Continuous Glucose Monitoring-Guided Insulin Administration in Long-Term Care Facilities: A Randomized Clinical Trial.

OBJECTIVES: To evaluate the efficacy of real-time continuous glucose monitoring (rt-CGM) in adjusting insulin therapy in long-term care facilities (LTCF). DESIGN: Prospective randomized clinical trial. SETTINGS AND PARTICIPANTS: Insulin-treated patients with type 2 diabetes (T2D) admitted to LTCF. METHODS: Participants in the standard of care wore a blinded CGM with treatment adjusted based on point-of-care capillary glucose results before meals and bedtime (POC group). Participants in the intervention (CGM group) wore a Dexcom G6 CGM with treatment adjusted based on daily CGM profile. Treatment adjustment was performed by the LTCF medical team, with a duration of intervention up to 60 days. The primary endpoint was difference in time in range (TIR 70-180 mg/dL) between treatment groups. RESULTS: Among 100 participants (age 74.73 ± 11 years, 80% admitted for subacute rehabilitation and 20% for nursing home care), there were no significant differences in baseline clinical characteristics between groups, and CGM data were compared for a median of 17 days. There were no differences in TIR (53.38% ± 30.16% vs 48.81% ± 28.03%, P = .40), mean daily mean CGM glucose (184.10 ± 43.4 mg/dL vs 190.0 ± 45.82 mg/dL, P = .71), or the percentage of time below range (TBR) <70 mg/dL (0.83% ± 2.59% vs 1.18% ± 3.54%, P = .51), or TBR <54 mg/dL (0.23% ± 0.85% vs 0.56% ± 2.24%, P = .88) between rt-CGM and POC groups. CONCLUSIONS AND IMPLICATIONS: The use of rtCGM is safe and effective in guiding insulin therapy in patients with T2D in LTCF resulting in a similar improvement in glycemic control compared to POC-guided insulin adjustment.

"Call 911 - That's my [Advance Care] Plan": Factors that Inform Advance Care Planning Conversation Readiness Among Aging Persons Living With HIV.

Antiretroviral therapy has dramatically increased the lifespan of people living with HIV (PLWH), but advance care planning (ACP) and hospice services are underutilized in this population. The purpose of this study was to understand barriers and facilitators to ACP among this group. PLWH (n = 25) were recruited from an HIV Clinic at a Veterans Affairs (VA) Medical Center in Atlanta, GA to represent a range of sociodemographic characteristics and experiences. Semi-structured interviews were analyzed using thematic analysis. More than half of participants (64%) indicated not engaging in ACP. We identified four key barriers to ACP: (1) a self-image among PLWH as "survivors" (and a reluctance to think about ACP); (2) a history of mistrust and mistreatment; (3) weak social ties and a desire to avoid disclosure of HIV status; and (4) a value for self-reliance. Findings have important implications for interventions to overcome these barriers.

Indoximod-based chemo-immunotherapy for pediatric brain tumors: A first-in-children phase I trial.

BACKGROUND: Recurrent brain tumors are the leading cause of cancer death in children. Indoleamine 2,3-dioxygenase (IDO) is a targetable metabolic checkpoint that, in preclinical models, inhibits anti-tumor immunity following chemotherapy. METHODS: We conducted a phase I trial (NCT02502708) of the oral IDO-pathway inhibitor indoximod in children with recurrent brain tumors or newly diagnosed diffuse intrinsic pontine glioma (DIPG). Separate dose-finding arms were performed for indoximod in combination with oral temozolomide (200 mg/m2/day x 5 days in 28-day cycles), or with palliative conformal radiation. Blood samples were collected at baseline and monthly for single-cell RNA-sequencing with paired single-cell T cell receptor sequencing. RESULTS: Eighty-one patients were treated with indoximod-based combination therapy. Median follow-up was 52 months (range 39-77 months). Maximum tolerated dose was not reached, and the pediatric dose of indoximod was determined as 19.2 mg/kg/dose, twice daily. Median overall survival was 13.3 months (n = 68, range 0.2-62.7) for all patients with recurrent disease and 14.4 months (n = 13, range 4.7-29.7) for DIPG. The subset of n = 26 patients who showed evidence of objective response (even a partial or mixed response) had over 3-fold longer median OS (25.2 months, range 5.4-61.9, p = 0.006) compared to n = 37 nonresponders (7.3 months, range 0.2-62.7). Four patients remain free of active disease longer than 36 months. Single-cell sequencing confirmed emergence of new circulating CD8 T cell clonotypes with late effector phenotype. CONCLUSIONS: Indoximod was well tolerated and could be safely combined with chemotherapy and radiation. Encouraging preliminary evidence of efficacy supports advancing to Phase II/III trials for pediatric brain tumors.

Use of Natural Language Processing of Patient-Initiated Electronic Health Record Messages to Identify Patients With COVID-19 Infection.

Importance: Natural language processing (NLP) has the potential to enable faster treatment access by reducing clinician response time and improving electronic health record (EHR) efficiency. Objective: To develop an NLP model that can accurately classify patient-initiated EHR messages and triage COVID-19 cases to reduce clinician response time and improve access to antiviral treatment. Design, Setting, and Participants: This retrospective cohort study assessed development of a novel NLP framework to classify patient-initiated EHR messages and subsequently evaluate the model's accuracy. Included patients sent messages via the EHR patient portal from 5 Atlanta, Georgia, hospitals between March 30 and September 1, 2022. Assessment of the model's accuracy consisted of manual review of message contents to confirm the classification label by a team of physicians, nurses, and medical students, followed by retrospective propensity score-matched clinical outcomes analysis. Exposure: Prescription of antiviral treatment for COVID-19. Main Outcomes and Measures: The 2 primary outcomes were (1) physician-validated evaluation of the NLP model's message classification accuracy and (2) analysis of the model's potential clinical effect via increased patient access to treatment. The model classified messages into COVID-19-other (pertaining to COVID-19 but not reporting a positive test), COVID-19-positive (reporting a positive at-home COVID-19 test result), and non-COVID-19 (not pertaining to COVID-19). Results: Among 10 172 patients whose messages were included in analyses, the mean (SD) age was 58 (17) years; 6509 patients (64.0%) were women and 3663 (36.0%) were men. In terms of race and ethnicity, 2544 patients (25.0%) were African American or Black, 20 (0.2%) were American Indian or Alaska Native, 1508 (14.8%) were Asian, 28 (0.3%) were Native Hawaiian or other Pacific Islander, 5980 (58.8%) were White, 91 (0.9%) were more than 1 race or ethnicity, and 1 (0.01%) chose not to answer. The NLP model had high accuracy and sensitivity, with a macro F1 score of 94% and sensitivity of 85% for COVID-19-other, 96% for COVID-19-positive, and 100% for non-COVID-19 messages. Among the 3048 patient-generated messages reporting positive SARS-CoV-2 test results, 2982 (97.8%) were not documented in structured EHR data. Mean (SD) message response time for COVID-19-positive patients who received treatment (364.10 [784.47] minutes) was faster than for those who did not (490.38 [1132.14] minutes; P = .03). Likelihood of antiviral prescription was inversely correlated with message response time (odds ratio, 0.99 [95% CI, 0.98-1.00]; P = .003). Conclusions and Relevance: In this cohort study of 2982 COVID-19-positive patients, a novel NLP model classified patient-initiated EHR messages reporting positive COVID-19 test results with high sensitivity. Furthermore, when responses to patient messages occurred faster, patients were more likely to receive antiviral medical prescription within the 5-day treatment window. Although additional analysis on the effect on clinical outcomes is needed, these findings represent a possible use case for integration of NLP algorithms into clinical care.

Parkinson's Disease and Diabetes Mellitus: Individual and Combined Effects on Motor, Cognitive, and Psychosocial Functions.

BACKGROUND/OBJECTIVE: Understanding the effects of multimorbidity on motor and cognitive function is important for tailoring therapies. Individuals with diabetes mellitus (DM) have a greater risk of developing Parkinson's disease (PD). This study investigated if individuals with comorbid PD and DM experienced poorer functional ability compared to individuals with only PD or DM. METHODS: A cross-sectional analysis of 424 individuals: healthy older adults (HOA), n = 170; PD without DM (PD-only), n = 162; DM without PD (DM-only), n = 56; and comorbid PD and DM (PD+DM), n = 36. Motor, motor-cognitive, cognitive, and psychosocial functions and PD motor symptoms were compared among groups using a two-way analyses of covariance with PD and DM as factors. RESULTS: The PD-only and DM-only participants exhibited slower gait, worse balance, reduced strength, and less endurance. Motor-cognitive function was impaired in individuals with PD but not DM. DM-only participants exhibited impaired inhibition. Individuals with comorbid PD+DM had worse PD motor symptoms and exhibited impaired attention compared to the PD-only group. CONCLUSIONS: Having PD or DM was independently associated with poorer physical and mental quality of life, depression, and greater risk for loss of function. Both PD and DM have independent adverse effects on motor function. Comorbid PD+DM further impairs attention compared to the effect of PD-only, suggesting the importance of therapies focusing on attention. Understanding the functional ability levels for motor and cognitive domains will enhance the clinical care for PD, DM, and PD+DM.

Efficacy and Imaging-Enabled Pharmacodynamic Profiling of KRAS G12C Inhibitors in Xenograft and Genetically Engineered Mouse Models of Cancer.

KRAS is one of the most commonly mutated oncogenes in lung, colorectal, and pancreatic cancers. Recent clinical trials directly targeting KRAS G12C presented encouraging results for a large population of non-small cell lung cancer (NSCLC), but resistance to treatment is a concern. Continued exploration of new inhibitors and preclinical models is needed to address resistance mechanisms and improve duration of patient responses. To further enable the development of KRAS G12C inhibitors, we present a preclinical framework involving translational, non-invasive imaging modalities (CT and PET) and histopathology in a conventional xenograft model and a novel KRAS G12C knock-in mouse model of NSCLC. We utilized an in-house developed KRAS G12C inhibitor (Compound A) as a tool to demonstrate the value of this framework in studying in vivo pharmacokinetic/pharmacodynamic (PK/PD) relationship and anti-tumor efficacy. We characterized the Kras G12C-driven genetically engineered mouse model (GEMM) and identify tumor growth and signaling differences compared to its Kras G12D-driven counterpart. We also find that Compound A has comparable efficacy to sotorasib in the Kras G12C-driven lung tumors arising in the GEMM, but like observations in the clinic, some tumors inevitably progress on treatment. These findings establish a foundation for evaluating future KRAS G12C inhibitors that is not limited to xenograft studies and can be applied in a translationally relevant mouse model that mirrors human disease progression and resistance.

Referent Values for Commonly Used Clinical Mobility Tests in Black and White Adults Aged 50-95 Years.

OBJECTIVE: To estimate referent values for performance on clinical mobility tests conducted amongst racially diverse adults aged 50-95 years in the Southeast US. DESIGN: This is an observational study of community-dwelling older adults from diverse racial groups who participated in observational and rehabilitative studies conducted from 2011-2019. SETTING: Rehabilitation clinics around the greater metropolitan Atlanta, Georgia, region. PARTICIPANTS: A total of 314 adults (N=314; 222 women). Individuals were predominantly Black (n=121) or White (n=164), with some participants from other racial groups (n=29). INTERVENTIONS: Clinical and demographic data were collected at individual visits for each participant. MAIN OUTCOME MEASURES: Four Square Step Test (FSST), timed Up and Go (TUG) test, dual TUG test, 6-minute walk test (6MWT), 30-second chair stand, and gait speed were all used as assessments in each cohort. RESULTS: Performance slowly declines with increasing age, with a sharp drop in the ninth decade for preferred forward, backward, and fast gait speed; backward gait cadence; 6MWT, TUG test, dual-task TUG-Cognitive, and the 360° turn test. Declines were also seen in the eighth and ninth decades in the FSST. Among White participants, there were significant overall differences across age groups except in the assessment variable, preferred gait cadence. For Black individuals, there were significant overall differences across age groups for backward gait speed, fast gait speed, TUG-Cognitive, dual task, 6MWT, FSST, and 30-second chair stand. CONCLUSIONS: These data enrich current referent values for brief, commonly used clinical tests in a diverse, older Southeast US cohort. These data include representatives of the oldest old cohort. This study will support race- and age-specific fall prevention and mobility-enhancing therapeutic application among older patients in clinical practice.

Annual Foot Exams are Associated with Reduced Incident Amputation among Older Veterans with Diabetes.

We conducted a secondary data analysis to evaluate the association between annual foot exams and incident lower extremity amputations (LEA) among older veterans with diabetes during FY2007-FY2014. Older Veterans with at least one primary care provider visit each year (N = 664,162) and at least one foot exam each year (N = 72,892) and the overlap were identified from the 5 years prior to the study period of interest (FY2002-FY2006 (N = 71,122)). After excluding incident LEA related to cancer and trauma, 71,018 veterans (mean age +/- SD, % male) were included in the final cohort, which was followed from FY2007-FY2014 to evaluate the influence of subsequent annual foot exams and incident LEA. Consistent annual foot exams were protective for incident LEA in older veterans with diabetes, adjusted OR was 0.85 (97% CI: 0.74-0.96). Results indicate that adherence to annual foot exam guidelines can reduce incident LEA in older veterans with diabetes.

Mirabegron and antimuscarinic use in frail overactive bladder patients in the United States Medicare population.

INTRODUCTION: Overactive bladder (OAB) and frailty are independently associated with patient burden. However, economic burden and treatment-taking behavior have not been well characterized among frail patients with OAB, which, given the varying safety and tolerability profiles of available treatments, is crucial. OBJECTIVES: To assess costs, health care resource utilization, treatment-taking behavior (persistence and adherence) to OAB medication in older, frail OAB patients. METHODS: This was a retrospective cohort study using international business machines MarketScan Medicare Supplemental claims data. Eligible frail patients (per Claims-based Frailty Index score) initiating mirabegron were 1:2 propensity score matched (based on age, sex, and other characteristics) with those initiating antimuscarinics and were followed up to 1 year. All-cause, per-person, per-month costs, health care encounters, persistence (median days to discontinuation assessed using Kaplan-Meier methods) and adherence (≥80% of proportion of days covered at Day 365) were compared. RESULTS: From 2527 patients with incident mirabegron (21%) or antimuscarinic (79%) dispensations, 516 incident mirabegron users (median age: 82 years, 64% female) were matched to 1032 incident antimuscarinic users (median age: 81 years, 62% female). Median cost was higher in mirabegron group ($1581 vs. $1197 per month); this was primarily driven by medication cost. There was no difference in medical encounters. Adherence (39.1% vs. 33.8%) and persistence (103 vs. 90 days) were higher in mirabegron users. CONCLUSIONS: Among frail older adults with OAB, mirabegron use was associated with higher costs and potential improvements in treatment-taking behaviors, particularly with respect to treatment adherence, versus those initiating antimuscarinics.

Analysis of lorlatinib analogs reveals a roadmap for targeting diverse compound resistance mutations in ALK-positive lung cancer.

Lorlatinib is currently the most advanced, potent and selective anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor for the treatment of ALK-positive non-small cell lung cancer in the clinic; however, diverse compound ALK mutations driving therapy resistance emerge. Here, we determine the spectrum of lorlatinib-resistant compound ALK mutations in patients, following treatment with lorlatinib, the majority of which involve ALK G1202R or I1171N/S/T. We further identify structurally diverse lorlatinib analogs that harbor differential selective profiles against G1202R versus I1171N/S/T compound ALK mutations. Structural analysis revealed increased potency against compound mutations through improved inhibition of either G1202R or I1171N/S/T mutant kinases. Overall, we propose a classification of heterogenous ALK compound mutations enabling the development of distinct therapeutic strategies for precision targeting following sequential tyrosine kinase inhibitors.

Perioperative Mobile Telehealth Program for Post-Prostatectomy Incontinence: A Randomized Clinical Trial.

PURPOSE: Perioperative pelvic floor muscle training can hasten recovery of bladder control and reduce severity of urinary incontinence following radical prostatectomy. Nevertheless, most men undergoing prostatectomy do not receive this training. The purpose of this trial was to test the effectiveness of interactive mobile telehealth (mHealth) to deliver an evidence-based perioperative behavioral training program for post-prostatectomy incontinence. MATERIALS AND METHODS: This was a 3-site, 2-arm, randomized trial (2014-2019). Men with prostate cancer scheduled to undergo radical prostatectomy were randomized to a perioperative behavioral program (education, pelvic floor muscle training, progressive exercises, bladder control techniques) or a general prostate cancer education control condition, both delivered by mHealth for 1-4 weeks preoperatively and 8 weeks postoperatively. The primary outcome was time to continence following surgery measured by the ICIQ (International Consultation on Incontinence Questionnaire) Short-Form. Secondary outcomes measured at 6, 9 and 12 months included Urinary Incontinence Subscale of Expanded Prostate Cancer Index Composite; pad use; International Prostate Symptom Score QoL Question and Global Perception of Improvement. RESULTS: A total of 245 men (ages 42-78 years; mean=61.7) were randomized. Survival analysis using the Kaplan-Meier estimate showed no statistically significant between-group differences in time to continence. Analyses at 6 months indicated no statistically significant between-group differences in ICIQ scores (mean=7.1 vs 7.0, p=0.7) or other secondary outcomes. CONCLUSIONS: mHealth delivery of a perioperative program to reduce post-prostatectomy incontinence was not more effective than an mHealth education program. More research is needed to assess whether perioperative mHealth programs can be a helpful addition to standard prostate cancer care.

Quantifying Risk for SARS-CoV-2 Infection Among Nursing Home Workers for the 2020-2021 Winter Surge of the COVID-19 Pandemic in Georgia, USA.

OBJECTIVES: Estimate incidence of and risks for SARS-CoV-2 infection among nursing home staff in the state of Georgia during the 2020-2021 Winter COVID-19 Surge in the United States. DESIGN: Serial survey and serologic testing at 2 time points with 3-month interval exposure assessment. SETTING AND PARTICIPANTS: Fourteen nursing homes in the state of Georgia; 203 contracted or employed staff members from those 14 participating nursing homes who were seronegative at the first time point and provided a serology specimen at second time point, at which time they reported no COVID-19 vaccination or only very recent vaccination (≤4 weeks). METHODS: Interval infection was defined as seroconversion to antibody presence for both nucleocapsid protein and spike protein. We estimated adjusted odds ratios (aORs) and 95% CIs by job type, using multivariable logistic regression, accounting for community-based risks including interval community incidence and interval change in resident infections per bed. RESULTS: Among 203 eligible staff, 72 (35.5%) had evidence of interval infection. In multivariable analysis among unvaccinated staff, staff SARS-CoV-2 infection-induced seroconversion was significantly higher among nurses and certified nursing assistants accounting for race and interval infection incidence in both the community and facility (aOR 5.3, 95% CI 1.0-28.4). This risk persisted but was attenuated when using the full study cohort including those with very recent vaccination. CONCLUSIONS AND IMPLICATIONS: Midway through the first year of the pandemic, job type continues to be associated with increased risk for infection despite enhanced infection prevention efforts including routine screening of staff. These results suggest that mitigation strategies prior to vaccination did not eliminate occupational risk for infection and emphasize critical need to maximize vaccine utilization to eliminate excess risk among front-line providers.

Exploratory evaluation of baseline cognition as a predictor of perceived benefit in a study of behavioral therapy for urinary incontinence in Parkinson disease.

AIMS: While behavior-based pelvic floor muscle exercise therapy is an effective treatment for overactive bladder in Parkinson's disease (PD) patients, cognitive function may be a predictor of rehabilitation outcomes. METHODS: In a planned exploratory analysis, participants who had a Montreal Cognitive Assessment (MoCA) with a score ≥18 who were randomized in a clinical trial to behavioral treatment were classified by perceived improvement (Benefit vs. No Benefit) as reported on a validated Satisfaction and Benefit Questionnaire. General cognition (MoCA), motor procedural learning (Serial reaction time task), verbal memory (Buschke delayed recall), spatial memory (Nonverbal/Spatial selective reminding test), and working memory (Wisconsin card sorting task) were compared between the two groups using Wilcoxon rank-sum test. RESULTS: Of the 26 participants randomized to behavioral treatment (70% male, mean age 71 ± 6.1 years), 22 participants (85%) reported Benefit and four reported No Benefit. General cognition, motor procedural learning, verbal memory, spatial memory, and working memory did not differ between these groups. While the difference between the time to complete the final practiced series and the random series of the Serial Reaction Time Task (SRTT) was statistically similar between the groups, the Benefit group performed the random sequence more quickly (567.0 ± 136.5 ms) compared to the No Benefit group (959.4 ± 443.0 ms; p = 0.03) and trended toward faster performance in the final practiced series. CONCLUSIONS: Perceived benefit from behavioral treatment for overactive bladder was not associated with measures of baseline cognition other than faster completion of the SRTT. This is noteworthy because many behavior-based therapy studies exclude participants with mild cognitive impairment. Additional studies may evaluate if domain-specific cognitive function, particularly the assessment of implicit memory, could lead to individualized behavioral therapy recommendations.

The Georgia Memory Net: Implementation of a statewide program to diagnose and treat Alzheimer's disease and related dementias.

OBJECTIVES: The number of people living with dementia is growing and most patients go years without receiving a specific diagnosis or support services, leading to suboptimal care, negative impacts on the quality of life, and increased costs of care. To address these gaps, the State of Georgia Department of Human Services collaborated with academic and community partners to create the Georgia Memory Net (GMN). DESIGN: GMN is a hub and spoke model partnered with Emory University's Cognitive Neurology Clinic and Emory Goizueta Alzheimer's Disease Research Center to provide training and support for best practices in diagnosis and management to Memory Assessment Clinics (MACs) throughout the state. SETTING: Communities across the State of Georgia. PARTICIPANTS: GMN is a mix of academic and community providers, hospital systems, state and community agencies. Patients and families are evaluated at the MACs and connected to community services. INTERVENTION: A dedicated clinic workflow: primary care providers (PCPs) identify a memory problem and refer to the MACs for diagnostic evaluation; meeting with a community services educator, and development of a care plan. The patient is reconnected with the PCP for continuity of care. MEASUREMENTS: Initial metrics include numbers of unique patients, total patient visits, and referrals to state agency partners for community services. RESULTS: GMN established five MACs across Georgia with annual state funding. Partners at Emory University provided initial training; refined patient workflows for best practices; and provide ongoing support, guidance, and continuing education for MAC teams. Local PCPs and community services partners demonstrated strong engagement with the new model. CONCLUSIONS: GMN is an innovative care model to improve access to accurate and timely diagnosis in patients with memory loss. GMN may help improve the quality of life for patients and families through preventive and early care.

Roles of Academic Writers in a Department: Benefits, Structures, and Funding.

BACKGROUND AND OBJECTIVES: Despite the prevalence of published opinions about the use of professional academic writers to help disseminate the results of clinical research, particularly opinions about the use of ghost writers, very little information has been published on the possible roles for professional writers within academic medical departments or the mechanisms by which these departments can hire and compensate such writers. To begin addressing this lack of information, the Association of Departments of Family Medicine hosted an online discussion and a subsequent webinar in which we obtained input from three departments of family medicine in the United States regarding their use of academic writers. This discussion revealed three basic models by which academic writers have benefitted these departments: (1) grant writing support, (2) research and academic support for clinical faculty, and (3) departmental communication support. Drawing on specific examples from these institutions, the purpose of this paper is to describe the key support activities, advantages, disadvantages, and funding opportunities for each model for other departments to consider and adapt.

Updating the landmark literature for the practice of geriatrics: Notable articles from 2012-2019.

BACKGROUND: Remaining current on the latest advances in the peer-reviewed literature is a basic tenant of medical education and evidence-based practice. We updated an important prior publication (Vaughan, et al.) identifying landmark articles in geriatric medicine by considering the influence of altmetrics and updating the list with notable articles published between 2012 and 2019. METHODS: Articles were identified by searching Web of Science and Scopus for highly cited articles clinically relevant to geriatrics or gerontology and by searching the Altmetric Explorer database for relevant articles with high altmetric scores. The results of the literature search were screened and evaluated using a bibliometric score consisting of an adjusted journal impact factor, citation count, and altmetric score. RESULTS: The top 12 notable articles in geriatrics were selected by a consensus panel and ranked using an expert opinion survey. This process reinforces the concept of combining subjective and objective measures to identify notable articles to be used for the education of healthcare professionals in geriatrics principles of care for older adults. CONCLUSIONS: While our update was performed approximately 9 years after the initial identification of landmark articles, we propose that future updates are conducted at an interval of every 5 years by the governance of a national professional society.

Palliative care aspects of wound healing in complex patients: a case report.

DECLARATION OF INTEREST: The authors have no conflicts of interest to declare.