Inclination to pursue Veterans Health Administration for primary care practice: survey of medical residents.

Introduction: Health systems like the Veterans Health Administration (VA) face challenges in recruiting and retaining a primary care physician workforce. This cross-sectional study of recent or current VA medical residents sought to identify determinants of intent to pursue primary care practice in VA after residency training. Methods: Residents were identified from administrative data between 2020 and 2021 and recruited via an emailed self-administered survey. Multivariable logistic regression, accounting for survey non-response, was applied to examine the association between intent to pursue VA practice and two sets of measures: VA training experiences and individual preferences for work conditions. Results: Of 268 responses received, 141 (56%) of the sample reported inclination to consider VA employment post-residency. Experiences with training in VA were rated more positively in the VA-inclined group compared to the not-inclined group. In the multivariable model, intent to practice primary care was the strongest predictor (OR 4.04, p < 0001). Preceptors' modeling of work-life balance (OR 3.23, p = 0.009) and perceptions of quality of clinical staff and services (OR 2.64, p = 0.004), ability to get patients the care they need (OR 2.51, p = 0.017), and quality of patient care (OR 2.30, p = 0.075) were independent predictors of being in the VA inclined group. Conclusion: Overall, we found that intent to practice primary care and the quality of VA training experiences are important determinants of inclination to consider VA for employment. These results provide an important perspective relevant to medical education, the hiring and retention of the United States (U.S). primary care workforce.

Evaluating equity in a national virtual care management intervention: Delivery and outcomes by race/ethnicity among Veterans with hypertension and diabetes.

OBJECTIVE: To evaluate whether the Preventive Health Inventory (PHI)-a virtual care management intervention addressing hypertension and diabetes management implemented nationally in the Veterans Health Administration (VHA)-was delivered equitably among racial/ethnic groups and if existing inequities in hypertension and diabetes outcomes changed following PHI receipt. DATA SOURCES AND STUDY SETTING: We used data from the VHA Corporate Data Warehouse among Veterans enrolled in primary care nationally from February 28, 2021 to March 31, 2022. STUDY DESIGN: We used logistic regression to evaluate PHI receipt and hypertension and diabetes outcomes after PHI implementation among Veterans with hypertension and/or diabetes. We conducted unadjusted analyses and analyses adjusting for clinic fixed effects using dummy variables. DATA COLLECTION/EXTRACTION METHODS: We identified Veterans engaged in primary care with documented race/ethnicity and hypertension and/or diabetes diagnoses in all months during the study period. PRINCIPLE FINDINGS: Prior to PHI, Non-Hispanic Black (NHB) (42.2%) and Hispanic (39.5%) Veterans were less likely to have controlled hypertension vs. Non-Hispanic White (NHW) Veterans (47.5%); NHB Veterans (32.9%) were more likely to have uncontrolled diabetes vs. NHW Veterans (25.1%). Among 1,805,658 Veterans, 5.7% NHW (N = 68,744), 5.6% NHB (N = 22,580), 10.2% Hispanic (N = 13,313), 6.2% Asian/Pacific Islander/Native Hawaiian (N = 1868), 5.1% American Indian/Native Alaskan (N = 744), and 5.6% multiple races or other race (N = 1647) Veterans received PHI. We found no significant racial inequities in PHI receipt in unadjusted and adjusted models. Hypertension and diabetes measures improved more in the intervention group compared with the group who did not receive the intervention. There were no new or worsened inequities after PHI, and in pre-/post-intervention analysis, among NHB Veterans, the inequity in uncontrolled diabetes improved by 1.9 percentage points (95% CI 0.2, 3.6). CONCLUSIONS: Our findings suggest the PHI intervention was equitably deployed across race/ethnicity groups without significantly impacting most existing inequities in diabetes and hypertension.

Implementing evidence-based practices to improve primary care for high-risk patients: study protocol for the VA high-RIsk VETerans (RIVET) type III effectiveness-implementation trial.

BACKGROUND: Patients with significant multimorbidity and other factors that make healthcare challenging to access and coordinate are at high risk for poor health outcomes. Although most (93%) of Veterans' Health Administration (VHA) patients at high risk for hospitalization or death ("high-risk Veterans") are primarily managed by primary care teams, few of these teams have implemented evidence-based practices (EBPs) known to improve outcomes for the high-risk patient population's complex healthcare issues. Effective implementation strategies could increase adoption of these EBPs in primary care; however, the most effective implementation strategies to increase evidence-based care for high-risk patients are unknown. The high-RIsk VETerans (RIVET) Quality Enhancement Research Initiative (QUERI) will compare two variants of Evidence-Based Quality Improvement (EBQI) strategies to implement two distinct EBPs for high-risk Veterans: individual coaching (EBQI-IC; tailored training with individual implementation sites to meet site-specific needs) versus learning collaborative (EBQI-LC; implementation sites trained in groups to encourage collaboration among sites). One EBP, Comprehensive Assessment and Care Planning (CACP), guides teams in addressing patients' cognitive, functional, and social needs through a comprehensive care plan. The other EBP, Medication Adherence Assessment (MAA), addresses common challenges to medication adherence using a patient-centered approach. METHODS: We will recruit and randomize 16 sites to either EBQI-IC or EBQI-LC to implement one of the EBPs, chosen by the site. Each site will have a site champion (front-line staff) who will participate in 18 months of EBQI facilitation. ANALYSIS: We will use a mixed-methods type 3 hybrid Effectiveness-Implementation trial to test EBQI-IC versus EBQI-LC versus usual care using a Concurrent Stepped Wedge design. We will use the Practical, Robust Implementation and Sustainability Model (PRISM) framework to compare and evaluate Reach, Effectiveness, Adoption, Implementation, and costs. We will then assess the maintenance/sustainment and spread of both EBPs in primary care after the 18-month implementation period. Our primary outcome will be Reach, measured by the percentage of eligible high-risk patients who received the EBP. DISCUSSION: Our study will identify which implementation strategy is most effective overall, and under various contexts, accounting for unique barriers, facilitators, EBP characteristics, and adaptations. Ultimately this study will identify ways for primary care clinics and teams to choose implementation strategies that can improve care and outcomes for patients with complex healthcare needs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05050643. Registered September 9th, 2021, https://clinicaltrials.gov/study/NCT05050643 PROTOCOL VERSION: This protocol is Version 1.0 which was created on 6/3/2020.

Primary Care Telehealth Initiation and Engagement Among Veterans at High Risk, 2019-2022.

Importance: During the COVID-19 pandemic, the Veterans Health Administration (VHA) expanded telehealth infrastructure. Understanding telehealth initiation and sustained engagement could inform future resource allocation for high-need populations. Objective: To describe and examine primary care use, including initiation, use, and engagement factors, of telehealth modalities (telephone, video visits, and secure messaging) from 2020 to 2022. Design, Setting, and Participants: This cohort study was conducted among 1 383 070 patients in the 75th or higher percentile for 90-day risk of hospitalization or mortality (using previously validated Care Assessment Need scores) engaged in VHA primary care from March 11, 2019, to March 10, 2022. Exposures: Patient sociodemographic characteristics (age, sex, race and ethnicity, and marital and housing status), health characteristics (chronic condition count, military service disability, serious mental illness, or substance use disorder diagnoses), geographic characteristics (driving distance to clinic and rural or urban location), and Federal Communications Commission-reported broadband speed among subgroups of patients at high risk categorized by telehealth use from 2020 to 2022. Main Outcomes and Measures: Primary care utilization by modality. Results: A total of 1 383 070 patients at high risk were engaged in VHA primary care in March 2020 (median age, 73.0 years [IQR, 65-80 years]; 92.4% male; 77.7% regular telehealth users in 2019). With the onset of the COVID-19 pandemic from March 2020 to March 2021, 92.7% of patients at high risk (1 158 804 of 1 250 438 retained in care) became regular telehealth users. The following year, most patients continued as telehealth users (83.4% [942 151 of 1 129 683 retained]), including 38.2% retention of users at high risk newly engaged in 2020. Between 2019 and 2022 among those living and engaged in VHA primary care, adjusted exploratory multinomial logit models estimated that new telehealth users in 2020 (both sustained or only transiently engaged) were more often Black non-Hispanic individuals with greater comorbidity burdens than those who never engaged in telehealth use (Black non-Hispanic with new persistent telehealth use: adjusted relative risk ratio [ARR], 1.18 [95% CI, 1.16-1.20]; Black non-Hispanic with transient telehealth use: ARR, 1.11 [95% CI, 1.08-1.13]; ≥5 chronic conditions with new persistent telehealth use: ARR, 1.92 [95% CI, 1.88-1.96]; ≥5 chronic conditions with transient telehealth use: ARR, 1.43 [95% CI, 1.40-1.46]). Conclusions and Relevance: This cohort study suggests that primary care telehealth initiation, use and sustained engagement differed among subgroups of patients at high risk throughout the COVID-19 pandemic. Those never or only transiently engaged with telehealth had lower illness burdens and were less likely to identify as members of racial or ethnic minority groups. Variation in telehealth use among subgroups of patients at high risk during this period could inform future resource allocation.

Factors associated with primary care physician turnover in the VA.

OBJECTIVES: To quantify the association between primary care team workload satisfaction and primary care physician (PCP) turnover and examine potential mediation of workplace climate factors using survey and administrative data. STUDY DESIGN: Longitudinal observational study using data from 2008 to 2016. METHODS: The outcome variable was PCP turnover. The main explanatory variable was satisfaction with amount of workload. We included 7 additional workplace climate measures (eg, satisfaction with direct supervision) as mediators. We included characteristics of PCPs (eg, PCP years of experience, gender), salary, and clinic factors (eg, urban vs rural geography, community vs hospital based) as covariates. RESULTS: US Department of Veterans Affairs (VA) PCPs working at 787 VA primary care clinics nationally were recruited for this study. Over the 9-year study period, 8362 unique PCPs were employed in the VA. The unadjusted mean quarterly turnover rate was 1.83%, and the mean (SD) workload satisfaction score was 3.58 ( 0.24) on a 5-point Likert scale over the study period. In adjusted analysis, a 1-point increase in workload satisfaction was associated with a decrease of 0.73 (95% CI, 0.36-1.10) percentage points in the probability of turnover in a calendar quarter. In the mediation analysis, we found that workload satisfaction impacted turnover through only 1 of the 7 workplace climate measures: satisfaction with direction by senior managers. CONCLUSIONS: Our study findings highlight the key role that achieving primary care workload satisfaction can play in reducing PCP turnover. Identification of direction by senior managers as an underlying mechanism is an important finding for strategic planning to mitigate PCP turnover.

Aging-related alterations in mechanistic target of rapamycin signaling promote platelet hyperreactivity and thrombosis.

BACKGROUND: Aging is an independent risk factor for the development of cardiovascular, thrombotic, and other chronic diseases. However, mechanisms of platelet hyperactivation in aging remain poorly understood. OBJECTIVES: Here, we examine whether and how aging alters intracellular signaling in platelets to support platelet hyperactivity and thrombosis. METHODS: Quantitative mass spectrometry with tandem mass tag labeling systematically measured protein phosphorylation in platelets from healthy aged (>65 years) and young human (<45 years) subjects. The role of platelet mechanistic target of rapamycin (mTOR) in aging-induced platelet hyperreactivity was assessed using pharmacologic mTOR inhibition and a platelet-specific mTOR-deficient mouse model (mTORplt-/-). RESULTS: Quantitative phosphoproteomics uncovered differential site-specific protein phosphorylation within mTOR, Rho GTPase, and MAPK pathways in platelets from aged donors. Western blot confirmed constitutive activation of the mTOR pathway in platelets from both aged humans and mice, which was associated with increased aggregation compared with that in young controls. Inhibition of mTOR with either Torin 1 in aged humans or genetic deletion in aged mice reversed platelet hyperreactivity. In a collagen-epinephrine pulmonary thrombosis model, aged wild-type (mTORplt+/+) mice succumbed significantly faster than young controls, while time to death of aged mTORplt-/- mice was similar to that of young mTORplt+/+ mice. Mechanistically, we noted increased Rac1 activation and levels of mitochondrial reactive oxygen species in resting platelets from aged mice, as well as increased p38 phosphorylation upstream of thromboxane generation following agonist stimulation. CONCLUSION: Aging-related changes in mTOR phosphorylation enhance Rac1 and p38 activation to enhance thromboxane generation, platelet hyperactivity, and thrombosis.

Tear Proteins Altered in Patients with Persistent Eye Pain after Refractive Surgery: Biomarker Candidate Discovery.

Some patients develop persistent eye pain after refractive surgery, but factors that cause or sustain pain are unknown. We tested whether tear proteins of patients with pain 3 months after surgery differ from those of patients without pain. Patients undergoing refractive surgery (laser in situ keratomileusis or photorefractive keratectomy ) were recruited from 2 clinics, and tears were collected 3 months after surgery. Participants rated their eye pain using a numerical rating scale (NRS, 0-10; no pain-worst pain) at baseline, 1 day, and 3 months after surgery. Using tandem mass tag proteomic analysis, we examined tears from patients with pain [NRS ≥ 3 at 3 months (n = 16)] and patients with no pain [NRS ≤ 1 at 3 months (n = 32)] after surgery. A subset of proteins (83 of 2748 detected, 3.0%) were associated with pain 3 months after surgery. High-dimensional statistical models showed that the magnitude of differential expression was not the only important factor in classifying tear samples from pain patients. Models utilizing 3 or 4 proteins had better classification performance than single proteins and represented differences in both directions (higher or lower in pain). Thus, patterns of protein differences may serve as biomarkers of postsurgical eye pain as well as potential therapeutic targets.

Disparities in telemedicine use among Native Hawaiian and Pacific Islander individuals insured through Medicaid.

States have implemented policy changes to increase access to telemedicine services for individuals receiving Medicaid benefits. Native Hawaiian and Pacific Islander (NHPI) individuals experienced disproportionate harms from COVID-19 and have long experienced disparities in health care access compared with other racial and ethnic groups, making the issue of telemedicine access particularly salient for NHPI individuals on Medicaid. Utilizing 100% 2020-2021 Medicaid claims, we compared trends in telemedicine use between NHPI and non-Hispanic White individuals on Medicaid in Washington State and conducted a decomposition analysis to identify drivers of underlying disparities. In both years, NHPI individuals were 38%-39% less likely to use any telemedicine than White individuals after adjusting for patient- and area-level characteristics. Decomposition analysis revealed that most of this difference was due to differential effects of characteristics, rather than group differences in characteristics. Namely, several characteristics that were associated with increased telemedicine use had more muted associations for NHPI vs White individuals, such as English as the primary spoken language and female sex. These findings suggest the presence of limited acceptability of or group-specific barriers to telemedicine for NHPI individuals, including potential discrimination in being offered telemedicine visits. These issues should be understood and mitigated through close collaboration between health care leaders and NHPI communities.

Identifying Patterns of Primary Care In-Person and Telemedicine Use in the Veterans Health Administration: A Latent Class Analysis.

BACKGROUND: The Veterans Health Administration increased synchronous telemedicine (video and telephone visits) in primary care in response to the COVID-19 pandemic. OBJECTIVE: Our objective was to determine veteran use patterns of in-person and telemedicine primary care when all modalities were available. DESIGN: A retrospective cohort analysis. We performed a latent class analysis of primary care visits over a 1-year period to identify veteran subgroup (i.e., class) membership based on amount of primary care use and modality used. Then, we used multinomial logistic regression with a categorical outcome to identify patient characteristics associated with class identification. PARTICIPANTS: A random national sample consisting of 564,580 primary care empaneled veterans in June 2021. MAIN MEASURES: Latent class membership. KEY RESULTS: We identified three latent classes: those with few primary care visits that were predominantly telephone-based (45%), intermediate number of visits of all modalities (50%), and many visits of all modalities (5%). In an adjusted model, characteristics associated with the "few" visits class, compared to the intermediate class, were older age, male sex, White race, further driving distance to primary care, higher Gagne, optimal internet speed, and unmarried status (OR 1.002, 1.52, 1.13, 1.004, 1.04, 1.05, 1.06, respectively; p < .05). Characteristics associated with membership in the "many" visits class, compared to the intermediate class, were Hispanic race, higher JEN Frailty Index and Gagne (OR 1.12, 1.11, 1.02, respectively; p < .05), and higher comorbidity by Care Assessment Need score quartile (Q2 1.73, Q3 2.80, Q4 4.12; p < 0.05). CONCLUSIONS: Veterans accessing primary care in-person or via telemedicine do so primarily in three ways: (1) few visits, predominantly telephone; (2) intermediate visits, all modalities, (3) many visits, all modalities. We found no groups of veterans receiving a majority of primary care through video.

Factors Associated With Use of the Preventive Health Inventory in US Veterans.

Importance: The COVID-19 pandemic caused significant declines in the quality of preventive and chronic disease care. The Veterans Health Administration (VHA) used the Preventive Health Inventory (PHI), a multicomponent care management intervention, to catch up on care disrupted by the pandemic. Objective: To identify key factors associated with PHI use. Design, Setting, and Participants: This cohort study of veterans receiving primary care used administrative data from national VHA primary care clinics for February 1, 2021, through February 1, 2022. Exposure: Patient PHI receipt. Main Outcomes and Measures: The main outcomes were patient, practitioner, and clinic factors associated with PHI receipt. Binomial generalized linear models with fixed effects for clinic were used to analyze factors associated with receipt of PHI. Least absolute shrinkage and selection operator procedures were used for variable selection. Results: A total of 4 358 038 veterans (mean [SD] age, 63.7 [16.0] years; 90% male; 76% non-Hispanic White) formed the study cohort, of whom 389 757 (9%) received the PHI. Veterans who received the PHI had higher mean Care Assessment Need (CAN) scores, which indicate the likelihood of hospitalization or death within 1 year (mean [SD], 51.9 [28.6] vs 47.2 [28.6]; standardized mean difference [SMD], -0.16). They were also more likely to live in urban areas (77% vs 64%; SMD, 0.28) and have a shorter drive distance to primary care (mean [SD], 13.2 [12.4] vs 15.7 [14.6] miles; SMD, 0.19). The mean outpatient use was higher among PHI recipients compared with non-PHI recipients (mean [SD], 18.4 [27.8] vs 15.1 [24.1] visits; SMD, -0.13). In addition, veterans with primary care practitioners with higher caseloads were more likely to receive the PHI (mean [SD], 778 [231] vs 744 [249] patients; SMD, -0.14), and they were more likely to be seen at larger clinics (mean [SD], 9670 [6876] vs 8786 [6892] patients; SMD, -0.13). Prior outpatient use and CAN score were associated with PHI receipt in the final model. Conclusions and Relevance: In this cohort study of the VHA's PHI, patients with higher CAN scores and more outpatient use in the previous year were more likely to receive the PHI. This study identifies potential intervention points to improve care coordination for veterans.

Efficacy of the Canadian CT Head Rule in Patients Presenting to the Emergency Department with Minor Head Injury.

Introduction: Approximately, one in three computed tomography (CT) scans performed for head injury may be avoidable. We evaluate the efficacy of the Canadian CT head rule (CCHR) on head CT imaging in minor head injury (MHI) and its association of Glasgow Coma Scale (GCS) and structural abnormality. Materials and methods: We conducted a prospective cross-sectional study from May 2018 to October 2019 in the Department of Emergency Medicine, Pushpagiri Institute of Medical Sciences and Research Centre, Thiruvalla, Kerala. The CCHR is applied to patients with MHIs (GCS 13-15) after initial stabilization and it is ascertained, if they require a non-contrast CT head and imaging is done. For those who do not require CT head as per the CCHR are excluded from this study. After imaging the patients who have a positive finding on CT head are admitted and followed up if they underwent any neurosurgical intervention, those with no findings in CT head are discharged from the hospital. A total of 203 patients were included during study period. Results: A total of 203 patients were included in study with mean age of 49.5 years. Approximately, 70% (142) were male. Sensitivity of CCHR for predicting positive CT finding in the present study sample was 68% and specificity was 42.5%. Conclusion: Canadian CT head rule is a useful tool in the Emergency Department for predicting the requirement of CT in patients with MHI. Canadian CT head rule can reduce the number of CT scans ordered following MHI in ED, thus improving the healthcare costs. How to cite this article: Reddy A, Poonthottathil F, Jonnakuti R, Thomas R. Efficacy of the Canadian CT Head Rule in Patients Presenting to the Emergency Department with Minor Head Injury. Indian J Crit Care Med 2024;28(2):148-151.

Defining and Improving Outcomes Measurement for Virtual Care: Report from the VHA State-of-the-Art Conference on Virtual Care.

Virtual care, including synchronous and asynchronous telehealth, remote patient monitoring, and the collection and interpretation of patient-generated health data (PGHD), has the potential to transform healthcare delivery and increase access to care. The Veterans Health Administration (VHA) Office of Health Services Research and Development (HSR&D) convened a State-of-the-Art (SOTA) Conference on Virtual Care to identify future virtual care research priorities. Participants were divided into three workgroups focused on virtual care access, engagement, and outcomes. In this article, we report the findings of the Outcomes Workgroup. The group identified virtual care outcome areas with sufficient evidence, areas in need of additional research, and areas that are particularly well-suited to be studied within VHA. Following a rigorous process of literature review and consensus, the group focused on four questions: (1) What outcomes of virtual care should we be measuring and how should we measure them?; (2) how do we choose the "right" care modality for the "right" patient?; (3) what are potential consequences of virtual care on patient safety?; and (4) how can PGHD be used to benefit provider decision-making and patient self-management?. The current article outlines key conclusions that emerged following discussion of these questions, including recommendations for future research.

Automated Reminders Enhance Mailed Fecal Immunochemical Test Completion Among Veterans: a Randomized Controlled Trial.

BACKGROUND: The Veterans Affairs (VHA) is working to establish a population-based colorectal cancer screening program for average-risk patients using mailed fecal immunochemical testing (FIT). However, low response rates to mailed FIT may hinder success. Key features of mailed FIT programs, including the use of reminders, differ among various national programs, with limited evidence among veterans. OBJECTIVE: We sought to test whether using reminders, either via telephone call or text message, was effective in improving mailed FIT response rates. DESIGN: We conducted a prospective, randomized quality improvement trial ( ClinicalTrials.gov NCT05012007). Veterans who had not returned a FIT within 2 weeks of receiving the kit were randomized to one of three groups: (1) control (no reminder); (2) an automated telephone call reminder; or (3) an automated text message reminder. PARTICIPANTS: A total of 2658 veterans enrolled at VA Puget Sound Health Care System who were aged 45-75 and had an average risk of colorectal cancer. INTERVENTIONS: A single automated telephone call or text message reminder prompting veterans to return the FIT kit. MAIN MEASURES: Our primary outcome was FIT return at 90 days and our secondary outcome was FIT return at 180 days. KEY RESULTS: Participant average age was 62 years, 88% were men, and 66% White. At 90 days, both the phone and text reminder interventions had higher FIT return rates compared to control (intention-to-treat results (ITT): control 28%, phone 39%, text 38%; p<0.001). At 180 days, FIT kit return remained higher in the reminder interventions (ITT: control 32%, phone 42%, text 40%; p<0.001). CONCLUSIONS: Automated reminders increased colorectal cancer screening completion among average-risk veterans. An automated phone call or text message was equally effective. VHA facilities seeking to implement a mailed FIT program should consider using phone or text reminders, depending on available resources.

The amniotic fluid proteome changes across gestation in humans and rhesus macaques.

Amniotic fluid is a complex biological medium that offers protection to the fetus and plays a key role in normal fetal nutrition, organogenesis, and potentially fetal programming. Amniotic fluid is also critically involved in longitudinally shaping the in utero milieu during pregnancy. Yet, the molecular mechanism(s) of action by which amniotic fluid regulates fetal development is ill-defined partly due to an incomplete understanding of the evolving composition of the amniotic fluid proteome. Prior research consisting of cross-sectional studies suggests that the amniotic fluid proteome changes as pregnancy advances, yet longitudinal alterations have not been confirmed because repeated sampling is prohibitive in humans. We therefore performed serial amniocenteses at early, mid, and late gestational time-points within the same pregnancies in a rhesus macaque model. Longitudinally-collected rhesus amniotic fluid samples were paired with gestational-age matched cross-sectional human samples. Utilizing LC-MS/MS isobaric labeling quantitative proteomics, we demonstrate considerable cross-species similarity between the amniotic fluid proteomes and large scale gestational-age associated changes in protein content throughout pregnancy. This is the first study to compare human and rhesus amniotic fluid proteomic profiles across gestation and establishes a reference amniotic fluid proteome. The non-human primate model holds promise as a translational platform for amniotic fluid studies.

Unraveling the role of TGFß signaling in thoracic aortic aneurysm and dissection using Fbn1 mutant mouse models.

Although abnormal TGFß signaling is observed in several heritable forms of thoracic aortic aneurysms and dissections including Marfan syndrome, its precise role in aortic disease progression is still disputed. Using a mouse genetic approach and quantitative isobaric labeling proteomics, we sought to elucidate the role of TGFß signaling in three Fbn1 mutant mouse models representing a range of aortic disease from microdissection (without aneurysm) to aneurysm (without rupture) to aneurysm and rupture. Results indicated that reduced TGFß signaling and increased mast cell proteases were associated with microdissection. In contrast, increased abundance of extracellular matrix proteins, which could be reporters for positive TGFß signaling, were associated with aneurysm. Marked reductions in collagens and fibrillins, and increased TGFß signaling, were associated with aortic rupture. Our data indicate that TGFß signaling performs context-dependent roles in the pathogenesis of thoracic aortic disease.

Automated Opt-Out vs Opt-In Patient Outreach Strategies for Breast Cancer Screening: A Randomized Clinical Trial.

Importance: Optimal strategies for population-based outreach for breast cancer screening remain unknown. Objective: To evaluate the effect on breast cancer screening of an opt-out automatic mammography referral strategy compared with an opt-in automated telephone message strategy. Design, Setting, and Participants: This pragmatic randomized clinical trial was conducted from April 2022 to January 2023 at a single Veterans Affairs (VA) medical center. Participants were female veterans aged 45 to 75 years who were eligible for breast cancer screening and enrolled in VA primary care. Intervention: Veterans were randomized 1:1 to receive either an automatic mammography referral (opt-out arm) or an automated telephone call with an option for mammography referral (opt-in arm). Main Outcomes and Measures: The primary outcome was completed mammography 100 days after outreach. Secondary outcomes were scheduled or completed mammography by 100 days after outreach and referrals canceled if mammography was not scheduled within 90 days. Both intention-to-treat analyses and a restricted analysis were conducted. The restricted analysis excluded veterans who were unable to be reached by telephone (eg, a nonworking number) or who were found to be ineligible after randomization (eg, medical record documentation of recent mammography). Results: Of 883 veterans due for mammography (mean [SD] age, 59.13 [8.24] years; 656 [74.3%] had received prior mammography), 442 were randomized to the opt-in group and 441 to the opt-out group. In the intention-to-treat analysis, there was no significant difference in the primary outcome of completed mammography at 100 days between the opt-out and opt-in groups (67 [15.2%] vs 66 [14.9%]; P = .90) or the secondary outcome of completed or scheduled mammography (84 [19%] vs 106 [24.0%]; P = .07). A higher number of referrals were canceled in the opt-out group compared with the opt-in group (104 [23.6%] vs 24 [5.4%]; P < .001). The restricted analysis demonstrated similar results except more veterans completed or scheduled mammography within 100 days in the opt-out group compared with the opt-in group (102 of 388 [26.3%] vs 80 of 415 [19.3%]; P = .02). Conclusions and Relevance: In this randomized clinical trial, an opt-out population-based breast cancer screening outreach approach compared with an opt-in approach did not result in a significant difference in mammography completion but did lead to substantially more canceled mammography referrals, increasing staff burden. Trial Registration: ClinicalTrials.gov Identifier: NCT05313737.

MicroRNA137-loaded lipid nanoparticles regulate synaptic proteins in the prefrontal cortex.

Genome-wide association studies indicate that allele variants in MIR137, the host gene of microRNA137 (miR137), confer an increased risk of schizophrenia (SCZ). Aberrant expression of miR137 and its targets, many of which regulate synaptic functioning, are also associated with an increased risk of SCZ. Thus, miR137 represents an attractive target aimed at correcting the molecular basis for synaptic dysfunction in individuals with high genetic risk for SCZ. Advancements in nanotechnology utilize lipid nanoparticles (LNPs) to transport and deliver therapeutic RNA. However, there remains a gap in using LNPs to regulate gene and protein expression in the brain. To study the delivery of nucleic acids by LNPs to the brain, we found that LNPs released miR137 cargo and inhibited target transcripts of interest in neuroblastoma cells. Biodistribution of LNPs loaded with firefly luciferase mRNA remained localized to the mouse prefrontal cortex (PFC) injection site without circulating to off-target organs. LNPs encapsulating Cre mRNA preferentially co-expressed in neuronal over microglial or astrocytic cells. Using quantitative proteomics, we found miR137 modulated glutamatergic synaptic protein networks that are commonly dysregulated in SCZ. These studies support engineering the next generation of brain-specific LNPs to deliver RNA therapeutics and improve symptoms of central nervous system disorders.