VA National Research Articles

Implementation of Cognitive Behavioral Therapy for psychosis via telehealth: An expert consultation and clinical service model.

Individuals living with psychosis are often underserved in the United States, partly due to the dearth of providers trained in evidence-based practices for this population. One such practice is Cognitive Behavioral Therapy for psychosis, which the Substance Abuse and Mental Health Services Administration has identified as a standard of care for this population. The explosion of telehealth, in large part due to the COVID-19 pandemic, has led to increased opportunities for virtual psychotherapy. Telehealth offers a number of benefits, such as the ability to address service inequities, including lack of access to a local provider well-trained in the modality of therapy needed. The current article describes the National Psychosis Telehealth Program within the National Expert Consultation and Specialized Services (formerly VA National Telemental Health Center) program, U.S. Department of Veterans Affairs. The goal of this telehealth program is to utilize an expert consultation model and offer a remote individual, time-limited Cognitive Behavioral Therapy for psychosis protocol to Veterans across the nation in order to decrease access disparities to this relatively scarce service. We share our initiation activities and lessons learned as we developed this program in hopes of encouraging others to consider similar efforts at their sites. We also include a typical, complex case that serves to illustrate the challenges and benefits of this approach. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Veterans Affairs seamless phase II/III randomized trial of standard systemic therapy with or without PET-directed local therapy for oligometastatic prostate cancer (VA STARPORT).

TPS5120 Background: The concept of metastasis-directed therapy (MDT) using radiation or surgery for oligometastatic (OM) prostate cancer (pCa) has evolved from an anecdotal hypothesis to a promising approach that may optimally balance toxicity and oncologic efficacy. Recently, there have been multiple smaller phase II randomized trials that have shown a signal of efficacy for MDT in OM pCa. Most studies have compared MDT to observation alone as the control arm, included only recurrent OM patients, and included up to 3-5 sites of metastasis. It is in this context, that the VA STARPORT trial was initiated in 2021 to definitively determine the role of MDT in Veterans with oligorecurrent pCa in 1-5 sites. Yet, the diagnosis and management of metastatic pCa have since evolved. The SABR-COMET-10 trial recently completed enrollment and compares systemic therapy alone or with MDT in patients with 1-10 metastases from various histologies. While pCa PET/CT imaging was only available for Veterans with biochemical recurrence in 2021, PSMA PET/CT now allows for the improved diagnosis of OM in Veterans with de novo pCa—a growing cohort of patients without a clear standard of care. Therefore, to maximize the impact and generalizability of the trial, VA STARPORT has been amended to allow for de novoOM and 1-10 metastases. The primary goal of VA STARPORT is to determine if adding PET-directed local therapy (PDLT) to standard systemic therapy (SST) improves disease control compared to SST alone in Veterans with recurrent and de novooligometastatic pCa. Methods: VA STARPORT is a phase II/III randomized trial open at 18 VA medical centers comparing SST alone (Arm 1) or with PDLT (Arm 2) in Veterans with OM pCa. Key eligibility criteria include recurrent or de novohormone-sensitive metastatic pCa and 1-10 metastatic lesions on any FDA-approved pCa PET/CT. The primary endpoint is castration-resistant prostate cancer-free survival (CRPC-free survival). Secondary endpoints include radiographic PFS, clinical PFS, freedom from index lesion progression, toxicity, quality of life, and prostate cancer-specific and overall survival. SST is delivered using any NCCN guideline-concordant regimen in both arms. PDLT can be either radiation or surgery to all sites of cancer. Regarding local therapy, de novo patients in Arm 1 receive prostate-directed RT, and in Arm 2 receive PDLT to all metastases and the prostate. For recurrent patients in Arm 1 there is no local therapy, while in Arm 2 patients receive PDLT. All participants undergo somatic tumor sequencing using the VA National Precision Oncology Program. Assuming a hazard ratio of 0.60 for SST + PDLT vs SST, two-sided alpha = 0.05 and 90% power, a total of 464 participants will be randomized to generate 166 CRPC-free survival events by the end of the active study phase. Recruitment is ongoing and 150 patients have been enrolled. Clinical trial information: NCT04787744 .

Abstract 143: Electronic Consultation for Outpatient Stroke/TIA Care: Are Recommendations Followed?

Background: Including electronic consultations (e-consults) in addition to video visits in a teleneurology program can improve patient access and allow early recommendations (recs) to be communicated to referrers of patients with prior stroke/TIA. We sought to compare how attention to recs differed by type of teleneurology care. Methods: We evaluated outpatient video and e-consults for Veterans with stroke/TIA receiving care in the VA National TeleNeurology Program from 12/2022-4/2023. E-consults were completed if relevant records were available in the electronic health record (EHR). Video consults were scheduled as part of the NTNP. Clinical information, recs (categorized by type), and subsequent orders were assessed with EHR data and chart review. Rec attention was defined as ordered or completed within 60 days of a completed consult. We used two-sided two-sample t-tests, two-sample Wilcoxon rank sum tests and chi-square tests to compare demographics and rec attention rates between e-consult and video groups. Results: Of 391 consults requested for a stroke/TIA diagnosis, 214 (55%) had a neurologist stroke/TIA diagnosis and at least one rec; 57 (27%) of these were e-consults. Patients were similar in both groups (Table); e-consults were completed faster (mean 3.9 days vs. 60.3 days). E-consults had a similar number of recs (mean 2.2 recs vs 1.9 per consult, p = 0.17) but slightly more imaging recs (0.89 vs 0.62 per consult, p = 0.04). Overall, e-consult recs were less likely to receive attention: 55% in e-consult vs 69%, p = 0.05; this gap was worst for attention to lab recs (40% vs 70%, p = 0.03). Conclusion: E-consults for outpatient stroke/TIA questions can improve the timeliness of care, but recs are less likely to be followed than if care is directly provided via telehealth video visits. Consideration for care models that improve communication between the neurologist and the referrer may be necessary to improve attention to consult recommendations.

514. Nirmatrelvir/ritonavir or Molnupiravir for Treatment of Non-hospitalized Patients with COVID-19 at Risk of Disease Progression

Abstract Background In randomized controlled trials, Nirmatrelvir/ritonavir (NMV/r) and Molnupiravir (MPV) reduced the risk of severe/fatal COVID-19 disease. Real-world data are limited, particularly studies directly comparing the two agents. Methods Using the VA National COVID-19 database, we identified previously uninfected, non-hospitalized individuals with COVID-19 with >1 risk factor for disease progression who were prescribed either NMV/r or MPV within 3 days of a positive test. We used inverse probability of treatment weights (IPTW) to account for providers’ preferences for a specific treatment. Absolute risk difference (ARD) with 95% confidence intervals were determined for those treated with NMV/r vs. MPV. The primary outcome was severe, critical, or fatal disease within 30 days of treatment prescription using the IPTW approach. Analyses were repeated using propensity-score matched groups and 1:1 matched groups. Cohort construction Results Between January 1 and November 30, 2022, 9,172 individuals were eligible for inclusion (6,692 prescribed NMV/r; 2,480 prescribed MPV). The ARD for severe, critical, or fatal disease for NMV/r vs MPV was -0.18 (95% CI -0.45 to 0.09). There was no statistically significant difference in ARD among strata by age, race, sex, comorbidities, or symptoms at baseline. Kaplan-Meier curves did not demonstrate a difference between the two groups (p-value=0.43). Analysis of the propensity-score matched cohort yielded similar results (ARD for NMV/r vs. MPV -0.12, 95% CI -0.71 to 0.47). Conclusion We found no significant difference in short term risk of severe, critical or fatal disease in non-hospitalized individuals with COVID-19 at risk of disease progression treated with either NMV/r or MPV. Disclosures Adeel A. Butt, MBBS, MS, Gilead Sciences: Grant/Research Support|Merck and Company: Grant/Research Support

Очерк растительности окрестностей Окуневых озер (Приполярный Урал, национальный парк «Югыд ва»)

The article presents new information about the plant cover diversity of the study site within the large nature protected area, the Yugyd Va National Park, that is poorly studied in the botanical aspect. It characterizes the vegetation of light woodland, mountain-tundra, and bare rock belts and demonstrates the change of phytocenoses along the height gradient.

Success of Liquid Tumor Biopsy in Men with Metastatic Prostate Cancer According to Self-Identified Race.

Liquid biopsy using cell-free DNA (cfDNA) is increasingly used to identify somatic prostate cancer (PrCa) alterations when tissue biopsy of a metastatic lesion is infeasible or impractical. High-risk somatic alterations identified by cfDNA have been recently shown to predict the benefit of metastasis-directed therapy with stereotactic body radiation therapy in PrCa. However, given the older age of PrCa patients, liquid biopsy is often contaminated with alterations related to clonal hematopoiesis of indeterminate potential (CHIP), generating uncertainty in the clinical utility of the results. Given the higher incidence and aggressiveness of metastatic PrCa in Black men, we sought to determine if the success of cfDNA testing varied by race in a large and diverse cohort of United States Veterans with metastatic PrCa, hypothesizing that race would not influence the success of cfDNA testing. Veterans with metastatic PrCa underwent next-generation sequencing of cfDNA biopsy specimens through the VA National Precision Oncology Program from February 2019 to November 2022. Successful identification of PrCa with cfDNA testing was defined as the identification of an alteration in one or more PrCa-related related genes in the gene panel tested (AR, CDK12, SPOP, MED12, CCND1, BRAF, AKT1, TMPRSS2, ERG, ETV1, and ETV4). Univariate logistic regression was employed to explore the association between patient self-identified race, as well as other patient and disease-specific factors at the time of cfDNA biopsy, with the likelihood of yielding a successful cfDNA biopsy result. A total of 2066 cfDNA tests from 1985 Veterans were related to a diagnosis of PrCa, passed quality control measures, and were linkable to patient-level demographics. Median age at testing was 74, median PSA at testing was 22.7, median PSA doubling time (PSADT) was 3.6 months, and median Gleason score was 8. 57% of Veterans self-identified as White, 33% as Black, and 10% as Other. Eight hundred fourteen (39%) tests were deemed successful by finding a PrCa related gene alteration. Among successful tests, the most frequently encountered alterations were AR alterations in 60.4% White men and 33.9% Black men (p = 0.72), followed by TMPRSS2 alterations in 70.3% White men and 22.0% Black men (p<0.001). Despite a lower rate of PrCa-specific alterations in Black men, on univariate analysis, Veteran self-identified race was not associated with successful cfDNA testing (OR 0.95, 95% CI 0.78-1.14, p = 0.6), whereas PSA in quintiles 2-4, PSADT <12 months, and unit increase in Gleason score were associated with successful cfDNA testing (p<0.01 for all). Successful cfDNA biopsy in metastatic PrCa is associated with PSA and PSADT, but not related to patient self-identified race. In appropriate clinical scenarios, patients who self-identify as Black or White are equally likely to have PrCa-specific alterations detected on cfDNA testing when evaluating metastatic PrCa patients for local and systemic therapies.

The VA National Teleneurology Program (NTNP): Implementing Teleneurology to Improve Equitable Access to Outpatient Neurology Care

BackgroundTelehealth is increasingly utilized in many healthcare systems to improve access to specialty care and better allocate limited resources, especially for rurally residing persons who face unique barriers to care.ObjectivesThe VHA sought to address critical gaps in access to neurology care by developing and implementing the first outpatient National Teleneurology Program (NTNP).DesignPre-post evaluation of intervention and control sites.ParticipantsNTNP sites and VA control sites; Veterans completing an NTNP consult and their referring providers.InterventionImplementation of the NTNP at participating sites.Main MeasuresNTNP and community care neurology (CCN) volume of consults before and after implementation; time to schedule and complete consults; Veteran satisfaction.Key ResultsIn FY2021, the NTNP was implemented at 12 VA sites; 1521 consults were placed and 1084 (71.3%) were completed. NTNP consults were scheduled (10.1 vs 29.0 days, p < 0.001) and completed (44.0 vs 96.9 days, p < 0.001) significantly faster than CCN consults. Post-implementation, monthly CCN consult volume was unchanged at NTNP sites compared to pre-implementation (mean change of 4.6 consults per month, [95% CI − 4.3, 13.6]), but control sites had a significant increase (mean change of 24.4 [5.2, 43.7]). The estimated difference in mean change in CCN consults between NTNP and control sites persisted after adjusting for local neurology availability (p < 0.001). Veterans (N = 259) were highly satisfied with NTNP care (mean (SD) overall satisfaction score 6.3 (1.2) on a 7-point Likert scale).ConclusionsImplementation of NTNP resulted in more timely neurologic care than care in the community. The observed significant increase in monthly CCN consults at non-participating sites during the post-implementation period was not seen at NTNP sites. Veterans were highly satisfied with Teleneurology care.

A Research Agenda forCriminal Justice Involvement Among U.S. Veterans.

A substantial proportion of adults in the U.S. criminal justice system are military veterans. Justice-involved veterans are of particular public concern given their service to the country and the high rates of health and social problems in the general veteran population. This article describes the development of a national research agenda for justice-involved veterans. In the summer of 2022, the VA National Center on Homelessness among Veterans in partnership with the VA Veterans Justice Programs Office convened a national group of subject matter experts and stakeholders across three listening sessions that included 40-63 attendees per session. These sessions were recorded, and transcriptions of all sessions and chats were synthesized to generate a preliminary list of 41 agenda items. The Delphi method involving two rounds of ratings from subject matter experts was used to develop consensus. The final research agenda consists of 22 items covering five domains: Epidemiology and knowledge of the population, treatment and services, systems and systems interface, methodology and research resources, and policies. The intent of sharing this research agenda is to spur stakeholders to conduct, collaborate, and support further study in these areas.

Clinical factors associated with successful liquid tumor biopsy in men with prostate cancer.

e13567 Background: Liquid biopsies using cell-free DNA (cfDNA) can be used in prostate cancer (PrCa) patients when tissue is unavailable and repeat biopsy is not feasible. Given the older age of PrCa patients, liquid biopsy may detect alterations related to clonal hematopoiesis of indeterminate potential (CHIP), generating uncertainty in the clinical utility of the results. We sought to identify clinical predictors of successful cfDNA biopsy, where the reported alterations are more likely to reflect the individual’s prostate cancer cfDNA instead of CHIP in a large cohort of United States Veterans with PrCa. Methods: Next-generation sequencing of cfDNA biopsy specimens was performed through the VA National Precision Oncology Program (NPOP) from February 2019 to November 2022. Successful identification of PrCa cfDNA testing was defined as the identification of an alteration in one or more PrCa-related genes included on the panel ( AR, CDK12, SPOP, MED12, CCND1, BRAF, AKT1, TMPRSS2, ERG, ETV1, and ETV4). Student’s t-tests, univariate, and multivariate logistic regression estimated significant patient and disease-specific factors at the time of cfDNA biopsy and the likelihood of obtaining a successful cfDNA biopsy result. Results: Among 5611 total cfDNA tests performed, 2066 cfDNA tests from 1985 Veterans listed PrCa as the clinical indication, passed quality control measures, and could be linked to patient-level demographics. 814 (39%) tests were deemed successful based upon identification of at least one PrCa related gene alteration. The most frequently encountered PrCa alterations were in AR (76.5%) and TMPRSS2 (22.4%). PSA was significantly higher (IQR 209.1 ng/ml) and PSA doubling time (PSADT) was significantly shorter (IQR 2.4 months) in the cohort of Veterans with successful cfDNA testing (p&lt;0.001). Among 1581 tests that reported tumor fraction, an elevated tumor fraction &gt;10 was also significantly associated with success (46.3% vs 8.1%, p&lt;0.001). On multivariate analysis, PSA elevation above 4.8 ng/ml (p&lt;0.001) and PSADT &lt;6 months (p&lt;0.001) were significantly associated with successful cfDNA testing. Actionable DDR mutations, including ATM (15.2% vs 11.7%, p=0.02), BRCA1 (1.7% vs 0.6%, p=0.03), and BRCA2 (7.4% vs 4.4%, p=0.01) were significantly more likely to be detected in a successful test compared to an unsuccessful test. Conclusions: High PSA and short PSADT are significant predictors of a cfDNA test identifying PrCa-related gene alterations in Veterans with metastatic disease instead of alterations due solely to CHIP. Liquid biopsy in PrCa should be reserved for patients with relatively higher disease burden or more aggressive growth rate, reflected by PSA values &gt; 4.8 and PSADT &lt; 6 months, to increase the likelihood of identifying actionable alterations and improve interpretation of testing.

Barriers and facilitators to implementing the Veterans Health Administration National Teleoncology Service: A qualitative descriptive study.

e13684 Background: Many Veterans lack local access to specialized cancer services. When timely VA care is not accessible, the VA covers the cost of care provided in a Veteran’s community. This benefit disrupts integrated care delivery within VA and may be less applicable for Veterans in areas where specialized cancer services may also not be available locally. The National TeleOncology (NTO) service was established to provide remotely delivered cancer services and increase access for Veterans to specialized cancer care. We sought to understand early implementation experiences as part of an ongoing evaluation of the VA National TeleOncology (NTO) service. Methods: Informed by the Consolidated Framework for Implementation Research (CFIR), we conducted a qualitative descriptive study using virtual individual interviews with Veterans (results not reported) and focus groups with clinicians. To identify and describe implementation barriers and facilitators, oncologists, nurse practitioners (NPs), and registered nurses (RNs) who provide care via teleoncology were asked about the need for NTO, its advantages/disadvantages compared to alternatives, and how to operationalize and measure NTO’s success. Additionally, Veterans who have participated in the teleoncology program were asked about their experiences; the analysis of this data is ongoing. We employed a team-based, rapid qualitative analysis using structured forms for notetaking. Theme matrix techniques facilitated data analysis and presentation. Findings were mapped to CFIR domains and constructs. Results: Guided by information power, we conducted 15 individual interviews with Veterans and three focus groups, separated by clinician type. The individual interviews lasted approximately 36 minutes, and focus groups lasted approximately 30 minutes. Most Veteran participants were male (87%), white (60%), and had prostate cancer (47%). Results from our analysis suggest that clinicians feel there are key challenges/barriers to engaging NTO: 1) can delay care; 2) perception that NTO may not be as personable as in-person care; 3) technology access/use can be difficult for some Veterans. They also reported key advantages/facilitators: 1) provides Veterans nationwide with accessibility to cancer specialists; 2) keeps patients in VA system to support better care coordination and team-based care that expedites needed follow-up services. Conclusions: Those involved in implementing NTO feel supported and that it works well overall, especially to provide better coordinated cancer care for Veterans. These data will support an ongoing NTO evaluation. Separate data collection efforts are underway to understand the quality of care delivered to inform the widespread scale-out and delivery of NTO.

Печеночники (Marchantiophyta) бассейна р. Большой Паток (национальный парк «Югыд ва», Республика Коми)

An annotated list of liverworts collected in the Bolshoy Patok River Basin (Pechora River Basin, Yugyd Va National Park, Komi Republic, Russia) is presented for the first time. The list includes 101 species and one subspecies of 53 genera, 27 families, six orders, and two classes (Marchantiopsida and Jungermanniopsida). Data on collecting places, habitats, substrate, and structures associated with reproduction are provided for every species. Solenostoma subellipticum is reported for the first time for the Komi Republic flora. Six species listed in the Red Data Book of the Komi Republic (Arnellia fennica, Heterogemma laxa, Lophozia ascendens, Odontoschisma elongatum, Oleolophozia perssonii, Scapania apiculata) have been found in the flora. Forest habitats and rock outcrops are characterized by the highest taxonomic diversity: 72 and 60 species, respectively. Spruce forests dominate in number of species (38) among the forest formations. Revealed liverworts prefer to grow on rocky substrates and disturbed soil. About 78% of the identified species form reproductive structures.

Assessment of the Population of the European Grayling under Limited Data

The state of populations of European grayling Thymallus thymallus (Linnaeus, 1758) has been assessed and compared in two Ural tributaries of the Pechora River. The grayling inhabiting the Shchugor River (the territory of Yugyd Va National Park) has been satisfactorily preserved with minimal shifts in population characteristics. In the Bolshaya Synya River, protected only at the river source, the grayling population decreased mostly by the fish of the maximum age (up to 7+), the share of repeatedly spawning individuals has decreased as well (4.0–4.8%), and the overall mortality rate has increased. Deterioration of the grayling population in the Bolshaya Synya River was due to intensive illegal fishing. Under limited initial data, using a set of traditional indicators appeared a more universal assessment approach, while the length-based indicators (LBIs) method has only limited application.

Inocybe stellatospora и I. teraturgus (Inocybaceae, Agaricales) — первые находки плодовых тел на территории России

Here we present information about the first findings of basidiomes of two species of the genus Inocybe (I. stellatospora, I. teraturgus) in Russia. The species were collected in the foothills and mountains of the western macroslope of the Subpolar and Northern Urals, on the territory of two protected areas: Yugyd Va National Park and Pechoro-Ilychsky Reserve (Komi Republic). Analysis of the ITS1-5.8s rRNA-ITS2 sequences of I. stellatospora and I. teraturgus samples confirmed their identification by morphological features. The article provides morphological descriptions of the species, photographs of microscopic features as well as discusses differences with morphologically similar species.

Posttraumatic stress disorder, suicide, and unintended overdose death in later life: A national cohort study of veterans aged 50 and older.

Although studies have shown posttraumatic stress disorder (PTSD) associated with risk of suicide, the relationship in later life, especially for overdose death, remains unclear. Thus, the aim of the current study was to determine associations between PTSD, suicide, and unintended overdose death in mid- to late-life. A nationwide cohort study integrating Department of Veterans Affairs' (VA) data, Centers for Medicare & Medicaid Services data, and national cause-specific mortality data. Participants were US veterans aged ≥50 years with PTSD diagnoses at baseline (2012-2013) and were propensity-matched 1:1 with patients without PTSD based on sociodemographics, Charlson Comorbidity Index, and neuropsychiatric disorders (N=951,018). Information on suicide attempts and unintended death by overdose through December 31, 2017 was provided by the VA's National Suicide Prevention Applications Network (non-fatal attempts) and Mortality Data Repository (death). Veterans with PTSD (N=475,509) had increased risk of suicide attempt (Hazard Ratio [HR], 1.59; 95% CI, 1.54-1.65; p < 0.001), non-fatal attempt (HR, 1.74; 95% CI, 1.67-1.81; p < 0.001), drug overdose death overall (HR, 1.32; 95% CI, 1.22-1.42; p < 0.001), and suicide overdose death (HR, 1.44; 95% CI, 1.15-1.80; p=0.002), even after adjusting for sociodemographics, Charlson comorbidity index, and neuropsychiatric disorders. We found increased risk for overdose death by narcotics (HR, 1.30; 95% CI, 1.15-1.46; p < 0.001), antiepileptic/sedative-hypnotics (HR, 1.29; 95% CI, 1.02-1.62; p=0.032), and for other/unspecified drugs (HR, 1.35; 95% CI, 1.20-1.51; p < 0.001), the last category indicative of polydrug. Results remained robust when examined for unintentional, suicide, and undetermined intent for cause-specific death by other/unspecified drugs. PTSD persists throughout mid- to late-life with considerable increased risk for non-fatal suicide attempts and suicide overdose death. These findings suggest the importance of drug-monitoring in preventing late-life suicide.

FLORA OF BARKOV MOUNTAIN (FLORA OF MOUNT BARKOV (SUBPOLAR URALS) AND ITS ROLE IN THE CONSERVATION OF RARE PLANTS

A list of vascular plants of the Barkova Mountain in Subpolar Urals (1320 m above sea level) made up of 237 species from 124 genera and 45 families is published. The high taxonomic diversity of the flora is predicated on a number of factors: mountainous relief and significant altitudinal range (670 m), the presence of several altitudinal vegetation belts and a vast mountain-top plateau, heterogeneous bedrocks, climatic conditions of subarctic highlands, and the general history of the flora formation during the Late Pleistocene. The flora of the Barkova Mountain occupies a transitional position, with both arctic montane and boreal features, and is classified as hypoarctic montane with regional characteristics. Two taxa (Sedum roseum and Castilleja arctica subsp. vorkutensis) are included in the Red Data Book of the Russian Federation, 27 taxa - in the Red Data Book of the Komi Republic, and 13 - in the Appendix to the regional Red Data Book. Many protected species are represented by marginal populations in the study area. Two species (Ranunculus kamchaticus and Draba pauciflora) have single records for the Komi Republic. Despite the recent significant human impact, the Barkova Mountain is important for the conservation of the floral diversity of the region, the Yugyd Va National Park and the Virgin Komi Forests UNESCO World Heritage Site.

PTSD, major depression, and advanced transcriptomic age in brain tissue.

Psychiatric disorders have been associated with advanced epigenetic age in DNA methylation, yet this relationship has not been studied in the brain transcriptome. We examined transcriptomic age using an RNA-based algorithm recently developed by Ren and Kuan ("RNAAgeCalc") and the associations between posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and alcohol use disorderwith age-adjusted RNA age ("RNA age residuals") in three brain regions: dorsolateral prefrontal cortex, ventromedial prefrontal cortex (vmPFC), and motor cortex. RNA sequencing was used to measure gene expression in postmortem brain tissue from the VA National PTSD Brain Bank (n = 94; 59% male). Linear models revealed that diagnoses of PTSD and/or MDD were positively associated with RNA age residuals in vmPFC only (p-adj = 0.012). Three genes in the RNAAgeCalc algorithm (KCNJ16, HYAL2, and CEBPB) were also differentially expressed in association with PTSD/MDD in vmPFC (p-adj = 6.45E-05 to 0.02). Enrichment analysis revealed that inflammatory and immune-related pathways were overrepresented (p-adj < 0.05) among the 43 genes in RNAAgeCalc that were also at least nominally associated with PTSD/MDD in vmPFC relative to the 448 RNAAgeCalc genes. Endothelial and mural cells were negatively associated with RNA age residuals in vmPFC (both p-adj = 0.028) and with PTSD/MDD (both p-adj = 0.017). Results highlight the importance of inflammation and immune system dysregulation in the link between psychopathology and accelerated cellular aging and raise the possibility that blood-brain barrier degradation may play an important role in stress-related accelerated brain aging.

Ecological and habitat ranges of orchids in the northernmost regions of their distribution areas: A case study from Ural Mountains, Russia

The Orchidaceae, which is one of the most interesting families of angiosperms, contains a large number of rare species. Despite their acknowledged importance, little attention has been paid to the study of orchids distributed in northern territories. In this study, we determined the syntaxonomical diversity and ecological parameters of orchid habitats in two of Europe's largest protected areas, the Pechoro-Ilychsky Reserve and the Yugyd Va National Park (northeastern European Russia), and then compared our findings to those in other parts of orchid distribution ranges. For this purpose, we studied 345 descriptions of plant communities (releves) containing species from Orchidaceae and defined habitat parameters using Ellenberg indicator values with the community weight mean approach, nonmetric multidimensional scaling (NMS), and relative niche width. We found that orchids were distributed in eight habitat types and 97 plant associations. The largest number of orchid species is found in forest communities. Half of the orchid species under study occur in the mires and rock habitats with open vegetation. Several orchids consistently occur in areas disturbed by human activity. In addition, our study indicates that the main drivers of orchid distribution across the vegetation types are light and soil nitrogen. Our analysis of the ecological parameters of orchid habitats indicates that some orchid species can be classified as habitat specialists that are confined to a relatively narrow ecological niche in the Urals (e.g., Goodyera repens, Cypripedium guttatum and Dactylorhiza maculata). Several other species (e.g. Neottia cordata and Dactylorhiza fuchsia) grow under diverse ecological parameters.

Analysis of actionable genetic alterations in lung carcinoma from the VA National Precision Oncology Program

Lung cancer is the leading cause of cancer mortality in men and women. Genomic sequencing of non-small cell lung cancer (NSCLC) is critical for the optimal treatment of NSCLC. In this study we sought to describe the frequencies of highly actionable driver mutations in lung adenocarcinoma (LUAD), squamous cell (LUSQ) and other NSCLC histologies (LUOT) in Veterans tested through the VA's National Precision Oncology Program (NPOP) and compare these frequencies to other published datasets from highly specialized academic cancer centers. The NPOP cohort included 3,376 unique Veterans with a diagnosis of lung carcinoma tested between February 2019 and January 2021 including 1892 with LUAD, 940 with LUSQ, and 549 with LUOT. Among patients with LUAD, 27.5% had highly actionable genetic variants. The frequency of targetable mutations was as follows: ALK rearrangement 0.8%, BRAF V600E 2.1%, EGFR exon 20 insertion mutation 0.48%, EGFR sensitizing mutations 6.6%, ERBB2 small variants 1.2%, KRAS G12C 14.0%, MET exon 14 skipping mutation 1.5%, NTRK rearrangement 0.1%, RET rearrangement 0.4%, and ROS1 rearrangement 0.3%. The frequency of EGFR mutations, RET rearrangement, MET exon 14 and ERBB2 small variants frequencies were significantly lower in NPOP compared to other published reports while MET amplification was more common in NPOP. Combined rates of highly actionable genetic variants were 2.7% and 13.4% in LUSQ and LUOT, respectively. In this study, 27.5% of Veterans with lung adenocarcinoma have actionable genetic alterations eligible for FDA approved targeted therapies, a frequency only slightly lower than other published datasets despite higher smoking rates in Veterans. Genomic sequencing should be performed in all Veterans with advanced LUAD and LUOT.

Frequency and outcomes of molecularly guided off-label targeted agent prescriptions in the VA National Precision Oncology Program (NPOP).

e18676 Background: The increasing availability of comprehensive genomic profiling (CGP) and a growing number of targeted agents (TAs) has led to substantial improvements in outcomes among cancer pts with actionable mutations. CGP has led to identification of both on-label (level 1) variants, for which TAs have known efficacy, and off-label variants with lesser strength of supporting data. We sought to evaluate real-world prescription patterns and outcomes of off-label TA prescriptions among pts who underwent CGP. Methods: The NPOP database and VA Corporate Data Warehouse were queried to identify pts who had underwent CGP between February 2019 and December 2021 and were prescribed at least 1 of 73 TAs before January 2022. TAs prescribed for FDA-approved indications not relying on CGP as a companion diagnostic were excluded. OncoKB was used to annotate gene variants and evaluated against prescriptions to select pts who received off-label TAs. The frequency of off-label TA use, and for those treated &gt; 4 weeks, rate of pts treated for 6 months or longer, median treatment duration and overall survival (OS) were computed. Results: Of the 18686 patients who underwent CGP, 2107 (11%) were prescribed any TA, and 191 (1%) were prescribed off-label TAs, with 31 receiving multiple concurrent or sequential off-label TAs. Mean age was 65.5 years, and 88% were male. TAs were most often prescribed for cancers of unknown primary (CUP, 29), NSCLC (24), and colorectal cancer (22). Frequency of off-label prescriptions was highest for pts who completed CGP for thyroid cancer (9%), breast cancer (8%), and CUP (2%). Most common variants involved BRAF (21%), ERBB2 (18%), BRCA1/BRCA2/ATM (9%), and PIK3CA (6%). Among all 164 pts treated &gt; 4 weeks, 40% received TAs for 6 months or longer, including 50%, 47%, and 46% of pts bearing BRAF-, ERBB2-, and PIK3CA-mutant disease, respectively. Median therapy duration and OS was 141 [78.5 – 317, IQR] days and 181 [96.5 – 304.5, IQR] days, respectively. Conclusions: Though overall use of off-label TAs following CGP is low, nearly 10% of advanced thyroid and breast cancer patients are prescribed TAs for off-label indications. Forty percent of all pts receiving off-label TAs continue for at least 6 months, with higher rates for pts bearing BRAF-, ERBB2-, and PIK3CA-mutant disease. CGP-guided off-label treatment approaches offer unique options for advanced stage cancer with amenable molecular profiles.

Veterans affairs seamless phase II/III randomized trial of standard systemic therapy with or without PET-directed local therapy for oligorecurrent prostate cancer (VA STARPORT).

TPS5112 Background: Two diverging paradigms have been studied in recent years to improve the survival of men with recurrent metastatic prostate cancer (PCa). First, multiple recent phase II randomized trials have demonstrated improved long-term progression-free survival (PFS) with metastasis-directed therapy (MDT) in men with oligorecurrent PCa in the absence of systemic therapy. Yet, most patients receiving MDT for oligorecurrent PCa develop progression in new areas, arguing that systemic therapy is needed to treat occult metastases. The second approach that has recently been studied is whether escalating systemic therapy by adding novel androgen receptor axis targeted agents or chemotherapy improves outcomes in men with metastatic PCa. Multiple phase III randomized trials demonstrate that enhancing hormonal therapy with these therapeutic agents improves progression-free survival (PFS) and overall survival. Therefore, these agents have been integrated into today’s standard systemic therapy (SST) for metastatic recurrence, and SST is the current NCCN guidelines standard of care for recurrent metastatic PCa. The primary goal of our study is to determine if adding PET-directed local therapy (PDLT) to SST improves disease control compared to SST alone in Veterans with oligorecurrent PCa. Methods: VA STARPORT is a phase II/III randomized trial open at 16 VA medical centers comparing SST with or without PDLT in Veterans with oligorecurrent PCa. Key eligibility criteria include prior localized PCa with biochemical recurrence after initial curative-intent local therapy and workup including any FDA-approved PCa PET/CT that reveals oligorecurrence in 1-5 metastatic lesions. The primary endpoint is castration-resistant prostate cancer-free survival (CRPC-free survival). Secondary endpoints include radiographic PFS, clinical PFS, freedom from index lesion progression, toxicity, quality of life, and prostate cancer-specific and overall survival. SST is delivered with an intent for indefinite SST using any NCCN guideline-concordant regimen in both arms. PDLT (Arm 2) consists of surgery or radiation to metastases and any present prostate/prostate bed local recurrence. Metastasis-directed radiation can consist of stereotactic body radiotherapy or elective nodal radiotherapy per clinician discretion from dose/fractionation options defined in the protocol. All participants undergo somatic tumor sequencing using the VA National Precision Oncology Program. Germline sequencing and tumor banking in a separate biorepository study is recommended. Assuming a hazard ratio of 0.60 for SST + PDLT vs SST, two-sided alpha = 0.05 and 90% power, a total of 464 participants will be randomized to generate 166 primary events (CRPC-free survival) by the end of the 48-month active study phase. The study began enrollment in August 2021. Clinical trial information: NCT04787744.