Multimodal analysis for human ex vivo studies shows extensive molecular changes from delays in blood processing.

Multi-omic profiling of human peripheral blood is increasingly utilized to identify biomarkers and pathophysiologic mechanisms of disease. The importance of these platforms in clinical and translational studies led us to investigate the impact of delayed blood processing on the numbers and state of peripheral blood mononuclear cells (PBMC) and on the plasma proteome. Similar to previous studies, we show minimal effects of delayed processing on the numbers and general phenotype of PBMC up to 18 hours. In contrast, profound changes in the single-cell transcriptome and composition of the plasma proteome become evident as early as 6 hours after blood draw. These reflect patterns of cellular activation across diverse cell types that lead to progressive distancing of the gene expression state and plasma proteome from native in vivo biology. Differences accumulating during an overnight rest (18 hours) could confound relevant biologic variance related to many underlying disease states.

Longitudinal immune dynamics of mild COVID-19 define signatures of recovery and persistence.

SARS-CoV-2 has infected over 200 million and caused more than 4 million deaths to date. Most individuals (>80%) have mild symptoms and recover in the outpatient setting, but detailed studies of immune responses have focused primarily on moderate to severe COVID-19. We deeply profiled the longitudinal immune response in individuals with mild COVID-19 beginning with early time points post-infection (1-15 days) and proceeding through convalescence to >100 days after symptom onset. We correlated data from single cell analyses of peripheral blood cells, serum proteomics, virus-specific cellular and humoral immune responses, and clinical metadata. Acute infection was characterized by vigorous coordinated innate and adaptive immune activation that differed in character by age (young vs. old). We then characterized signals associated with recovery and convalescence to define and validate a new signature of inflammatory cytokines, gene expression, and chromatin accessibility that persists in individuals with post-acute sequelae of SARS-CoV-2 infection (PASC).

Analysis of the Appropriateness of Off-Label Antipsychotic Use for Mental Health Indications in a Veteran Population.

STUDY OBJECTIVE: A substantial proportion of antipsychotic (AP) use in veterans is for nonapproved indications (i.e., off-label prescribing). Not all off-label use is necessarily detrimental to patients, however, and in certain situations, off-label prescribing could be considered justifiable. The objective of this study was to determine the extent to which off-label AP prescribing in a veteran population was potentially appropriate. DESIGN: Expert panel and retrospective analysis. DATA SOURCE: Veterans Health Administration (VHA) Corporate Data Warehouse. PATIENTS: A total of 69,823 veterans who had at least one pharmacy record for an AP medication during fiscal years 2005-2012. MEASUREMENTS AND MAIN RESULTS: An expert panel was convened to determine if agreement exists on the appropriateness of AP use in various scenarios. The panel consisted of 10 experts in the field of psychiatry: nine physicians with various specialties, and one pharmacist. We used a modified RAND appropriateness method approach to identify potentially appropriate, uncertain, and inappropriate cases of AP use. The use of six second-generation APs was examined individually, and the use of first-generation APs was examined as a class. Based on data previously collected quantifying VHA AP use, the panel was given disease state scenarios for the most commonly occurring off-label diagnoses for AP prescriptions. Disease states were coupled with scenario modifiers that the expert panel considered potentially significant clinical factors. Among the four disease states-anxiety, dementia, insomnia, and posttraumatic stress disorder-29 scenarios were investigated for each AP. None of the scenarios were judged by the expert panel to be appropriate for the use of APs. Of the 203 scenarios for all APs, 60% were judged to be inappropriate by the expert panel, and the remaining 40% were considered uncertain. Of the AP medications, risperidone (72%) and olanzapine (62%) were the most likely to be seen as uncertain, whereas first-generation APs (86%) were the most likely to be considered inappropriate in a given scenario. Widespread off-label use of APs outside of the approved indications of treatment of schizophrenia and bipolar disorder, or adjunctive treatment of major depressive disorder, may not be an appropriate treatment option. According to this expert panel, no examined situations were considered appropriate for the use of APs. CONCLUSION: The consensus of our expert panel was that off-label AP use is uncertain at best and more likely, even in complicated cases, inappropriate. These findings strengthen the case for stronger control of APs in integrated health care settings such as the VHA, as well as better education and information for practitioners who provide care for patients with anxiety, dementia, insomnia, or posttraumatic stress disorder.

Overcoming Barriers to Sustained Engagement in Mental Health Care: Perspectives of Rural Veterans and Providers.

PURPOSE: To better understand the attitudes, beliefs, and values that influence use of mental health care among rural veterans. METHODS: In-depth, semistructured interviews were conducted with 25 rural veterans and 11 rural mental health care providers in 4 states. Experienced qualitative interviewers asked participants about the attitudinal factors they thought most influenced rural veterans' decisions to seek and sustain mental health care. Verbatim transcriptions were analyzed using content analysis and constant comparison. FINDINGS: Rural veterans and their mental health care providers reported the same major attitudinal barriers to veterans' mental health treatment-seeking. Pre-eminent among those barriers was the importance rural veterans place on independence and self-reliance. The centrality of self-reliance was attributed variously to rural, military, religious, and/or gender-based belief systems. Stoicism, the stigma associated with mental illness and health care, and a lack of trust in the VA as a caring organization were also frequently mentioned. Perceived need for care and the support of other veterans were critical to overcoming attitudinal barriers to initial treatment-seeking, whereas critical facilitators of ongoing service use included "warm handoffs" from medical to mental health care providers, perceived respect and caring from providers, as well as provider accessibility and continuity. CONCLUSIONS: Attitudes and values, like self-reliance, commonly associated with rural culture may play an important role in underutilization of needed mental health services. System support for peer and provider behaviors that generate trust and demonstrate caring may help overcome attitudinal barriers to treatment-seeking and sustained engagement in mental health care among rural veterans.

Partnering with health system operations leadership to develop a controlled implementation trial.

BACKGROUND: Outcome for mental health conditions is suboptimal, and care is fragmented. Evidence from controlled trials indicates that collaborative chronic care models (CCMs) can improve outcomes in a broad array of mental health conditions. US Department of Veterans Affairs leadership launched a nationwide initiative to establish multidisciplinary teams in general mental health clinics in all medical centers. As part of this effort, leadership partnered with implementation researchers to develop a program evaluation protocol to provide rigorous scientific data to address two implementation questions: (1) Can evidence-based CCMs be successfully implemented using existing staff in general mental health clinics supported by internal and external implementation facilitation? (2) What is the impact of CCM implementation efforts on patient health status and perceptions of care? METHODS/DESIGN: Health system operation leaders and researchers partnered in an iterative process to design a protocol that balances operational priorities, scientific rigor, and feasibility. Joint design decisions addressed identification of study sites, patient population of interest, intervention design, and outcome assessment and analysis. Nine sites have been enrolled in the intervention-implementation hybrid type III stepped-wedge design. Using balanced randomization, sites have been assigned to receive implementation support in one of three waves beginning at 4-month intervals, with support lasting 12 months. Implementation support consists of US Center for Disease Control's Replicating Effective Programs strategy supplemented by external and internal implementation facilitation support and is compared to dissemination of materials plus technical assistance conference calls. Formative evaluation focuses on the recipients, context, innovation, and facilitation process. Summative evaluation combines quantitative and qualitative outcomes. Quantitative CCM fidelity measures (at the site level) plus health outcome measures (at the patient level; n = 765) are collected in a repeated measures design and analyzed with general linear modeling. Qualitative data from provider interviews at baseline and 1 year elaborate CCM fidelity data and provide insights into barriers and facilitators of implementation. DISCUSSION: Conducting a jointly designed, highly controlled protocol in the context of health system operational priorities increases the likelihood that time-sensitive questions of operational importance will be answered rigorously and that the outcomes will result in sustainable change in the health-care system. TRIAL REGISTRATION: NCT02543840 ( https://www.clinicaltrials.gov/ct2/show/NCT02543840).

A system-wide innovation in transition services: transforming the home care liaison role.

This article describes how a provincial health authority in Canada improved patient care and staff satisfaction by transforming the role of home care (HC) liaison. The transformation focused on clearly defining the role, function and reporting structure, and identifying which healthcare providers could fill the liaison role. The transformation included adoption of transition best practices, leveraging an electronic referral system, creation of an interprofessional team, standardization of tools/orientation, and strong evaluation metrics, centralizing decision making, and developing a process for streaming referrals. The authors identify key success factors that made the transformation possible, as well as challenges and work that remains to sustain the change.

Reasons for antidepressant nonadherence among veterans treated in primary care clinics.

OBJECTIVE: To examine the experiences of veterans (mostly middle-aged and elderly men) prescribed antidepressants, specifically with regard to different types of nonadherence, reasons for nonadherence, and side effects. METHOD: A mixed-methods analysis of Department of Veterans Affairs primary care patients (N = 395) with depression (9-item depression scale of the Patient Health Questionnaire criteria) enrolled in a randomized collaborative care trial was conducted. Adherence was measured from patient self-report and pharmacy data. Qualitative interviews elicited in-depth information regarding adherence. The study was conducted from April 2003 to September 2005. RESULTS: The intervention significantly improved self-reported adherence at 6 months (OR = 2.1; 95% CI, 1.0-4.4; P = .04) and 12 months (OR = 2.7; 95% CI, 1.4-5.4; P < .01), as well as medication possession at 12 months (OR = 1.82; 95% CI, 1.0-3.2; P = .04). The most common type of nonadherence at 6 months was discontinuation (12.2%), followed by not taking as prescribed (10.9%) and never took (4.8%). For patients discontinuing their antidepressant in the first 6 months, the most common and important reason was that it was not helping. Only 19.4% of patients with self-reported adherence ≥ 80% responded to treatment by 6 months. Side effects were also a commonly reported reason for discontinuation at 6 months, with 82% reporting experiencing side effects. One-third (31.4%) reported difficulty with sexual activity at 6 months, with 66.1% reporting that it was severe. Qualitative interviews supported the finding that side effects, and generally not feeling like oneself, are important adherence barriers. CONCLUSIONS: In this sample of mostly middle-aged and elderly men with depression, treatment nonresponse and side effects were the rule rather than the exception. These findings suggest that nonadherence may have resulted primarily from patients' negative experiences with antidepressants rather than structural barriers or noncompliant behaviors. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT00105690.

Using a multi-level approach to implement a primary care mental health (PCMH) program.

Successfully spreading innovation across large health care systems is a complex process requiring participation of stakeholders from a broad spectrum of professional backgrounds, skill sets, and organizational levels. We describe a process for engaging and activating stakeholders across individual, team, organization, and system levels to implement primary care-mental health integrated care programs in one regional Veterans Affairs health care network. Key stakeholders and researchers collaborated to propose and implement the program. Preliminary findings indicate that the program may reduce referrals to specialty mental health care.

Equity in veterans' mental health care: Veterans Affairs medical center clinics versus community-based outpatient clinics.

This study examined differences in structures and processes of mental health care at Veterans Administration (VA) primary care clinics, comparing VA medical center (VAMC) clinics to community-based outpatient clinics (CBOCs). A survey was conducted of nurse managers at 46 of 49 primary care clinics (23 VAMC clinics and 23 CBOCs) within a VA health care network in the south central United States. Integration of care and services overall was comparable between VAMC clinics and CBOCs. The service mix differed. Integrated CBOCs more often offered group therapy, medication management, and smoking cessation. Integrated VAMC clinics more frequently used written suicide protocols and depression screening. Distance to offsite specialty care and wait times for referrals were shorter for patients at VAMCs than at CBOCs. The provision of mental health care at CBOCs is comparable to that at VAMC clinics, although differences in patient access to offsite care indicate that full equity was not achieved at the time of the survey. Since 2000, the VA has initiated several programs to address this need.

A randomized trial of telemedicine-based collaborative care for depression.

BACKGROUND: Evidence-based practices designed for large urban clinics are not necessarily portable into smaller isolated clinics. Implementing practice-based collaborative care for depression in smaller primary care clinics presents unique challenges because it is often not feasible to employ on-site psychiatrists. OBJECTIVE: The purpose of the Telemedicine Enhanced Antidepressant Management (TEAM) study was to evaluate a telemedicine-based collaborative care model adapted for small clinics without on-site psychiatrists. DESIGN: Matched sites were randomized to the intervention or usual care. PARTICIPANTS: Small VA Community-based outpatient clinics with no on-site psychiatrists, but access to telepsychiatrists. In 2003-2004, 395 primary care patients with PHQ9 depression severity scores > or = 12 were enrolled, and followed for 12 months. Patients with serious mental illness and current substance dependence were excluded. MEASURES: Medication adherence, treatment response, remission, health status, health-related quality of life, and treatment satisfaction. RESULTS: The sample comprised mostly elderly, white, males with substantial physical and behavioral health comorbidity. At baseline, subjects had moderate depression severity (Hopkins Symptom Checklist, SCL-20 = 1.8), 3.7 prior depression episodes, and 67% had received prior depression treatment. Multivariate analyses indicated that intervention patients were more likely to be adherent at both 6 (odds ratio [OR] = 2.1, p = .04) and 12 months (OR = 2.7, p = .01). Intervention patients were more likely to respond by 6 months (OR = 2.0, p = .02), and remit by 12 months (OR = 2.4, p = .02). Intervention patients reported larger gains in mental health status and health-related quality of life, and reported higher satisfaction. CONCLUSIONS: Collaborative care can be successfully adapted for primary care clinics without on-site psychiatrists using telemedicine technologies.

Swept away: use of general medical and mental health services among veterans displaced by Hurricane Katrina.

OBJECTIVE: This study examined national patterns of outpatient service use by veterans from regions affected by Hurricane Katrina. METHODS: Analyses tracked use of general medical and mental/substance use services in September and October through December 2005 in New Orleans and Biloxi-Gulfport compared to a cohort receiving care during the same months in the previous 2 years. RESULTS: In adjusted models, veterans from New Orleans and Biloxi-Gulfport were, respectively, 73% and 41% less likely in September 2005 to use any outpatient services as were cohorts from 2003-2004. Particularly in New Orleans, the relative decline in service use was substantially greater for specialty mental health and substance use services than for general medical services. CONCLUSIONS: Although many veterans were able to obtain care after Hurricane Katrina, there was a substantial disruption in delivery of Veterans Administration services, with disproportionate declines in mental health and substance use care.

Design and implementation of the telemedicine-enhanced antidepressant management study.

OBJECTIVE: Evidence-based practices designed for large urban clinics are not necessarily transportable into small rural practices. Implementing collaborative care for depression in small rural primary care clinics presents unique challenges because it is typically not feasible to employ on-site mental health specialists. The purpose of the Telemedicine-Enhanced Antidepressant Management (TEAM) study was to evaluate a collaborative care model adapted for small rural clinics using telemedicine technologies. The purpose of this paper is to describe the TEAM study design. METHOD: The TEAM study was conducted in small rural Veterans Administration community-based outpatient clinics with interactive video equipment available for mental health, but no on-site psychiatrists/psychologists. The study attempted to enroll all patients whose depression could be appropriately treated in primary care. RESULTS: The clinical characteristics of the 395 study participants differed significantly from most previous trials of collaborative care. At baseline, 41% were already receiving primary care depression treatment. Study participants averaged 5.5 chronic physical health illnesses and 56.5% had a comorbid anxiety disorder. Over half (57.2%) reported that pain impaired their functioning extremely or quite a bit. CONCLUSIONS: Despite small patient populations in rural clinics, enough patients with depression can be successfully enrolled to evaluate telemedicine-based collaborative care.

The role of services researchers in facilitating intervention research.

Even when interventions are shown to be both clinically effective and cost-effective within a system of care, they are rarely sustained beyond the period of external funding. The reason may be that these interventions are often developed and introduced in a "top-down" manner, with little input from frontline clinicians. The purpose of this article is to describe a "bottom-up" approach in which services researchers assist frontline clinicians in testing interventions that clinicians themselves have devised. This approach is explored in the clinical partnership program developed by the Veterans Healthcare Administration's South Central Mental Illness Research, Education, and Clinical Center. The program is expected to expand the evaluation and research capacity of clinicians, enhance the collaborative skills of services researchers, and result in interventions that are more likely to be sustained over time.

Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival.

Multiple myeloma (MM) is a progressive disease that is thought to result from multiple genetic insults to the precursor plasma cell that ultimately affords the tumor cell with proliferative potential despite its differentiated phenotype and resistance to undergoing apoptosis. Altered expression of antiapoptotic factors as well as growth factors have been described in a significant number of patients. However, the key regulatory elements that control myeloma development and progression remain largely undefined. Because of the knowledge that B-lymphocyte stimulator (BLyS), a tumor necrosis factor (TNF) family member shown to be critical for maintenance of normal B-cell development and homeostasis, promotes the survival of malignant B cells, we began a coordinated study of BLyS and its receptors in MM. All MM cells studied expressed one or more of 3 known receptors (B-cell maturation antigen [BCMA], transmembrane activator and CAML interactor [TACI], and B-cell activating factor receptor [BAFF-R]) for BLyS; however, the pattern of expression was variable. Additionally, we provide evidence that BLyS can modulate the proliferative capacity and survival of MM cells. Finally, we provide evidence that BLyS is expressed by MM cells and is present in the bone marrow of patients with MM. Expression of BCMA, TACI, and BAFF-R by MM taken together with the ability of BLyS to support MM cell growth and survival has exciting implications because they may be potential therapeutic targets.

How mental health providers spend their time: a survey of 10 Veterans Health Administration mental health services.

BACKGROUND: Allocation of provider time across clinical, administrative, educational, and research activities may influence job satisfaction, productivity, and quality of care, yet we know little about what determines time allocation. AIMS: To investigate factors associated with time allocation, we surveyed all mental health providers in one Veterans Health Administration (VHA) network. We hypothesized that both facility characteristics (academic affiliation, type of organization of services, serving as a hub for treatment of severely mentally ill, facility size) and individual provider characteristics (discipline, length of time in job, having an academic appointment) would influence time allocation. METHODS: Eligible providers were psychiatrists, psychologists, social workers, physician assistants, registered or licensed practical nurses or other providers (psychology technicians, addiction therapists, nursing assistants, rehabilitation, recreational, occupational therapists) who were providing care in mental health services. A brief self-report survey was collected from all eligible providers at ten VHA facilities in late 1998 (N = 997). Data regarding facility characteristics were obtained by site visits and interviews with managers. Multilevel modeling was used to examine factors associated with three dependent variables: (i) total time allocation by activity (clinical, administrative, educational, research); (ii) clinical time allocation by treatment setting (inpatient vs. outpatient); and (iii) clinical time allocation by type of care (mental vs. physical). Licensed Practical Nurses (LPNs) were used as the reference group for all analyses because LPNs were expected to spend the majority of their time on clinical activities. RESULTS: Overall, providers spent most of their time on clinical activities (77%), followed by administrative (11%), and educational (10%). Surprisingly, research activities accounted for only 2% of their time. Multilevel analysis indicated none of the facility-level variables were significant in explaining facility variance in time allocation, but individual characteristics were associated with time allocation. The model for predicting time allocation by inpatient or outpatient settings explained 16-18% of the variance in the dependent variable. In all models, provider discipline and length of time in job played an important role. Having an academic appointment was important only in the model examining total time allocation by activity type. DISCUSSION: These simple models explained only a small amount of variance in the three dependent variables which were intended to capture issues related to time allocation; and the low number of facilities limited our power to examine effects of facility-level factors. Our models performed better in predicting allocation of clinical time to treatment setting and type of treatment than in predicting overall time allocation. Discipline and length of time in job were significant across all models. In contrast, having an academic appointment was associated with allocating significantly less time to clinical activities and more time to administrative activities but not to any significant difference in time spent in either research or education. IMPLICATIONS: While a gold standard of optimal time allocation does not exist, it is striking that research, a stated mission of the VHA, accounted for so little of providers' time. The lack of involvement of clinicians in research has implications for recruitment and retention of high-quality mental health providers in this network and for the education of future providers. Without involvement of clinicians, research conducted in the network by nonclinicians may be less relevant to "real-world" clinical issues. Reductions of funds available to mental health, coupled with increased clinical demands, may have prompted this pattern of time allocation, and these findings attest to the challenges faced by large institutions that are charged with balancing many often seemingly competing missions.