined predictors of FOF among community-dwelling older adults using data from two longitudinal randomized controlled trials that implemented fall prevention programs for community-dwelling older adults. RESULTS: Two hundred fifty-nine participants were included in the analysis; 145 reported low FOF, while 59 reported high FOF. After controlling for mobility performance, ADL independence, and sociodemographic factors, Black older adults were more likely to report FOF (OR = 2.17) compared to White older adults. Overall, older adults with lower mobility performance/functioning scores were more likely to have FOF (OR = 0.08). CONCLUSIONS: Older adults (aged ≥65 years) who are at higher risk, based on a prior history of fall(s), are more susceptible to developing FOF, as evidenced by the older adults within this study, due to limited mobility performance and functioning. CLINICAL IMPLICATIONS: Black older adults may be at greater risk of FOF than their White counterparts based on previous fall history and level of functional mobility. Incorporating measures of objective performance-based function along with measures of psychological factors are viable methods to identify and address FOF within Black older adult populations.

Fall prevention education can increase knowledge of fall risks and promote behavior changes to help reduce the incidence of falls among older adults. Fall Prevention Bingo (FPB) was created as an e...

Importance: Informal caregivers often receive limited training and support, especially in providing assistance with toileting, a physically and emotionally demanding activity of daily living. This increases caregivers’ risk for physical injury and burnout and jeopardizes older adults’ ability to age in place. Objective: To assess the feasibility, acceptability, and preliminary efficacy of a toileting intervention using an automated bidet to reduce the amount of physical assistance required from caregivers. Design: Randomized wait-list control feasibility study. Setting: Caregiver’s home. Participants: Ten informal caregivers. Intervention: An occupational therapy intervention to educate and train caregiving dyads to use an automated bidet system. Outcomes and Measures: Feasibility was measured in terms of recruitment and retention, bidet installation, ability to operate the bidet, acceptability (a process evaluation), preliminary efficacy (physical barriers and impact on caregiver outcomes of performance, satisfaction, and self-efficacy), and adverse events. Results: All bidets were installed successfully. All caregivers reported that the intervention made toileting easier and increased their confidence. Physical barriers decreased for the treatment group. The bidet had a large effect on self-efficacy for the treatment group. Conclusions and Relevance: The results suggest that the automated bidet intervention is feasible and acceptable and can have a positive impact on caregiver outcomes when assisting with toileting. What This Article Adds: A toileting intervention using an automated bidet is feasible and acceptable for caregivers of older adults and can reduce the amount of physical assistance required from caregivers.

Monolayer transition metal dichalcogenides (TMDs) have emerged as widely accepted 2D gain materials in the field of light sources owing to their direct bandgap and high photoluminescence quantum yield. However, the monolayer medium suffers from weak emission because only a single layer of molecules can absorb the pump energy. Moreover, the material degradation when transferring these fragile materials hinders their cooperation with the optical cavity further. In this study, for the first time, a high-quality monolithic structure is developed by directly growing single-domain tungsten diselenide (WSe

Key Points Question What is the effect of a home hazard removal program on hazard of a fall in community-dwelling older adults at risk for falling? Findings This randomized clinical trial included 310 older adults. There was no difference in the primary outcome, risk of falling, between the intervention and control groups. The intervention group had a 38% reduction in falls, a secondary outcome, compared with usual care. Meaning This randomized clinical trial found that this low-cost behavioral intervention did not result in a significant difference in risk of falling or the number of home hazards removed., This randomized clinical trial examines the effectiveness of a home hazard removal program in reducing risk of falls among older adults., Importance Falls are the leading preventable cause of morbidity, mortality, and premature institutionalization for community-dwelling older adults. Objective To test the effectiveness of a behavioral intervention on fall risk among older adults receiving services from an Area Agency on Aging. Design, Setting, and Participants This randomized clinical trial examined a home hazard removal intervention in the community using a race- and sex-stratified randomization design. Older adults receiving services from the Area Agency on Aging in urban St Louis, Missouri, were assigned to a home hazard removal intervention delivered over 2 weeks with a 6-month booster or usual care control. Eligible participants were adults aged 65 years or older who did not have dementia, were at high risk for falling, and resided in the community. Enrollment occurred from January 2015 to September 2016; 12-month follow-up occurred from February 2016 to October 2017. Data were analyzed from February 2019 to July 2021. Interventions The intervention was a home hazard removal program delivered by an occupational therapist in the home that included a comprehensive clinical assessment and a tailored hazard removal plan. Usual care control consisted of annual assessments and community referral. Main Outcomes and Measures The primary outcome was the hazard of a fall over 12 months. Prespecified secondary outcomes included the rate of falls over 12 months, daily activity performance, falls self-efficacy, and self-reported quality of life. Results A total of 310 participants (mean [SD] age, 75 [7.4] years; 229 [74%] women; 161 Black participants [52%]) were randomized, with 155 participants assigned to the intervention and 155 participants assigned to usual care. Retention was 127 participants (82%) in the intervention group and 126 participants (81%) in the control group. There was no difference for our primary outcome of fall hazard (hazard ratio, 0.90; 95% CI, 0.66-1.27). There was a 38% reduction in the rate of falling in the intervention group compared with the control group (relative risk, 0.62; 95% CI, 0.40-0.95; P = .03). At 12 months, the rate of falls per person-year was 1.5 (95% CI, 1.32-1.75) in the intervention group and 2.3 (95% CI, 2.08-2.60) in the control group. There was no difference in daily activity performance (adjusted difference, −0.20; 95% CI, −0.95 to 0.55; P = .60), falls self-efficacy (adjusted difference, −0.12; 95% CI, −1.25 to 1.01; P = .84), or quality of life (adjusted difference, 0.84; 95% CI, −0.95 to 2.64; P = .35). Conclusions and Relevance This randomized clinical trial found that a brief home hazard removal program did not reduce the hazard of falls among community-dwelling older adults at high risk for falling. The intervention was effective in achieving a reduced rate of falls, a prespecified secondary outcome. This effectiveness study has the potential for delivery through the national aging services network. Trial Registration ClinicalTrials.gov Identifier: NCT02392013

Background and Objectives Older African Americans are at high risk for becoming frail in later life. Interventions can reverse or delay frailty, yet African Americans have largely been excluded from such research. Many interventions are also time- and resource-intensive, and thus inaccessible to socially disadvantaged older African Americans. We evaluated the feasibility of a low-dose frailty prevention intervention integrated with primary care among 60 community-dwelling, prefrail older African Americans aged 55+ recruited from a primary care clinic. Research Design and Methods We conducted a 2-arm randomized control trial. Participants were assigned to a 4-session intervention (1 session per month), delivered by an occupational therapist, or enhanced usual care. Feasibility criteria were set a priori at 75% for participant retention (including attrition due to death/hospitalization), 80% for session engagement, 2 participants/week for mean participant accrual, and 90% for program satisfaction. Results Participants were 65% female with an average age of 76.6 years, 51.7% lived alone and 39.1% reported Discussion and Implications The intervention was feasible to deliver. Qualitative findings from exit interviews suggested changes to the program dose, structure, and content that could improve it for future use.

Among all T and NK cell subsets, regulatory T (Treg) cells typically respond to the lowest concentrations of IL-2 due to elevated surface expression of the IL-2R alpha chain (IL2RA; CD25) and the high affinity IL-2 receptor (IL-2R) complex. This enhanced sensitivity forms the basis for low-dose (LD) IL-2 therapy for the treatment of inflammatory diseases, where efficacy correlates with increased Treg cell number and expression of functional markers. Despite strong preclinical support for this approach, moderate and variable clinical efficacy has raised concerns that adequate Treg selectivity still cannot be achieved with LD IL-2, and/or that doses are too low to stimulate effective Treg-mediated suppression within tissues. This has prompted development of IL-2 variants with greater Treg selectivity, achieved through attenuated affinity for the signaling chains of the IL-2R complex (IL2RB or CD122 and IL2RG or CD132) and, consequently, greater reliance on high CD25 levels for full receptor binding and signaling. While certain IL-2 variants have advanced to the clinic, it remains unknown if the full range of IL-2R signaling potency and Treg-selectivity observed with low concentrations of wildtype IL-2 can be sufficiently recapitulated with attenuated IL-2 muteins at high concentrations. Using a panel of engineered IL-2 muteins, we investigated how a range of IL-2R signaling intensity, benchmarked by the degree of STAT5 phosphorylation, relates to biologically relevant Treg cell responses such as proliferation, lineage and phenotypic marker expression, and suppressor function. Our results demonstrate that a surprisingly wide dynamic range of IL-2R signaling intensity leads to productive biological responses in Treg cells, with negligible STAT5 phosphorylation associating with nearly complete downstream effects such as Treg proliferation and suppressor activity. Furthermore, we show with both in vitro and humanized mouse in vivo systems that different biological responses in Treg cells require different minimal IL-2R signaling thresholds. Our findings suggest that more than minimal IL-2R signaling, beyond that capable of driving Treg cell proliferation, may be required to fully enhance Treg cell stability and suppressor function in vivo.

Introduction Stroke is a leading cause of serious, long-term disability in the United States. With shorter inpatient hospital stays, more time in rehabilitation is devoted to medical stabilization and less on skills to regain independence in daily activities. The transition home may be an opportunity for intervention focused on regaining independence. We propose an enhanced rehabilitation transition program called Community Participation Transition after Stroke. Method A prospective, randomized, single-blinded, parallel-group pilot study was completed with 15 participants to demonstrate feasibility. Findings Fidelity to the protocol was achieved: The Community Participation Transition after Stroke group received 81% of the planned minutes and 83% of the intervention visits. There was no difference between groups for healthcare utilization or falls. Adherence was 85% at three months and 71% at nine months for the home modification intervention. At 6 months, scores improved by 17.39 points for the Community Participation Transition after Stroke group, and 1.30 points for the control group. Environmental barriers decreased in both groups. Conclusion This pilot study demonstrated that it is feasible to implement a community participation intervention during the period of transitioning home from inpatient rehabilitation for stroke survivors. Additional studies are necessary to determine the efficacy of the intervention.

Falls remain the leading cause of injury, long-term disability, premature institutionalization, and injury-related mortality in the older adult population. Home modifications, when delivered by occupational therapists, can reduce falls among high-risk community-dwelling older adults by 39%. However, home-modification implementation is not standard practice in the United States. The goal of the Home Hazard Removal Program (HARP) study is to implement an evidence-based home modification intervention for older adults designed to reduce the incidence of falls through an aging services network. We will conduct a hybrid effectiveness/implementation trial of 300 older adults at risk for a fall who are randomized and followed for 12 months. Participants who are randomized to treatment will receive the home modification intervention provided by an occupational therapist in addition to usual care, defined as continued services from the area agency on aging. We will compare the effectiveness of the program and usual care using survival analysis with the time to the first fall over 12 months as the primary outcome of interest. Secondary outcomes include daily activity performance, fall self-efficacy, and health-related quality of life. Fidelity, dose, adherence, safety, cost, and health care utilization will also be examined in the implementation component of this study. This intervention targets an underserved, difficult to reach population of older adults. The tailored approach of the study intervention is a strength in improving adherence, as each recommendation is individualized to be acceptable to the participant. The effectiveness/implementation design of the study allows for rapid dissemination of results and implementation of the intervention in a United States social services agency. Clinicaltrials.gov identifier: NCT02392013 . Retrospectively registered on March 5, 2015.

Introduction Comprehensive evaluation and intervention provided by occupational therapists is effective in reducing the presence of fall hazards in the homes of older adults. The purpose of this study was to document known environmental hazards and to update a previous content analysis. A secondary goal reviewed a framework for evaluation and practice. Methods A comprehensive scoping review of published academic articles was performed from 1996 to 2019 to answer: What environmental hazards have been associated with falls in the homes of community-dwelling older adults? Data was extracted in a standardised critical appraisal worksheet and content analysis was conducted. A review of a conceptual framework for assessment and intervention was conducted by international experts (n = 6) in face-to-face interviews. Results Fourteen studies met the inclusion criteria for the scoping study. The studies reported 17 in-home environmental hazards: throw rugs/carpets, clutter, cords/wires, poorly placed light switches, items placed too low, items placed too high, no grab bars, toilet seats too low, uneven floor surfaces, slippery/wet surfaces, snowy/icy surfaces, backless/unsupportive shoes, unsteady stairs, inadequate lighting, inadequate heating/cooling, step stools without railings, and pets. Conclusion A comprehensive list of specific fall hazards in and around the homes of older adults and a guiding framework offers occupational therapists an evidence-based foundation for fall prevention efforts.

The Lifestyle-integrated Functional Exercise Program (LiFE) is proven to have high adherence rates and can significantly reduce falls, but it has not yet been implemented for diverse older adults residing in urban medically underserved (MU) areas. An exploratory sequential mixed methods study was conducted to adapt LiFE and test the adapted program’s preliminary feasibility. Focus groups with MU older adults and service providers were conducted to identify modifications. The new adapted program, Diverse Older Adults Doing LiFE (DO LiFE), was then evaluated with older adults. Thematic analysis revealed health literacy and lack of racial representation as barriers to implementing LIFE in this population. The pilot study showed that DO LiFE was feasible with good retention (89%) and high adherence (81.27%) rates. DO LiFE demonstrated preliminary feasibility for diverse MU older adults. Researchers should proceed to larger studies for translating DO LiFE from research to the community.

Intervening to change clients’ habits in the course of their everyday occupations could improve health. Habit formation interventions are an emerging area of science, however, and there is a need to better understand the current state of habit intervention research. The objective of this study is to examine the evidence related to habit formation interventions to modify health habits among adults. We performed a scoping review of peer-review articles published since January 1, 2008. The majority of the 18 studies included in the review were randomized control trials using one of two measures to assess habit change. Studies targeted a range of habits. Trial results were mixed but supportive of habit formation approaches. Through habit formation interventions, a range of everyday behaviors can become a habit. Occupational therapy professionals can use data and results generated from this review to inform the development of occupation-based habit formation treatments.

Aims: This analysis aims to identify what older adults self-report about engagement in home activities (EHA), if there is a difference between perceived and observed activity performance in the home, and what predicts EHA. Methods: Baseline data were analyzed from a randomized controlled trial of an occupational therapy fall prevention intervention with older adults age 65 and older with a fall within 6 months. A multiple linear regression model was used to compare perceived and observed activity performance. Results: Ninety-two participants (mean age 77.7 ± 7.4) were included. EHA can be predicted (F(6, 85) = 13.86, p < 0.001, R = 0.70, R2 = 0.50) by perceived activity performance (p = 0.02), fear of falling (FOF) (p < 0.001), and depression (p = 0.05). Conclusions: Perceived activity performance predicts EHA but observed activity performance does not, indicating clinicians should consider older adults' perceptions. Self-efficacy and awareness may be reasons for differences between perceived and ...

Optimization of the potency and pharmacokinetic profile of 2,3,4-trisubstituted quinoline, 4, led to the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 6a (AM-0687) and 7 (AM-1430). On the basis of their improved profile, these analogs were selected for in vivo pharmacodynamic (PD) and efficacy experiments in animal models of inflammation. The in vivo PD studies, which were carried out in a mouse pAKT inhibition animal model, confirmed the observed potency of 6a and 7 in biochemical and cellular assays. Efficacy experiments in a keyhole limpet hemocyanin model in rats demonstrated that administration of either 6a or 7 resulted in a strong dose-dependent reduction of IgG and IgM specific antibodies. The excellent in vitro and in vivo profiles of these analogs make them suitable for further development.

Frailty is more prevalent among African American (AA) older adults compared to their White counterparts. Physical activity (PA) interventions are effective to attenuate frailty progression. The Activpal is adhered to the thigh and allows unobtrusive PA measurement for up to 14 days. However, few studies have tested the acceptability and feasibility of activity trackers among older pre-frail AA. In this study, pre-frail AA older adults were asked to wear the ActivPAL tracker on their thigh for 7 consecutive days. Acceptability was measured by compliance. Feasibility was evaluated by the valid number of days and programing errors. Intraclass correlation coefficients were used to assess the agreement of light to vigorous PA level between ActivPAL and the Community Healthy Activities Model Program for Seniors (CHAMPS). In a sample of 28 pre-frail AA older adults (mean age= 73.21,SD= 9.37, 100% female), 24 completed the 7-day data tracking. Reasons for non-compliance included skin irritation (n=1), and fear of causing other health issues (n=3). The number of valid days was= 6.9 0.33 with 1 incident of programming error. The agreement between ActivPAL and CHAMPS was fair (ICC =0.57, [95%CI]= -.08 -.85) with most participants (61.6%) over-reporting PA on CHAMPS. The ActivPAL accelerometer was acceptable and feasible to use among pre-frail AA older adults. Communication prior to applying the accelerometer is crucial to prevent non-compliance. The results confirm prior studies, which suggest that older adults may over-report PA levels. ActivPAL offers a feasible and accurate approach to assess PA among older AA.

Fear of falling (FOF) is a common issue and health concern reported by adults 65 years of age and older.There is mixed evidence about potential disparity in fall incident rates due to race and FOF, and it is unclear if and under what circumstance falls rates and risks differ by racial ethnicity. The purpose of this study is to determine if race predicts fear of falling in older adults at greater risk for falls; and to examine the relationship between activities of daily living (ADL) and mobility performance measures with FOF. A cross-sectional observational study was used to examine predictors of FOF among community dwelling-older adults using data from two longitudinal randomized clinical trials (RCT). Participants (N=259) had a mean age of 75.7 ±7.4, 78.8% female, 80.64% Black, and 77.03% White or Other, with ≥ 1 fall in the last 12 months. Subjects completed a demographic profile; the Tinetti and Short Falls Efficacy Scale to assess FOF; and activities of daily living (ADL) and mobility performance scales to assess function. The chi square analysis revealed Black older adults were two times more likely to report FOF (OR = 2.17, 95% CI = 1.14, 4.15; p=.05) in comparison to White older adults. The regression analysis demonstrated that race is a significant factor to predict FOF (OR = .67, 95% CI = 1.21, 3.24; p=.05); and the descriptive analysis revealed significantly worse ADL and mobility function scores within the high FOF group.

Nearly 50% of U.S. elders are prefrail and at risk for frailty. Identifying prefrail elders and escalating care could attenuate frailty progression. Screening tools are seldom used in practice. Thus, clinical judgment may be a realistic way to ensure widespread frailty screening. No studies, however, have assessed the validity of clinicians’ judgment in identifying prefrail elders. This study explored the level of agreement between clinical judgments of frailty status and status categorizations made using the validated Paulson Lichtenberg Frailty Index (PLFI). Older Blacks (n = 202) recruited from a primary care clinic were first categorized as healthy, pre-frail, or frail using the PLFI. Next, geriatric physicians and nurses categorized participants into one of the same categories based on clinical judgment. Clinicians could use medical records to make determinations. We used Cohen’s Kappa to determine the level of agreement of both approaches. We used descriptive statistics to explore if any of the 5 PLFI indicators explained discordant categorizations. Of the 202 participants (mean age: 76.7 8.6), 52 (26%) were prefrail and 57 (28%) were frail based on the PLFI. Physicians’ judgments aligned with the PLFI in 43% of prefrail and 65.7% of frail cases. Nurse judgments aligned with the PLFI in 43.9% of prefrail and 17% of frail cases. There was slight to fair agreement between clinical judgments and PLFI (physicians Cohen’s κ = .23; Nurses Cohen’s κ = .59). No specific PLFI indicators independently explained discordant categorizations. Findings suggest that clinical judgments did not align well with PLFI categorizations.

The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of 1 (AMG319), a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation.

Importance: Forty percent to 75% of community-dwelling older adults are not able to adhere to their medication routine. A medication management assessment can correctly identify the reasons for nonadherence and the barriers contributing to it. Objective: To further develop the HOME–Rx, an in-home medication management assessment, by modifying scoring metrics, improving clinical utility, and establishing psychometric properties. Design: In Phase 1, the scoring metrics were modified, and the clinical procedures were evaluated. In Phase 2, the psychometric properties were established. Setting: The homes of older adults. Participants: Older adults who took three or more medications, managed their own medications, and lived in their own home were eligible. Older adults with cognitive impairment were ineligible. Outcomes and Measures: We assessed concurrent validity with the Performance Assessment for Self-Care Skills (PASS) and Medication Management Instrument for Deficiencies in the Elderly (MedMaIDE) and established interrater reliability. Results: The PASS was positively correlated with the HOME–Rx Performance and Safety subscales; the MedMaIDE was negatively correlated with the HOME–Rx Performance subscale and positively correlated with the Barriers subscale. Interrater reliability was excellent (ICCs = .87–1.00). Conclusions and Relevance: All relationships were as predicted: The HOME–Rx is a valid and reliable performance-based assessment that provides clinicians and researchers with a measure of older adults’ actual medication management ability in the home using their medications. The results can potentially be used to guide treatment planning and improve medication management. What This Article Adds: Occupational therapy practitioners can use the HOME–Rx to adequately determine performance problems, safety concerns, and environmental barriers and potentially to guide treatment planning and improve medication management for older adults.

Specific interactions between Src homology 2 (SH2) domain-containing proteins and the phosphotyrosine-containing counterparts play significant role in cellular protein tyrosine kinase (PTK) signaling pathways. The SH2 domain inhibitors could potentially serve as drug candidates in treating human diseases. Here we have incorporated a novel phosphotyrosine mimetic, which is an unusual amino acid carrying a cyclosaligenyl (cycloSal) phosphodiester moiety, into dipeptides to investigate the inhibitory effect on SH2 domain-containing proteins. A plate-based assay was also established to screen for inhibitors that disrupt the interaction between a phosphopeptide of SLAM (signaling lymphocytic activation molecule) and its interacting protein SAP (SLAM-associated protein). We identified a number of inhibitors with IC50 values in the range of 17-35 μM, implying that the cycloSal phosphodiester-carrying amino acid could mimic the phosphotyrosyl residue. Our results also raise the possibility of integrating the newly developed phosphotyrosine mimetic moiety into inhibitors designed for other SH2 domain-containing proteins.

Optimization of the potency and pharmacokinetic profile of 2,3,4-trisubstituted quinoline, 4, led to the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 6a (AM-0687) and 7 (AM-1430). On the basis of their improved profile, these analogs were selected for in vivo pharmacodynamic (PD) and efficacy experiments in animal models of inflammation. The in vivo PD studies, which were carried out in a mouse pAKT inhibition animal model, confirmed the observed potency of 6a and 7 in biochemical and cellular assays. Efficacy experiments in a keyhole limpet hemocyanin model in rats demonstrated that administration of either 6a or 7 resulted in a strong dose-dependent reduction of IgG and IgM specific antibodies. The excellent in vitro and in vivo profiles of these analogs make them suitable for further development.

Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors. The optimized pyrrolopyridine analogue 63 was a potent and selective PI3Kβ/δ dual inhibitor that displayed suitable physicochemical properties and pharmacokinetic profile for animal studies. Analogue 63 was found to be efficacious in animal models of inflammation including a keyhole limpet hemocyanin (KLH) study and a collagen-induced arthritis (CIA) disease model of rheumatoid arthritis. These studies highlight the potential therapeutic value of inhibiting both the PI3Kβ and δ isoforms in the treatment of a number of inflammatory diseases.

A high attrition rate is a major barrier in conducting longitudinal studies. The aim of this retrospective cohort study is to explore the traits of participants in longitudinal Alzheimer Disease (AD) studies in order to investigate retention barriers and facilitators. To determine the relationships of baseline demographics, cognitive status (The mini–mental state examination), AD biomarkers (elevated cerebral amyloid-beta (Aβ) burden measured by positron emission tomography), and the retention rate in an AD research, Pearson correlation, Welch’s t test and chi-square were conducted. A retention score was calculated by dividing the number of missed appointments by the number of scheduled appointments. There were 660 participants (age mean = 74.9 ± 9.2; 60.2% female; 85% Caucasian) who have records of clinical assessments in our study; 71 participants (89.24%) who have a retention score lower than 70% were selected in low retention group for comparison. The results showed that older age (r=.599, p

Falls are the leading preventable cause of morbidity, mortality, and premature institutionalization for community-dwelling older adults. A hybrid effectiveness/implementation trial assigned 310 older adults receiving services from community agencies in urban St. Louis, Missouri, to a home hazard removal intervention delivered over 2 weeks with a 6-month booster, or usual care control. Eligible participants did not have dementia and were aged 65 years or older, were at high risk for falling, and resided in the community. The intervention (n=141) was a home hazard removal program delivered by an occupational therapist in the home that included a comprehensive clinical assessment of the individual, an environmental assessment, and implementation of a tailored hazard removal plan. The intervention was delivered in two or three sessions and included an additional booster session at 6 months. The primary outcome was the number of falls over 12 months. Participants were predominantly African American (56%). At baseline, the mean (SD) age was 75 (7.4) years; 79% were female. At 12 months, the mean (SD) number of falls was 1.5 (3.5) in the intervention group and 2.3 (6.6) in the control group. There was a 38% reduction in the risk of falling (P=0.027) in the intervention group. A brief home hazard removal program significantly reduced the rate of falls among community-dwelling older adults at high risk for falling.

Herein we describe the development of activity-based probes toward protein tyrosine phosphatase (PTP) subfamilies. A novel phosphotyrosine analog serving as the latent trapping unit has been designed and explored. It allows addition of various amino acid residues to its C- and N-termini to extend the recognition element. As a proof-of-concept, we have synthesized three tripeptide probes, which carry the phosphotyrosine analog in the middle position and a leucinamide residue at the C-terminus. The three tripeptide probes differed only in their N-terminal amino acid (Glu, Phe, and Lys). The labeling properties of these probes were determined and the results showed the newly synthesized probes could selectively label PTPs in an activity-dependent manner. In addition, the probes’ target specificity was also shown to be influenced by the amino acid residues flanking the phosphotyrosine analog.

Compounds 4a-f, 5a-f and 6-9, showed significant growth inhibition activity against human tumor cell lines. Of these compounds, 1-(2-((Z)-6-(2-(trifluoromethyl)phenyl)hexa-3-en-1,5-diynyl)phenyl)piperidin-2-one (8) displayed the most potent growth inhibition activity. Compound 8 also arrested cancer cells in G2/M phase and induced apoptosis via activation of caspase-3 and -9. According to western-blotting analysis, compound 8 can up-regulate Bax, down-regulate Bcl-2 and XIAP, as well as promote cytochrome c release.

SummaryKey aspects of the expression of long-term potentiation (LTP) and long-term depression (LTD) remain unresolved despite decades of investigation. Alterations in postsynaptic glutamate receptors are believed to contribute to the expression of various forms of LTP and LTD, but the relative importance of presynaptic mechanisms is controversial. In addition, while aggregate synaptic input to a cell can undergo sequential and graded (incremental) LTP and LTD, it has been suggested that individual synapses may only support binary changes between initial and modified levels of strength. We have addressed these issues by combining electrophysiological methods with two-photon optical quantal analysis of plasticity at individual active (non-silent) Schaffer collateral synapses on CA1 pyramidal neurons in acute slices of hippocampus from adolescent rats. We find that these synapses sustain graded, bidirectional long-term plasticity. Remarkably, changes in potency are small and insignificant; long-term plasticity at these synapses is expressed overwhelmingly via presynaptic changes in reliability of transmitter release.

Lead optimization efforts resulted in the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 1 (AM-8508) and 2 (AM-9635), with good pharmacokinetic properties. The compounds inhibit B cell receptor (BCR)-mediated AKT phosphorylation (pAKT) in PI3Kδ-dependent in vitro cell based assays. These compounds which share a benzimidazole bicycle are effective when administered in vivo at unbound concentrations consistent with their in vitro cell potency as a consequence of improved unbound drug concentration with lower unbound clearance. Furthermore, the compounds demonstrated efficacy in a Keyhole Limpet Hemocyanin (KLH) study in rats, where the blockade of PI3Kδ activity by inbibitors 1 and 2 led to effective inhibition of antigen-specific IgG and IgM formation after immunization with KLH.

OBJECTIVE. The aim of this study was to conduct a process evaluation to examine the implementation of a randomized controlled trial of home modifications designed to reduce the risk of falls and improve daily activity performance among community-dwelling older adults. METHOD. A process evaluation was conducted alongside a blinded, randomized sham-controlled trial (n = 92). Participants were followed for 1 yr after intervention. The process evaluation was framed using the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework. RESULTS. The treatment group improved daily activity performance over 12 mo compared with the sham control group (F = 4.13; p = .024). The intervention elements and dose were delivered with greater than 90% accuracy. Participants reported a 91% adherence rate at 12 mo. CONCLUSION. The complex intervention of home modifications examined in this study is acceptable to older adults, is feasible, and can be delivered with high fidelity for frail, community-dwelling older adults.

OBJECTIVE. This study assessed the initial psychometric properties of a novel in-home, performance-based instrument for older adults called the In-Home Medication Management Performance Evaluation (HOME–Rx). METHOD. Content validity of the HOME–Rx was determined through the multistep content validity index (CVI) process. Content experts provided qualitative and quantitative judgment of the instrument’s ability to measure medication management. The assessment’s target population provided qualitative feedback. CVI outcomes informed instrument revisions. RESULTS. Content experts (n = 7) were in agreement that the overall instrument was valid for measuring medication management (scale-level CVI = .95). Six items were deleted because of low agreement (item-level CVI CONCLUSION. The HOME–Rx appears to be a relevant and valid method to assess performance barriers to medication management in the home.