Impact of Implementation Facilitation on the REACH VET Clinical Program for Veterans at Risk for Suicide.

OBJECTIVE: In 2017, the Veterans Health Administration (VHA) implemented a national suicide prevention program, called Recovery Engagement and Coordination for Health-Veterans Enhanced Treatment (REACH VET), that uses a predictive algorithm to identify, attempt to reach, assess, and care for patients at the highest risk for suicide. The authors aimed to evaluate whether facilitation enhanced implementation of REACH VET at VHA facilities not meeting target completion rates. METHODS: In this hybrid effectiveness-implementation type 2 program evaluation, a quasi-experimental pre-post design was used to assess changes in implementation outcome measures evaluated 6 months before and 6 months after onset of facilitation of REACH VET implementation at 23 VHA facilities. Measures included percentages of patients with documented coordinator and provider acknowledgment of receipt, care evaluation, and outreach attempt. Generalized estimating equations were used to compare differences in REACH VET outcome measures before and after facilitation. Qualitative interviews were conducted with personnel and were explored via template analysis. RESULTS: Time had a significant effect in all outcomes models (p<0.001). An effect of facilitation was significant only for the outcome of attempted outreach. Patients identified by REACH VET had significantly higher odds of having a documented outreach attempt after facilitation of REACH VET implementation, compared with before facilitation. Site personnel felt supported and reported that the external facilitators were helpful and responsive. CONCLUSIONS: Facilitation of REACH VET implementation was associated with an improvement in outreach attempts to veterans identified as being at increased risk for suicide. Outreach is critical for engaging veterans in care.

Validated respiratory drug deposition predictions from 2D and 3D medical images with statistical shape models and convolutional neural networks.

For the one billion sufferers of respiratory disease, managing their disease with inhalers crucially influences their quality of life. Generic treatment plans could be improved with the aid of computational models that account for patient-specific features such as breathing pattern, lung pathology and morphology. Therefore, we aim to develop and validate an automated computational framework for patient-specific deposition modelling. To that end, an image processing approach is proposed that could produce 3D patient respiratory geometries from 2D chest X-rays and 3D CT images. We evaluated the airway and lung morphology produced by our image processing framework, and assessed deposition compared to in vivo data. The 2D-to-3D image processing reproduces airway diameter to 9% median error compared to ground truth segmentations, but is sensitive to outliers of up to 33% due to lung outline noise. Predicted regional deposition gave 5% median error compared to in vivo measurements. The proposed framework is capable of providing patient-specific deposition measurements for varying treatments, to determine which treatment would best satisfy the needs imposed by each patient (such as disease and lung/airway morphology). Integration of patient-specific modelling into clinical practice as an additional decision-making tool could optimise treatment plans and lower the burden of respiratory diseases.

Estimating the per-protocol effect of lithium on suicidality in a randomized trial of individuals with depression or bipolar disorder.

BACKGROUND: The CSP590 randomized trial was designed to estimate the effect of lithium on suicidality. After a third of the intended number of participants were enrolled, the hazard ratio of suicidality was 1.10 (95% CI: 0.77, 1.55). Based on this, the trial was stopped for futility. However, only 17% of patients adhered to the specified protocol. AIMS: The objective was to estimate the per-protocol effect of lithium on suicidality, that is, the effect of adhering to the treatment strategies as specified in the protocol. METHODS: We stopped individuals' follow-up if/when they showed evidence of nonadherence. We then conducted the analysis in the restricted sample, adjusting for prognostic factors that predict adherence via inverse probability weighting. The primary outcome was the 12-month risk of suicidality (including death from suicide, suicide attempt, interrupted attempt, hospitalization specifically to prevent suicide). RESULTS: The estimated 12-month risk of suicidality was 18.8% for lithium, and 24.3% for placebo. The risk ratio was 0.78 (95% CI: 0.43, 1.37) and the risk difference -5.5 percentage points (95% CI: -17.5, 5.5). Results were consistent across sensitivity analyses. CONCLUSIONS: With one-third of the targeted sample size, lithium effects (compared with placebo) ranging between a 17.5% reduction and a 5.5% increase in the risk of suicidality were highly compatible with the data. Thus, a protective effect of lithium on suicidality among patients with bipolar disorder or major depressive disorder cannot be ruled out. Trials should incorporate adequate per-protocol analyses into the decision-making processes for stopping trials for futility.

Argon pharmacokinetics: a solubility measurement technique.

The noble gas argon has demonstrated biological activity that may prove useful as a medical intervention. Pharmacokinetics, the disposition of the drug molecule in the body through time, is fundamental necessary knowledge to drug discovery, development and even post-marketing. The fundamental measurement in pharmacokinetic studies is blood concentration of the molecule (and its metabolites) of interest. While a physiologically based model of argon pharmacokinetics has appeared in the literature, no experimental data have been published. Thus, argon pharmaceutical development requires measurement of argon solubility in blood. This paper reports on the development of a technique based on mass spectrometry for measuring argon solubility in liquids, including blood, to be further employed in pharmacokinetics testing of argon. Based on a prototype, results are reported from sensitivity experiments using ambient air, water and rabbit blood. The key takeaway is that the system was sensitive to argon during all of the testing. We believe the technique and prototype of the quadrupole mass spectrometer gas analyzer will be capable of inferring argon pharmacokinetics through the analysis of blood samples.

Outcomes for treatment of depression in the Veterans Health Administration: Rates of response and remission calculated from clinical and survey data.

Healthcare Effectiveness Data and Information Set (HEDIS) quality measures for depression treatment aggregate Patient Health Questionnaire (PHQ)-9 data from routine clinical assessments recorded in electronic health records (EHR). To determine whether aggregated PHQ-9 data in US Veterans Health Administration (VHA) EHRs should be used to characterize the organization's performance, we compared rates for depression response and remission calculated from EHRs with rates calculated with data representing the underlying Veteran patient population estimated using Veterans Outcome Assessment (VOA) survey data. We analyzed data from initial assessments and 3-month follow-up for Veterans beginning treatment for depression. EHR data were available for only a minority of Veteran patients, and the group of Veterans with EHR data differed from the underlying Veteran patient population with respect to demographic and clinical characteristics. Aggregated rates of response and remission from EHR data were significantly different from estimates based on representative VOA data. The findings suggest that until patient-reported outcome from EHRs are available for a substantial majority of patients receiving care, aggregated measures of patient outcomes derived from these data cannot be assumed to be representative of the outcomes for the overall population, and they should not be used as outcome-based measures of quality or performance.

Gaseous nitric oxide failed to inhibit the replication cycle of SARS-CoV-2 in vitro.

Nitric oxide (NO) has been shown to have antimicrobial activity in vitro and in some in vivo models, while the virucidal activity of NO remains elusive. Some studies using NO donors have suggested that NO could be a potential candidate to treat SARS-CoV infection. The Covid-19 pandemic raised the hypothesis that NO gas might have an impact on Sars-CoV-2 replication cycle and might be considered as a candidate therapy to treat COVID-19. To our knowledge, there are no in vitro preclinical studies demonstrating a virucidal effect of gaseous NO on SARS-CoV-2. This study aims to determine whether gaseous NO has an impact on the replication cycle of SARS-CoV-2 in vitro. To that end, SARS-CoV-2 infected epithelial (VeroE6) and pulmonary (A549-hACE2) cells were treated with repeated doses of gaseous NO at different concentrations known to be efficient against bacteria. Our results show that exposing SARS-CoV-2 infected-cells to NO gas even at high doses (160 ppm, 6 h) does not influence the replication cycle of the virus in vitro. We report here that NO gas has no antiviral properties in vitro on SARS-COV-2. Therefore, there is no rationale for its usage in clinical settings to treat COVID-19 patients for direct antiviral purposes, which does not exclude other potential physiological benefits of this gas.

Suicide risk following a new cancer diagnosis among Veterans in Veterans Health Administration care.

BACKGROUND: Cancer diagnoses are associated with an increased risk for suicide. The aim of this study was to evaluate this association among Veterans receiving Veterans Health Administration (VHA) care, a population that has an especially high suicide risk. METHODS: Among 4,926,373 Veterans with VHA use in 2011 and in 2012 or 2013, and without VHA cancer diagnoses in 2011, we assessed suicide risk following incident cancer diagnoses. Risk time was from initial VHA use in 2012-2013 to 12/31/2018 or death, whichever came first. Cox proportional hazards regression models evaluated associations between new cancer diagnoses and suicide risk, adjusting for age, sex, VHA regional network, and mental health comorbidities. Suicide rates were calculated among Veterans with new cancer diagnoses through 84 months following diagnosis. RESULTS: A new cancer diagnosis corresponded to a 47% higher suicide risk (Adjusted Hazard Ratio [aHR] = 1.47, 95% CI: 1.33-1.63). The cancer subtype associated with the highest suicide risk was esophageal cancer (aHR = 6.01, 95% CI: 3.73-9.68), and other significant subtypes included head and neck (aHR = 3.55, 95% CI: 2.74-4.62) and lung cancer (aHR = 2.35, 95% CI: 1.85-3.00). Cancer stages 3 (aHR = 2.36, 95% CI: 1.80-3.11) and 4 (aHR = 3.53, 95% CI: 2.81-4.43) at diagnosis were positively associated with suicide risk. Suicide rates were highest within 3 months following diagnosis and remained elevated in the 3-6- and 6-12-month periods following diagnosis. CONCLUSION: Among Veteran VHA users, suicide risk was elevated following new cancer diagnoses. Risk was particularly high in the first 3 months. Additional screening and suicide prevention efforts may be warranted for VHA Veterans newly diagnosed with cancer.

The Veterans Health Administration REACH VET Program: Suicide Predictive Modeling in Practice.

The U.S. Veterans Health Administration developed a suicide prediction statistical model and implemented a novel clinical program, Recovery Engagement and Coordination for Health-Veterans Enhanced Treatment (REACH VET). This high-value suicide prevention program aims to efficiently identify patients at risk and connect them with care. Starting in April 2017, national REACH VET metric data were collected from electronic health records to evaluate required task completion. By October 2020, 98% of veterans identified (N=6,579) were contacted by providers and had their care evaluated. In the nation's largest health care system, it was feasible to implement a clinical program based on a suicide prediction model.

Identifying medically relevant xenon protein targets by in silico screening of the structural proteome.

In a previous study, in silico screening of the binding of almost all proteins in the Protein Data Bank to each of the five noble gases xenon, krypton, argon, neon, and helium was reported. This massive and rich data set requires analysis to identify the gas-protein interactions that have the best binding strengths, those where the binding of the noble gas occurs at a site that can modulate the function of the protein, and where this modulation might generate clinically relevant effects. Here, we report a preliminary analysis of this data set using a rational, heuristic score based on binding strength and location. We report a partial prioritized list of xenon protein targets and describe how these data can be analyzed, using arginase and carbonic anhydrase as examples. Our aim is to make the scientific community aware of this massive, rich data set and how it can be analyzed to accelerate future discoveries of xenon-induced biological activity and, ultimately, the development of new "atomic" drugs.

Progress toward a performance measure for mental health based on a generic patient- reported outcome measure: Findings from the Veterans Outcome Assessment survey.

We report on studies conducted to develop outcome-based performance measures (PROM-PMs) based on generic patient-reported outcome measures (PROMs) that could support strategies for quality improvement applicable to all patients in a mental health system. Data were from the Veterans Outcome Assessment Survey at baseline and three months for the Mental Component Score (MCS-12), a widely used measure of mental health-related quality of life, for 15,540 outpatients beginning treatment in General Mental Health clinics in 140 Veterans Affairs (VA) facilities. Mental health diagnoses from medical records were coded using hierarchical categories. Mental health staffing levels and quality measures were from administrative data. Changes in MCS-12 scores were associated with demographics, baseline scores, and diagnostic categories; in fully adjusted models, differences between facilities accounted for only 0.5% of the total variance between patients. There were small but significant associations of both baseline and changes in MCS-12 scores with staffing levels and administrative measures of the quality of care that support the potential value of adjusted measures of changes in MCS-12 as a PROM-PM. Remaining issues include the low proportion of variability that can be attributed to differences between facilities and the associations of staffing and quality with possible case-mix adjustment variables.

Comparative risks of all-cause mortality for Veterans with schizophrenia with ongoing receipt of clozapine and other antipsychotic medications.

To guide care for patients with schizophrenia, the Veterans Health Administration (VHA) evaluated the associations between current or recent use of clozapine and all-cause mortality and explored associations for other antipsychotic medications. Using a case-control design, patients with schizophrenia who died in fiscal years 2014-2018 were matched on age, sex, race, and VHA facility to up to 10 controls who were alive on the case's date of death (index date). Medication coverage during the 91 days before the index date was classified as none, partial (1-44 days), and consistent (45-91 days). Medication coverage patterns during the index period were compared to coverage patterns during the period of 92-182 days prior to index date with each medication coverage classified as no change, no coverage, increased, or decreased. Conditional logistic regression analyses controlling for patient characteristics identified no associations of consistent or increasing clozapine coverage with mortality; partial and decreasing coverage were associated with greater mortality and these effects did not differ from those of other the medications considered. Exploratory analyses considering non-clozapine antipsychotic agents suggest that consistent coverage by olanzapine may be associated with increased mortality, that mortality associated with olanzapine may be greater than aripiprazole, and that this effect can be attributed primarily to patients with diabetes. Further study of this topic is needed.

Risk for PTSD symptom worsening during new PTSD treatment episode in a nationally representative sample of treatment-seeking U.S. veterans with subthreshold PTSD.

Previous research has examined risk factors associated with poorer treatment outcomes for military Veterans with PTSD. However, work has not examined risk for symptom worsening among Veterans with subthreshold PTSD. The aim of this study was to examine demographic, psychiatric, physical health, and pre-treatment PTSD symptom clusters associated with clinically significant worsening of PTSD among a nationally representative sample of United States (U.S.) Veterans with subthreshold PTSD. Participants were Veterans (weighted N = 3162; unweighted N = 236) with subthreshold PTSD entering a new episode of treatment at U.S. Veterans Affairs PTSD specialty clinics during fiscal years 2018 and 2019. Data was collected as part of the Veterans Outcome Assessment, a yearly baseline and 3-month follow-up telephone survey. Analyses used weighted calculations to support the use of VOA data to draw inferences about all eligible Veterans, and binary logistic regression was used to examine risk factors for symptom worsening. Over 1/3 (37.7%) of Veterans with subthreshold PTSD experienced clinically significant symptom worsening from baseline to follow-up. Adjusted analyses revealed several risk factors for symptom worsening, including demographic (e.g., male sex, White race), psychiatric (personality and anxiety disorders), health care utilization (e.g., more primary care encounters in the previous year), physical health disability, and specific baseline PTSD symptom clusters (negative affect and anxious arousal). Findings suggest that Veterans with subthreshold symptoms seeking treatment for PTSD are at risk for symptom worsening, and highlight the importance of assessment, prevention, and treatment in targeting veterans with PTSD symptoms below the diagnostic threshold.

Method for the Identification of Potentially Bioactive Argon Binding Sites in Protein Families.

Argon belongs to the group of chemically inert noble gases, which display a remarkable spectrum of clinically useful biological properties. In an attempt to better understand noble gases, notably argon's mechanism of action, we mined a massive noble gas modeling database which lists all possible noble gas binding sites in the proteins from the Protein Data Bank. We developed a method of analysis to identify among all predicted noble gas binding sites the potentially relevant ones within protein families which are likely to be modulated by Ar. Our method consists in determining within structurally aligned proteins the conserved binding sites whose shape, localization, hydrophobicity, and binding energies are to be further examined. This method was applied to the analysis of two protein families where crystallographic noble gas binding sites have been experimentally determined. Our findings indicate that among the most conserved binding sites, either the most hydrophobic one and/or the site which has the best binding energy corresponds to the crystallographic noble gas binding sites with the best occupancies, therefore the best affinity for the gas. This method will allow us to predict relevant noble gas binding sites that have potential pharmacological interest and thus potential Ar targets that will be prioritized for further studies including in vitro validation.

Interpreting patient reports of perceived change during treatment for depression: Findings from the Veterans Outcome Assessment survey.

This study addressed ongoing questions about the meaning of patients' perceptions of change during treatment. The study used data from the Veterans Outcome Assessment survey for patients with a depressive disorder, without mental health comorbidities, treated in Department of Veterans Affairs general mental health clinics (n = 694). Perceived changes in problems/symptoms, other domains, and the quality of communication with providers were evaluated with items from the Experience of Care & Health Outcomes (ECHO) survey. Depressive symptoms were measured with the Patient Health Questionnaire-9 (PHQ-9). Linear regression models evaluated associations of perceived change at 3-months post-baseline with observed change in PHQ-9 scores, scores on other patient-reported outcome measures (PROMs), and ratings of communication with providers. Patients' reports of their clinical condition at follow-up together with ratings of communication accounted for approximately one-third of the variance in patients' perceptions of change. Adding change-scores based on baseline and follow-up scores on the PHQ-9 and other PROMs did not improve model fit. The findings suggest that patient reports of perceived change during treatment reflect their current clinical state and their experience of care more closely than actual changes in the PHQ-9 or other PROMs.

Associations between patient experience and clinical outcomes in substance use disorder clinics: Findings from the veterans outcomes assessment survey.

BACKGROUND: Patient-centeredness is a cornerstone of substance use disorder (SUD) treatment. Patient-experience measures are potential tools for the routine assessment of patient-centered SUD care and may be valuable measures to inform quality monitoring improvement efforts. Little research exists on the predictive validity of patient-experience measures in SUD care. PURPOSE: We report on findings from the Veterans Outcome Assessment (VOA) survey that provides information on Veterans Health Administration SUD specialty care at treatment initiation and approximately 3-months post-initiation. METHODS: The VOA includes patient-reported outcomes across multiple domains, including the Brief Addiction Monitor (BAM-R), the Short-Form-12 (SF-12) and the Experience of Care and Health Outcome Survey (ECHO), and provides patient reports of the quality of provider communication and overall quality of SUD care. RESULTS: Nearly 40% of veterans in SUD care gave the highest possible ratings for communication and quality at both baseline and follow-up. Ratings of communication at 3-months were associated with treatment discontinuation and both ratings of communication and quality at 3-months and were independently associated with SUD symptoms and with mental well-being at 3-months. CONCLUSIONS: This study provides preliminary support for the inclusion of patient experience measures, particularly ratings of provider communication, as part of routine assessment in SUD care. However, further work on the validity of ratings of provider communication using additional methodologies is likely important before piloting the inclusion of such measures in routine assessment, such as in measurement base care.

Lithium Treatment in the Prevention of Repeat Suicide-Related Outcomes in Veterans With Major Depression or Bipolar Disorder: A Randomized Clinical Trial.

Importance: Suicide and suicide attempts are persistent and increasing public health problems. Observational studies and meta-analyses of randomized clinical trials have suggested that lithium may prevent suicide in patients with bipolar disorder or depression. Objective: To assess whether lithium augmentation of usual care reduces the rate of repeated episodes of suicide-related events (repeated suicide attempts, interrupted attempts, hospitalizations to prevent suicide, and deaths from suicide) in participants with bipolar disorder or depression who have survived a recent event. Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial assessed lithium vs placebo augmentation of usual care in veterans with bipolar disorder or depression who had survived a recent suicide-related event. Veterans at 29 VA medical centers who had an episode of suicidal behavior or an inpatient admission to prevent suicide within 6 months were screened between July 1, 2015, and March 31, 2019. Interventions: Participants were randomized to receive extended-release lithium carbonate beginning at 600 mg/d or placebo. Main Outcomes and Measures: Time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide. Results: The trial was stopped for futility after 519 veterans (mean [SD] age, 42.8 [12.4] years; 437 [84.2%] male) were randomized: 255 to lithium and 264 to placebo. Mean lithium concentrations at 3 months were 0.54 mEq/L for patients with bipolar disorder and 0.46 mEq/L for patients with major depressive disorder. No overall difference in repeated suicide-related events between treatments was found (hazard ratio, 1.10; 95% CI, 0.77-1.55). No unanticipated safety concerns were observed. A total of 127 participants (24.5%) had suicide-related outcomes: 65 in the lithium group and 62 in the placebo group. One death occurred in the lithium group and 3 in the placebo group. Conclusions and Relevance: In this randomized clinical trial, the addition of lithium to usual Veterans Affairs mental health care did not reduce the incidence of suicide-related events in veterans with major depression or bipolar disorders who experienced a recent suicide event. Therefore, simply adding lithium to existing medication regimens is unlikely to be effective for preventing a broad range of suicide-related events in patients who are actively being treated for mood disorders and substantial comorbidities. Trial Registration: ClinicalTrials.gov Identifier: NCT01928446.

Evaluation of the Recovery Engagement and Coordination for Health-Veterans Enhanced Treatment Suicide Risk Modeling Clinical Program in the Veterans Health Administration.

Importance: The Veterans Health Administration (VHA) implemented a national clinical program using a suicide risk prediction algorithm, Recovery Engagement and Coordination for Health-Veterans Enhanced Treatment (REACH VET), in which clinicians facilitate care enhancements for individuals identified in local top 0.1% suicide risk tiers. Evaluation studies are needed. Objective: To determine associations with treatment engagement, health care utilization, suicide attempts, safety plan documentation, and 6-month mortality. Design, Setting, and Participants: This cohort study used triple differences analyses comparing 6-month changes in outcomes after vs before program entry for individuals entering the REACH VET program (March 2017-December 2018) vs a similarly identified top 0.1% suicide risk tier cohort from prior to program initiation (March 2014-December 2015), adjusting for trends across subthreshold cohorts. Subcohort analyses (including individuals from March 2017-June 2018) evaluated difference-in-differences for cause-specific mortality using death certificate data. The subthreshold cohorts included individuals in the top 0.3% to 0.1% suicide risk tier, below the threshold for REACH VET eligibility, from the concurrent REACH VET period and from the pre-REACH VET period. Data were analyzed from December 2019 through September 2021. Exposures: REACH VET-designated clinicians treatment reevaluation and outreach for care enhancements, including safety planning, increased monitoring, and interventions to enhance coping. Main Outcomes and Measures: Process outcomes included VHA scheduled, completed, and missed appointments; mental health visits; and safety plan documentation and documentation within 6 months for individuals without plans within the prior 2 years. Clinical outcomes included mental health admissions, emergency department visits, nonfatal suicide attempts, and all-cause, suicide, and nonsuicide external-cause mortality. Results: A total of 173 313 individuals (mean [SD] age, 51.0 [14.7] years; 161 264 [93.1%] men and 12 049 [7.0%] women) were included in analyses, including 40 816 individuals eligible for REACH VET care and 36 604 individuals from the pre-REACH VET period in the top 0.1% of suicide risk. The REACH VET intervention was associated with significant increases in completed outpatient appointments (adjusted triple difference [ATD], 0.31; 95% CI, 0.06 to 0.55) and proportion of individuals with new safety plans (ATD, 0.08; 95% CI, 0.06 to 0.10) and reductions in mental health admissions (ATD, -0.08; 95% CI, -0.10 to -0.05), emergency department visits (ADT, -0.03; 95% CI, -0.06 to -0.01), and suicide attempts (ADT, -0.05; 95% CI, -0.06 to -0.03). Subcohort analyses did not identify differences in suicide or all-cause mortality (eg, age-and-sex-adjusted difference-in-difference for suicide mortality, 0.0007; 95% CI, -0.0006 to 0.0019). Conclusions and Relevance: These findings suggest that REACH VET implementation was associated with greater treatment engagement and new safety plan documentation and fewer mental health admissions, emergency department visits, and suicide attempts. Clinical programs using risk modeling may be effective tools to support care enhancements and risk reduction.