ImportanceSuicide is a leading cause of death; however, the molecular genetic basis of suicidal t... more ImportanceSuicide is a leading cause of death; however, the molecular genetic basis of suicidal thoughts and behaviors (SITB) remains unknown.ObjectiveTo identify novel, replicable genomic risk loci for SITB.Design, Setting, and ParticipantsThis genome-wide association study included 633 778 US military veterans with and without SITB, as identified through electronic health records. GWAS was performed separately by ancestry, controlling for sex, age, and genetic substructure. Cross-ancestry risk loci were identified through meta-analysis. Study enrollment began in 2011 and is ongoing. Data were analyzed from November 2021 to August 2022.Main Outcome and MeasuresSITB.ResultsA total of 633 778 US military veterans were included in the analysis (57 152 [9%] female; 121 118 [19.1%] African ancestry, 8285 [1.3%] Asian ancestry, 452 767 [71.4%] European ancestry, and 51 608 [8.1%] Hispanic ancestry), including 121 211 individuals with SITB (19.1%). Meta-analysis identified more than 200 GWS (P < 5 × 10−8) cross-ancestry risk single-nucleotide variants for SITB concentrated in 7 regions on chromosomes 2, 6, 9, 11, 14, 16, and 18. Top single-nucleotide variants were largely intronic in nature; 5 were independently replicated in ISGC, including rs6557168 in ESR1, rs12808482 in DRD2, rs77641763 in EXD3, rs10671545 in DCC, and rs36006172 in TRAF3. Associations for FBXL19 and AC018880.2 were not replicated. Gene-based analyses implicated 24 additional GWS cross-ancestry risk genes, including FURIN, TSNARE1, and the NCAM1-TTC12-ANKK1-DRD2 gene cluster. Cross-ancestry enrichment analyses revealed significant enrichment for expression in brain and pituitary tissue, synapse and ubiquitination processes, amphetamine addiction, parathyroid hormone synthesis, axon guidance, and dopaminergic pathways. Seven other unique European ancestry–specific GWS loci were identified, 2 of which (POM121L2 and METTL15/LINC02758) were replicated. Two additional GWS ancestry-specific loci were identified within the African ancestry (PET112/GATB) and Hispanic ancestry (intergenic locus on chromosome 4) subsets, both of which were replicated. No GWS loci were identified within the Asian ancestry subset; however, significant enrichment was observed for axon guidance, cyclic adenosine monophosphate signaling, focal adhesion, glutamatergic synapse, and oxytocin signaling pathways across all ancestries. Within the European ancestry subset, genetic correlations (r > 0.75) were observed between the SITB phenotype and a suicide attempt-only phenotype, depression, and posttraumatic stress disorder. Additionally, polygenic risk score analyses revealed that the Million Veteran Program polygenic risk score had nominally significant main effects in 2 independent samples of veterans of European and African ancestry.Conclusions and RelevanceThe findings of this analysis may advance understanding of the molecular genetic basis of SITB and provide evidence for ESR1, DRD2, TRAF3, and DCC as cross-ancestry candidate risk genes. More work is needed to replicate these findings and to determine if and how these genes might impact clinical care.
Objective To examine the associations between stopping treatment with opioids, length of treatmen... more Objective To examine the associations between stopping treatment with opioids, length of treatment, and death from overdose or suicide in the Veterans Health Administration. Design Observational evaluation. Setting Veterans Health Administration. Participants 1 394 102 patients in the Veterans Health Administration with an outpatient prescription for an opioid analgesic from fiscal year 2013 to the end of fiscal year 2014 (1 October 2012 to 30 September 2014). Main outcome measures A multivariable Cox non-proportional hazards regression model examined death from overdose or suicide, with the interaction of time varying opioid cessation by length of treatment (≤30, 31-90, 91-400, and >400 days) as the main covariates. Stopping treatment with opioids was measured as the time when a patient was estimated to have no prescription for opioids, up to the end of the next fiscal year (2014) or the patient’s death. Results 2887 deaths from overdose or suicide were found. The incidence of s...
Objective: Family and twin studies suggest that liability for suicide attempts is heritable and d... more Objective: Family and twin studies suggest that liability for suicide attempts is heritable and distinct from mood disorder susceptibility. The authors therefore examined the association between common genomewide variation and lifetime suicide attempts. Method: The authors analyzed data on lifetime suicide attempts from genomewide association studies of bipolar I and II disorder as well as major depressive disorder. Bipolar disorder subjects were drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder cohort, the Wellcome Trust Case Control Consortium bipolar cohort, and the University College London cohort. Replication was pursued in the NIMH Genetic Association Information Network bipolar disorder project and a German clinical cohort. Depression subjects were drawn from the Sequential Treatment Alternatives to Relieve Depression cohort, with replication in the Netherlands Study of Depression and Anxiety/Netherlands Twin Register depression cohort. Results: Strongest evidence of association for suicide attempt in bipolar disorder was observed in a region without identifi ed genes (rs1466846); fi ve loci also showed suggestive evidence of association. In major depression, strongest evidence of association was observed for a single nucleotide polymorphism in ABI3BP, with six loci also showing suggestive association. Replication cohorts did not provide further support for these loci. However, meta-analysis incorporating approximately 8,700 mood disorder subjects identifi ed four additional regions that met the threshold for suggestive association, including the locus containing the gene coding for protein kinase C-epsilon, previously implicated in models of mood and anxiety. Conclusions: The results suggest that inherited risk for suicide among mood disorder patients is unlikely to be the result of individual common variants of large effect. They nonetheless provide suggestive evidence for multiple loci, which merit further investigation.
Background: Postoperative opioid use can lead to chronic use and misuse. Few studies have examine... more Background: Postoperative opioid use can lead to chronic use and misuse. Few studies have examined effective approaches to taper postoperative opioid use while maintaining adequate analgesia. Methods: This randomized, assessor-blinded, pilot trial of postoperative motivational interviewing and guided opioid tapering support (MI-Opioid Taper) added to usual care (UC) enrolled patients undergoing total hip or knee arthroplasty at a single U.S. academic medical center. MI-Opioid Taper involved weekly (to seven weeks) and monthly (to one year) phone calls until patient-reported opioid cessation. Opioid tapering involved 25% weekly dose reductions. The primary feasibility outcome was study completion in the group to which participants were randomized. The primary efficacy outcome, time to baseline opioid use, was the first of five consecutive days of return to baseline preoperative dose. Intention-to-treat analysis with Cox proportional hazards regression was adjusted for operation. ClinicalTrials.gov registration: NCT02070003. Findings: From November 26, 2014, to April 27, 2018, 209 patients were screened, and 104 patients were assigned to receive MI-Opioid Taper (49 patients) or UC only (55 patients). Study completion after randomization was similar between groups (96.4%, 53 patients receiving UC, 91.8%, 45 patients receiving MI-Opioid Taper). Patients receiving MI-Opioid Taper had a 62% increase in the rate of return to baseline opioid use after surgery (HR 1.62; 95%CI 1.06À2.46; p = 003). No trial-related adverse events occurred. Interpretation: In patients undergoing total joint arthroplasty, MI-Opioid Taper is feasible and future research is needed to establish the efficacy of MI-Opioid Taper to promote postoperative opioid cessation.
Objective: To discover pharmacotherapy prescription patterns and their statistical associations w... more Objective: To discover pharmacotherapy prescription patterns and their statistical associations with outcomes through a clinical pathway inference framework applied on real-world data. Materials and Methods: We apply machine learning steps in our framework using a 2006 to 2020 cohort of veterans with major depressive disorder (MDD). Outpatient antidepressant pharmacy and emergency department visits, self-harm, and all-cause mortality data were extracted from the Department of Veterans Affairs Corporate Data Warehouse. Results: Our MDD cohort consisted of 252,179 individuals. During the study period there were 98,417 cases of emergency department visits, 1,016 cases of self-harm, and 1,507 deaths from all causes. The top ten prescription patterns accounted for 69.3% of the data for individuals starting antidepressants at the fluoxetine equivalent of 20-39mg. Additionally, we found associations between outcomes and dosage change. Discussion: For 252,179 Veterans who served in Iraq and...
OBJECTIVE Quality measures that are used to evaluate health care services have a central role in ... more OBJECTIVE Quality measures that are used to evaluate health care services have a central role in monitoring and incentivizing quality improvement and the provision of evidence-based treatment. This systematic scan aimed to catalog quality-of-care measures for mental and substance use disorders and assess gaps and redundancies to inform efforts to develop and retire measures. METHODS Quality measure inventories were analyzed from six organizations that evaluate health care quality in the United States. Measures were included if they were defined via symptoms or diagnoses of mental and substance use disorders or specialty treatments or treatment settings for adults. RESULTS Of 4,420 measures analyzed, 635 (14%) met inclusion criteria, and 376 unique quality-of-care measure constructs were cataloged and characterized. Symptoms or diagnoses of disorders were most commonly used to define measures (46%, N=172). Few measures were available for certain disorders (e.g., anxiety disorders), evidence-based treatments (e.g., psychotherapy), and quality domains (e.g., equity). Only one in four measures was endorsed by the National Quality Forum, which independently and critically evaluates quality measures. Among measures that were actively in use for national quality improvement initiatives (N=319), process measures (57%) were most common, followed by outcome measures (30%), the latter of which focused most often on experience of care. CONCLUSIONS A vast landscape of mental and substance use disorder quality-of-care measures currently exists, and continued efforts to harmonize duplicative measures and to develop measures for underrepresented evidence-based treatments and quality domains are warranted. The authors recommend reinvesting in a national, centralized system for measure curation, with a stakeholder-centered process for independent measure review and endorsement.
This technical report compares two sources of information on ambulatory care provided by the U.S.... more This technical report compares two sources of information on ambulatory care provided by the U.S. Department of Veterans Affairs (VA). We compared the VA electronic medical record to the VA national outpatient utilization database. We wished to validate data to be used in the economic component of the Multisite Opioid Substitution Treatment (MOST) study. The MOST study is evaluating the effect of adherence to clinical practice guidelines on the cost and outcomes of patients being treated for opiate dependence at seven sites.
effect was driven by medication treatment (OR = 2.42; CI = 2.24-2.63; p < 0.001), as opposed to s... more effect was driven by medication treatment (OR = 2.42; CI = 2.24-2.63; p < 0.001), as opposed to specialist follow-up (OR = 1.14; CI = 0.88-1.47; p = 0.32). Odds of treatment initiation were higher among minority (Asian > Latino > Black) than White patients, Spanishthan English-speaking patients, and uninsured than insured patients in
IMPORTANCE Acute postoperative pain is associated with the development of persistent postsurgical... more IMPORTANCE Acute postoperative pain is associated with the development of persistent postsurgical pain, but it is unclear which aspect is most estimable. OBJECTIVE To identify patient clusters based on acute pain trajectories, preoperative psychosocial characteristics associated with the high-risk cluster, and the best acute pain predictor of remote outcomes. DESIGN, SETTING, AND PARTICIPANTS A secondary analysis of the Stanford Accelerated Recovery Trial randomized, double-blind clinical trial was conducted at a single-center, tertiary, referral teaching hospital. A total of 422 participants scheduled for thoracotomy, video-assisted thoracoscopic surgery, total hip replacement, total knee replacement, mastectomy, breast lumpectomy, hand surgery, carpal tunnel surgery, knee arthroscopy, shoulder arthroplasty, or
The safe and effective prescribing of opioid therapy for chronic pain has become a significant he... more The safe and effective prescribing of opioid therapy for chronic pain has become a significant health care priority over the last several years. Substantial research has focused on patient-oriented interventions toward preventing problematic use, but provider and system level factors may be more amenable to quality improvement approaches. Here, we outline administrative data-based metrics that are intended to assess adherence to key practices outlined in the 2010 Department of Veterans Affairs/Department of Defense Clinical Practice Guideline for management of opioid therapy for chronic pain. In addition to the metrics, we discuss their development process, which was done in consultation with experts on chronic opioid therapy.
Problematic alcohol use has been shown to negatively impact cognitive functions germane to achiev... more Problematic alcohol use has been shown to negatively impact cognitive functions germane to achieving optimal HIV health outcomes. The present study, a secondary data analysis, examined the impact of problematic alcohol use on aspects of everyday memory functioning in a sample of 172 HIV-infected individuals (22 % female; M age = 48.37 years, SD = 8.64; 39 % Black/non-Hispanic). Additionally, we tested whether self-reported memory functioning explained the relation between problematic alcohol use and HIV symptom severity. Results indicated that problematic patterns of alcohol use were associated with lower total memory functioning, retrieval (e.g., recall-difficulty) and memory for activity (e.g., what you did yesterday) and greater HIV symptom severity. Memory functioning mediated the relation between problematic alcohol use and HIV symptom severity. However, the direction of this relation was unclear as HIV symptom severity also mediated the relation between problematic alcohol use and memory functioning. Findings highlight the importance of integrated care for HIV and alcohol use disorders and suggest that routine alcohol and cognitive screenings may bolster health outcomes among this vulnerable population.
Objective: To quantify overall trends in patients treated for mental health disorders and adverse... more Objective: To quantify overall trends in patients treated for mental health disorders and adverse events, including via tele-mental health (TMH) and psychopharmacology during pandemic-related health care transformation. Methods: This longitudinal observational study analyzes veterans receiving mental health treatment at a Veterans Health Administration (VHA) facility from January 1, 2017 to June 16, 2020. Observed and expected patient care for on-going and new treatment of depression, posttraumatic stress, substance use disorder, severe mental illness diagnoses, overdose, and suicide attempts, and psychotropic prescriptions for antidepressant, antipsychotic, benzodiazepine, opioid, and mood stabilizing medications are depicted. Percent change between actual and expected counts in the early months of the COVID pandemic (March 18-May 5, 2020) are computed. Results: Decreases in counts of patients receiving care for mental health treatment during early pandemic response ranged from 7% to 20% for on-going treatment, and 28 to 37% for new treatment. TMH rapidly expanded across VHA, becoming the primary means by which encounters were delivered. The number of patients receiving on-going care for suicide attempts were stable and for overdoses, decreased 17%, while patients initiating care declined by 30% and 38%, respectively. Weekly prescriptions and medication on-hand for psychotropics ranged from a 2% decline to 4% increase. Prescribing to new patients declined 21 to 50%. Conclusions: VHA needs to expand outreach and continue to utilize TMH to maintain care continuity and initiate care for existing and new patients. This knowledge is useful for healthcare systems in developing strategies for COVID-19 and future large-scale outbreaks, epidemic, and disasters. Funding: These studies were supported through funding for medical operations by the Department of Veterans Affairs through the VA Office of Mental Health and Suicide Prevention. Declaration of Interests: Matt Boden is a consultant for the Beneath the Surface Foundation. None of the other authors have any potential conflicts of interest to disclose. Ethics Approval Statement: Data used in this study is captured in electronic medical records as part of routine clinical care and is utilized for the purpose of ongoing program evaluation. Thus, no institutional review board review was required for the study.
In order to potentially enhance the impact of most effective policies and interventions in reduci... more In order to potentially enhance the impact of most effective policies and interventions in reducing the population level damage from alcohol, a new perspective with regard to education and persuasion interventions is offered. Recent studies were examined on the global burden of alcohol and also those focusing on the links between overall consumption and high-risk drinking, on one hand, and drinking-related damage on the other hand. A synopsis of main findings from reviews and other analysis provides the basis for conclusions about the impacts of education and persuasion interventions. There is a relative absence of evidence of the effectiveness of education and persuasion in reducing consumption, curtailing high-risk drinking or reducing damage from alcohol. This is in contrast to the rising levels of damage from alcohol, and also to the demonstrated effectiveness of certain alcohol policies and interventions, as summarized in Babor et al. Given that only a small fraction of education and persuasion interventions have any positive impact, generating &amp;amp;amp;amp;amp;amp;#39;more of the same&amp;amp;amp;amp;amp;amp;#39; is not an impact-effective and cost-efficient approach. Therefore, interventions that have not been shown to be effective need to be phased out and those most effective and of widest scope should receive more attention and enhanced resources. A reframing of the roles and foci of persuasion interventions is advised, including, for example, focusing on informing policy-makers, and stimulating public discussions about the rationale of alcohol policies and the roles that citizens can play in promoting and supporting these policies.
Background: Preoperative patient-specific risk factors may elucidate the mechanisms leading to th... more Background: Preoperative patient-specific risk factors may elucidate the mechanisms leading to the persistence of pain and opioid use after surgery. This study aimed to determine whether similar or discordant preoperative factors were associated with the duration of postoperative pain and opioid use. Methods: In this post hoc analysis of a randomized, double-blind, placebo-controlled trial of perioperative gabapentin vs active placebo, 410 patients aged 18-75 years, undergoing diverse operations underwent preoperative assessments of pain, opioid use, substance use, and psychosocial variables. After surgery, a modified Brief Pain Inventory was administered over the phone daily up to 3 months, weekly up to 6 months, and monthly up to 2 years after surgery. Pain and opioid cessation were defined as the first of 5 consecutive days of 0 out of 10 pain or no opioid use, respectively. Results: Overall, 36.1%, 19.8%, and 9.5% of patients continued to report pain, and 9.5%, 2.4%, and 1.7% reported continued opioid use at 3, 6, and 12 months after surgery. Preoperative pain at the future surgical site (every 1-point increase in the Numeric Pain Rating Scale; HR 0.93; 95% CI 0.87-1.00; P=0.034), trait anxiety (every 10-point increase in the Trait Anxiety Inventory; HR 0.79; 95% CI 0.68-0.92; P=0.002), and a history of delayed recovery after injury (HR 0.62; 95% CI 0.40-0.96; P=0.034) were associated with delayed pain cessation. Preoperative opioid use (HR 0.60; 95% CI 0.39-0.92; P=0.020), elevated depressive symptoms (every 5-point increase in the Beck Depression Inventory-II score; HR 0.88; 95% CI 0.80-0.98; P=0.017), and preoperative pain outside of the surgical site (HR 0.94; 95% CI 0.89-1.00; P=0.046) were associated with delayed opioid cessation, while perioperative gabapentin promoted opioid cessation (HR 1.37; 95% CI 1.06-1.77; P=0.016). Conclusion: Separate risk factors for prolonged post-surgical pain and opioid use indicate that preoperative risk stratification for each outcome may identify patients needing personalized care to augment universal protocols for perioperative pain management and conservative opioid prescribing to improve long-term outcomes.
IMPORTANCE Among people with diabetes, co-occurring mental health (MH) or substance use (SU) diso... more IMPORTANCE Among people with diabetes, co-occurring mental health (MH) or substance use (SU) disorders increase the risk of medical complications. Identifying how to effectively promote longterm medical benefits for at-risk populations, such as people with MH or SU disorders, is essential. Knowing more about how health care accessed before the onset of diabetes is associated with health benefits after the onset of diabetes could inform treatment planning and population health management. OBJECTIVE To analyze how preexisting MH or SU disorders and primary care utilization before a new diabetes diagnosis are associated with the long-term severity of diabetes complications. DESIGN, SETTING, AND PARTICIPANTS This cohort study analyzed medical record data from US Department of Veterans Affairs health care systems nationwide and used mixed-effects regressions to test associations between prediabetes patient or health care factors and longitudinal progression of diabetes complication severity from 2006 to 2015. Participants included patients who received a new diabetes diagnosis in 2008 and who were aged 18 to 85 years at the time of their diagnosis. Data analysis was conducted from March to August 2017. EXPOSURES Patients were assigned to groups on the basis of a 2-year look-back period for MH or SU disorders status (MH disorder only, SU disorder only, MH and SU disorder, or no MH or SU disorder diagnoses) and on the basis of the amount of primary care utilization before diabetes was diagnosed. MAIN OUTCOMES AND MEASURES Nine-year trajectories of Diabetes Complication Severity Index (DCSI) scores. RESULTS Among 122 992 patients with newly diagnosed diabetes, the mean (SD) age was 62.3 (11.1) years, 118 810 (96.6%) were male, and 28 633 (23.3%) had preexisting MH or SU disorders diagnoses. From the onset of diabetes to 7 years later, patients' mean estimated DCSI scores
Although the tachykinins substance P (SP) and neurokinin A (NKA) are coreleased from primary affe... more Although the tachykinins substance P (SP) and neurokinin A (NKA) are coreleased from primary afferent nociceptors and act via neurokinin (NK) receptors, their differential effects in vivo are not known. Despite pharmacological evidence that NKA preferentially binds NK-2 receptors, this receptor is not found in spinal cord neurons. Thus, in the present studies, we compared the extent to which SP and NKA contribute to spinal nociceptive processing via the NK-1 receptor. We found that SP and NKA induce NK-1 receptor internalization with identical dose dependence and induce increases in intracellular calcium at the same concentrations, suggesting that SP and NKA equally activate the NK-1 receptor. We found, however, that the selective NK-1 receptor antagonist GR 205171 blocked NKA but not SP-induced NK-1 receptor internalization in the rat spinal cord in vivo and in embryonic day 19 rat spinal neurons in vitro. Using this selectivity of GR 205171 for NKA-induced NK-1 receptor activation, we examined the relative contribution of SP and NKA to noxious stimulusinduced activation of spinal NK-1 receptors. We estimate that NKA contributes to at least 50% of the NK-1 receptor activation in lamina I. Under inflammatory conditions, all noxious stimulus-induced NK-1 receptor internalization in deep dorsal horn neurons was blocked by GR 205171, suggesting that it is entirely NKA-mediated. Substance P-mediated NK-1 receptor internalization was focused at the site of termination of stimulated nociceptors but NKA also activated NK-1 receptors at more distant sites. We conclude that NKA not only targets the NK-1 receptor but may be a predominant pronociceptive primary afferent neurotransmitter.
Mental health treatment access and quality are influenced by the interplay of structural, organiz... more Mental health treatment access and quality are influenced by the interplay of structural, organizational, and performance factors-including the number of mental health staff providing direct clinical care relative to patients treated (i.e., staffing ratio), mental health staff productivity, and wait times for scheduled mental health appointments. With no industry standards to follow, the Veterans Health Administration (VHA) developed an outpatient mental health staffing model and a recommended minimum total staffing ratio. At the level of VHA health care facility (N=140), we conducted cross-sectional regression analyses to examine the relative importance of outpatient mental health staffing and productivity and mental health patient wait times in predicting measures of mental health treatment access and quality. Outpatient mental health staffing ratios (especially total and therapist staffing ratios) had substantial, positive relationships with overall mental health treatment access and quality, broadly and in specific domains. Staffing ratios generally had stronger relationships with treatment access and quality than did staff productivity and patient wait times. Mental health staffing ratios should be a primary consideration when trying to improve mental health treatment access and quality at the facility level. Having more mental health staff of all types is associated with better overall access to and quality of mental health services, and multiple staff types are needed to provide high-quality mental health care. Knowledge gained may guide efforts to address challenges in improving access to and quality of mental health services within and outside of VHA.
ImportanceSuicide is a leading cause of death; however, the molecular genetic basis of suicidal t... more ImportanceSuicide is a leading cause of death; however, the molecular genetic basis of suicidal thoughts and behaviors (SITB) remains unknown.ObjectiveTo identify novel, replicable genomic risk loci for SITB.Design, Setting, and ParticipantsThis genome-wide association study included 633 778 US military veterans with and without SITB, as identified through electronic health records. GWAS was performed separately by ancestry, controlling for sex, age, and genetic substructure. Cross-ancestry risk loci were identified through meta-analysis. Study enrollment began in 2011 and is ongoing. Data were analyzed from November 2021 to August 2022.Main Outcome and MeasuresSITB.ResultsA total of 633 778 US military veterans were included in the analysis (57 152 [9%] female; 121 118 [19.1%] African ancestry, 8285 [1.3%] Asian ancestry, 452 767 [71.4%] European ancestry, and 51 608 [8.1%] Hispanic ancestry), including 121 211 individuals with SITB (19.1%). Meta-analysis identified more than 200 GWS (P &amp;lt; 5 × 10−8) cross-ancestry risk single-nucleotide variants for SITB concentrated in 7 regions on chromosomes 2, 6, 9, 11, 14, 16, and 18. Top single-nucleotide variants were largely intronic in nature; 5 were independently replicated in ISGC, including rs6557168 in ESR1, rs12808482 in DRD2, rs77641763 in EXD3, rs10671545 in DCC, and rs36006172 in TRAF3. Associations for FBXL19 and AC018880.2 were not replicated. Gene-based analyses implicated 24 additional GWS cross-ancestry risk genes, including FURIN, TSNARE1, and the NCAM1-TTC12-ANKK1-DRD2 gene cluster. Cross-ancestry enrichment analyses revealed significant enrichment for expression in brain and pituitary tissue, synapse and ubiquitination processes, amphetamine addiction, parathyroid hormone synthesis, axon guidance, and dopaminergic pathways. Seven other unique European ancestry–specific GWS loci were identified, 2 of which (POM121L2 and METTL15/LINC02758) were replicated. Two additional GWS ancestry-specific loci were identified within the African ancestry (PET112/GATB) and Hispanic ancestry (intergenic locus on chromosome 4) subsets, both of which were replicated. No GWS loci were identified within the Asian ancestry subset; however, significant enrichment was observed for axon guidance, cyclic adenosine monophosphate signaling, focal adhesion, glutamatergic synapse, and oxytocin signaling pathways across all ancestries. Within the European ancestry subset, genetic correlations (r &amp;gt; 0.75) were observed between the SITB phenotype and a suicide attempt-only phenotype, depression, and posttraumatic stress disorder. Additionally, polygenic risk score analyses revealed that the Million Veteran Program polygenic risk score had nominally significant main effects in 2 independent samples of veterans of European and African ancestry.Conclusions and RelevanceThe findings of this analysis may advance understanding of the molecular genetic basis of SITB and provide evidence for ESR1, DRD2, TRAF3, and DCC as cross-ancestry candidate risk genes. More work is needed to replicate these findings and to determine if and how these genes might impact clinical care.
Objective To examine the associations between stopping treatment with opioids, length of treatmen... more Objective To examine the associations between stopping treatment with opioids, length of treatment, and death from overdose or suicide in the Veterans Health Administration. Design Observational evaluation. Setting Veterans Health Administration. Participants 1 394 102 patients in the Veterans Health Administration with an outpatient prescription for an opioid analgesic from fiscal year 2013 to the end of fiscal year 2014 (1 October 2012 to 30 September 2014). Main outcome measures A multivariable Cox non-proportional hazards regression model examined death from overdose or suicide, with the interaction of time varying opioid cessation by length of treatment (≤30, 31-90, 91-400, and >400 days) as the main covariates. Stopping treatment with opioids was measured as the time when a patient was estimated to have no prescription for opioids, up to the end of the next fiscal year (2014) or the patient’s death. Results 2887 deaths from overdose or suicide were found. The incidence of s...
Objective: Family and twin studies suggest that liability for suicide attempts is heritable and d... more Objective: Family and twin studies suggest that liability for suicide attempts is heritable and distinct from mood disorder susceptibility. The authors therefore examined the association between common genomewide variation and lifetime suicide attempts. Method: The authors analyzed data on lifetime suicide attempts from genomewide association studies of bipolar I and II disorder as well as major depressive disorder. Bipolar disorder subjects were drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder cohort, the Wellcome Trust Case Control Consortium bipolar cohort, and the University College London cohort. Replication was pursued in the NIMH Genetic Association Information Network bipolar disorder project and a German clinical cohort. Depression subjects were drawn from the Sequential Treatment Alternatives to Relieve Depression cohort, with replication in the Netherlands Study of Depression and Anxiety/Netherlands Twin Register depression cohort. Results: Strongest evidence of association for suicide attempt in bipolar disorder was observed in a region without identifi ed genes (rs1466846); fi ve loci also showed suggestive evidence of association. In major depression, strongest evidence of association was observed for a single nucleotide polymorphism in ABI3BP, with six loci also showing suggestive association. Replication cohorts did not provide further support for these loci. However, meta-analysis incorporating approximately 8,700 mood disorder subjects identifi ed four additional regions that met the threshold for suggestive association, including the locus containing the gene coding for protein kinase C-epsilon, previously implicated in models of mood and anxiety. Conclusions: The results suggest that inherited risk for suicide among mood disorder patients is unlikely to be the result of individual common variants of large effect. They nonetheless provide suggestive evidence for multiple loci, which merit further investigation.
Background: Postoperative opioid use can lead to chronic use and misuse. Few studies have examine... more Background: Postoperative opioid use can lead to chronic use and misuse. Few studies have examined effective approaches to taper postoperative opioid use while maintaining adequate analgesia. Methods: This randomized, assessor-blinded, pilot trial of postoperative motivational interviewing and guided opioid tapering support (MI-Opioid Taper) added to usual care (UC) enrolled patients undergoing total hip or knee arthroplasty at a single U.S. academic medical center. MI-Opioid Taper involved weekly (to seven weeks) and monthly (to one year) phone calls until patient-reported opioid cessation. Opioid tapering involved 25% weekly dose reductions. The primary feasibility outcome was study completion in the group to which participants were randomized. The primary efficacy outcome, time to baseline opioid use, was the first of five consecutive days of return to baseline preoperative dose. Intention-to-treat analysis with Cox proportional hazards regression was adjusted for operation. ClinicalTrials.gov registration: NCT02070003. Findings: From November 26, 2014, to April 27, 2018, 209 patients were screened, and 104 patients were assigned to receive MI-Opioid Taper (49 patients) or UC only (55 patients). Study completion after randomization was similar between groups (96.4%, 53 patients receiving UC, 91.8%, 45 patients receiving MI-Opioid Taper). Patients receiving MI-Opioid Taper had a 62% increase in the rate of return to baseline opioid use after surgery (HR 1.62; 95%CI 1.06À2.46; p = 003). No trial-related adverse events occurred. Interpretation: In patients undergoing total joint arthroplasty, MI-Opioid Taper is feasible and future research is needed to establish the efficacy of MI-Opioid Taper to promote postoperative opioid cessation.
Objective: To discover pharmacotherapy prescription patterns and their statistical associations w... more Objective: To discover pharmacotherapy prescription patterns and their statistical associations with outcomes through a clinical pathway inference framework applied on real-world data. Materials and Methods: We apply machine learning steps in our framework using a 2006 to 2020 cohort of veterans with major depressive disorder (MDD). Outpatient antidepressant pharmacy and emergency department visits, self-harm, and all-cause mortality data were extracted from the Department of Veterans Affairs Corporate Data Warehouse. Results: Our MDD cohort consisted of 252,179 individuals. During the study period there were 98,417 cases of emergency department visits, 1,016 cases of self-harm, and 1,507 deaths from all causes. The top ten prescription patterns accounted for 69.3% of the data for individuals starting antidepressants at the fluoxetine equivalent of 20-39mg. Additionally, we found associations between outcomes and dosage change. Discussion: For 252,179 Veterans who served in Iraq and...
OBJECTIVE Quality measures that are used to evaluate health care services have a central role in ... more OBJECTIVE Quality measures that are used to evaluate health care services have a central role in monitoring and incentivizing quality improvement and the provision of evidence-based treatment. This systematic scan aimed to catalog quality-of-care measures for mental and substance use disorders and assess gaps and redundancies to inform efforts to develop and retire measures. METHODS Quality measure inventories were analyzed from six organizations that evaluate health care quality in the United States. Measures were included if they were defined via symptoms or diagnoses of mental and substance use disorders or specialty treatments or treatment settings for adults. RESULTS Of 4,420 measures analyzed, 635 (14%) met inclusion criteria, and 376 unique quality-of-care measure constructs were cataloged and characterized. Symptoms or diagnoses of disorders were most commonly used to define measures (46%, N=172). Few measures were available for certain disorders (e.g., anxiety disorders), evidence-based treatments (e.g., psychotherapy), and quality domains (e.g., equity). Only one in four measures was endorsed by the National Quality Forum, which independently and critically evaluates quality measures. Among measures that were actively in use for national quality improvement initiatives (N=319), process measures (57%) were most common, followed by outcome measures (30%), the latter of which focused most often on experience of care. CONCLUSIONS A vast landscape of mental and substance use disorder quality-of-care measures currently exists, and continued efforts to harmonize duplicative measures and to develop measures for underrepresented evidence-based treatments and quality domains are warranted. The authors recommend reinvesting in a national, centralized system for measure curation, with a stakeholder-centered process for independent measure review and endorsement.
This technical report compares two sources of information on ambulatory care provided by the U.S.... more This technical report compares two sources of information on ambulatory care provided by the U.S. Department of Veterans Affairs (VA). We compared the VA electronic medical record to the VA national outpatient utilization database. We wished to validate data to be used in the economic component of the Multisite Opioid Substitution Treatment (MOST) study. The MOST study is evaluating the effect of adherence to clinical practice guidelines on the cost and outcomes of patients being treated for opiate dependence at seven sites.
effect was driven by medication treatment (OR = 2.42; CI = 2.24-2.63; p < 0.001), as opposed to s... more effect was driven by medication treatment (OR = 2.42; CI = 2.24-2.63; p < 0.001), as opposed to specialist follow-up (OR = 1.14; CI = 0.88-1.47; p = 0.32). Odds of treatment initiation were higher among minority (Asian > Latino > Black) than White patients, Spanishthan English-speaking patients, and uninsured than insured patients in
IMPORTANCE Acute postoperative pain is associated with the development of persistent postsurgical... more IMPORTANCE Acute postoperative pain is associated with the development of persistent postsurgical pain, but it is unclear which aspect is most estimable. OBJECTIVE To identify patient clusters based on acute pain trajectories, preoperative psychosocial characteristics associated with the high-risk cluster, and the best acute pain predictor of remote outcomes. DESIGN, SETTING, AND PARTICIPANTS A secondary analysis of the Stanford Accelerated Recovery Trial randomized, double-blind clinical trial was conducted at a single-center, tertiary, referral teaching hospital. A total of 422 participants scheduled for thoracotomy, video-assisted thoracoscopic surgery, total hip replacement, total knee replacement, mastectomy, breast lumpectomy, hand surgery, carpal tunnel surgery, knee arthroscopy, shoulder arthroplasty, or
The safe and effective prescribing of opioid therapy for chronic pain has become a significant he... more The safe and effective prescribing of opioid therapy for chronic pain has become a significant health care priority over the last several years. Substantial research has focused on patient-oriented interventions toward preventing problematic use, but provider and system level factors may be more amenable to quality improvement approaches. Here, we outline administrative data-based metrics that are intended to assess adherence to key practices outlined in the 2010 Department of Veterans Affairs/Department of Defense Clinical Practice Guideline for management of opioid therapy for chronic pain. In addition to the metrics, we discuss their development process, which was done in consultation with experts on chronic opioid therapy.
Problematic alcohol use has been shown to negatively impact cognitive functions germane to achiev... more Problematic alcohol use has been shown to negatively impact cognitive functions germane to achieving optimal HIV health outcomes. The present study, a secondary data analysis, examined the impact of problematic alcohol use on aspects of everyday memory functioning in a sample of 172 HIV-infected individuals (22 % female; M age = 48.37 years, SD = 8.64; 39 % Black/non-Hispanic). Additionally, we tested whether self-reported memory functioning explained the relation between problematic alcohol use and HIV symptom severity. Results indicated that problematic patterns of alcohol use were associated with lower total memory functioning, retrieval (e.g., recall-difficulty) and memory for activity (e.g., what you did yesterday) and greater HIV symptom severity. Memory functioning mediated the relation between problematic alcohol use and HIV symptom severity. However, the direction of this relation was unclear as HIV symptom severity also mediated the relation between problematic alcohol use and memory functioning. Findings highlight the importance of integrated care for HIV and alcohol use disorders and suggest that routine alcohol and cognitive screenings may bolster health outcomes among this vulnerable population.
Objective: To quantify overall trends in patients treated for mental health disorders and adverse... more Objective: To quantify overall trends in patients treated for mental health disorders and adverse events, including via tele-mental health (TMH) and psychopharmacology during pandemic-related health care transformation. Methods: This longitudinal observational study analyzes veterans receiving mental health treatment at a Veterans Health Administration (VHA) facility from January 1, 2017 to June 16, 2020. Observed and expected patient care for on-going and new treatment of depression, posttraumatic stress, substance use disorder, severe mental illness diagnoses, overdose, and suicide attempts, and psychotropic prescriptions for antidepressant, antipsychotic, benzodiazepine, opioid, and mood stabilizing medications are depicted. Percent change between actual and expected counts in the early months of the COVID pandemic (March 18-May 5, 2020) are computed. Results: Decreases in counts of patients receiving care for mental health treatment during early pandemic response ranged from 7% to 20% for on-going treatment, and 28 to 37% for new treatment. TMH rapidly expanded across VHA, becoming the primary means by which encounters were delivered. The number of patients receiving on-going care for suicide attempts were stable and for overdoses, decreased 17%, while patients initiating care declined by 30% and 38%, respectively. Weekly prescriptions and medication on-hand for psychotropics ranged from a 2% decline to 4% increase. Prescribing to new patients declined 21 to 50%. Conclusions: VHA needs to expand outreach and continue to utilize TMH to maintain care continuity and initiate care for existing and new patients. This knowledge is useful for healthcare systems in developing strategies for COVID-19 and future large-scale outbreaks, epidemic, and disasters. Funding: These studies were supported through funding for medical operations by the Department of Veterans Affairs through the VA Office of Mental Health and Suicide Prevention. Declaration of Interests: Matt Boden is a consultant for the Beneath the Surface Foundation. None of the other authors have any potential conflicts of interest to disclose. Ethics Approval Statement: Data used in this study is captured in electronic medical records as part of routine clinical care and is utilized for the purpose of ongoing program evaluation. Thus, no institutional review board review was required for the study.
In order to potentially enhance the impact of most effective policies and interventions in reduci... more In order to potentially enhance the impact of most effective policies and interventions in reducing the population level damage from alcohol, a new perspective with regard to education and persuasion interventions is offered. Recent studies were examined on the global burden of alcohol and also those focusing on the links between overall consumption and high-risk drinking, on one hand, and drinking-related damage on the other hand. A synopsis of main findings from reviews and other analysis provides the basis for conclusions about the impacts of education and persuasion interventions. There is a relative absence of evidence of the effectiveness of education and persuasion in reducing consumption, curtailing high-risk drinking or reducing damage from alcohol. This is in contrast to the rising levels of damage from alcohol, and also to the demonstrated effectiveness of certain alcohol policies and interventions, as summarized in Babor et al. Given that only a small fraction of education and persuasion interventions have any positive impact, generating &amp;amp;amp;amp;amp;amp;#39;more of the same&amp;amp;amp;amp;amp;amp;#39; is not an impact-effective and cost-efficient approach. Therefore, interventions that have not been shown to be effective need to be phased out and those most effective and of widest scope should receive more attention and enhanced resources. A reframing of the roles and foci of persuasion interventions is advised, including, for example, focusing on informing policy-makers, and stimulating public discussions about the rationale of alcohol policies and the roles that citizens can play in promoting and supporting these policies.
Background: Preoperative patient-specific risk factors may elucidate the mechanisms leading to th... more Background: Preoperative patient-specific risk factors may elucidate the mechanisms leading to the persistence of pain and opioid use after surgery. This study aimed to determine whether similar or discordant preoperative factors were associated with the duration of postoperative pain and opioid use. Methods: In this post hoc analysis of a randomized, double-blind, placebo-controlled trial of perioperative gabapentin vs active placebo, 410 patients aged 18-75 years, undergoing diverse operations underwent preoperative assessments of pain, opioid use, substance use, and psychosocial variables. After surgery, a modified Brief Pain Inventory was administered over the phone daily up to 3 months, weekly up to 6 months, and monthly up to 2 years after surgery. Pain and opioid cessation were defined as the first of 5 consecutive days of 0 out of 10 pain or no opioid use, respectively. Results: Overall, 36.1%, 19.8%, and 9.5% of patients continued to report pain, and 9.5%, 2.4%, and 1.7% reported continued opioid use at 3, 6, and 12 months after surgery. Preoperative pain at the future surgical site (every 1-point increase in the Numeric Pain Rating Scale; HR 0.93; 95% CI 0.87-1.00; P=0.034), trait anxiety (every 10-point increase in the Trait Anxiety Inventory; HR 0.79; 95% CI 0.68-0.92; P=0.002), and a history of delayed recovery after injury (HR 0.62; 95% CI 0.40-0.96; P=0.034) were associated with delayed pain cessation. Preoperative opioid use (HR 0.60; 95% CI 0.39-0.92; P=0.020), elevated depressive symptoms (every 5-point increase in the Beck Depression Inventory-II score; HR 0.88; 95% CI 0.80-0.98; P=0.017), and preoperative pain outside of the surgical site (HR 0.94; 95% CI 0.89-1.00; P=0.046) were associated with delayed opioid cessation, while perioperative gabapentin promoted opioid cessation (HR 1.37; 95% CI 1.06-1.77; P=0.016). Conclusion: Separate risk factors for prolonged post-surgical pain and opioid use indicate that preoperative risk stratification for each outcome may identify patients needing personalized care to augment universal protocols for perioperative pain management and conservative opioid prescribing to improve long-term outcomes.
IMPORTANCE Among people with diabetes, co-occurring mental health (MH) or substance use (SU) diso... more IMPORTANCE Among people with diabetes, co-occurring mental health (MH) or substance use (SU) disorders increase the risk of medical complications. Identifying how to effectively promote longterm medical benefits for at-risk populations, such as people with MH or SU disorders, is essential. Knowing more about how health care accessed before the onset of diabetes is associated with health benefits after the onset of diabetes could inform treatment planning and population health management. OBJECTIVE To analyze how preexisting MH or SU disorders and primary care utilization before a new diabetes diagnosis are associated with the long-term severity of diabetes complications. DESIGN, SETTING, AND PARTICIPANTS This cohort study analyzed medical record data from US Department of Veterans Affairs health care systems nationwide and used mixed-effects regressions to test associations between prediabetes patient or health care factors and longitudinal progression of diabetes complication severity from 2006 to 2015. Participants included patients who received a new diabetes diagnosis in 2008 and who were aged 18 to 85 years at the time of their diagnosis. Data analysis was conducted from March to August 2017. EXPOSURES Patients were assigned to groups on the basis of a 2-year look-back period for MH or SU disorders status (MH disorder only, SU disorder only, MH and SU disorder, or no MH or SU disorder diagnoses) and on the basis of the amount of primary care utilization before diabetes was diagnosed. MAIN OUTCOMES AND MEASURES Nine-year trajectories of Diabetes Complication Severity Index (DCSI) scores. RESULTS Among 122 992 patients with newly diagnosed diabetes, the mean (SD) age was 62.3 (11.1) years, 118 810 (96.6%) were male, and 28 633 (23.3%) had preexisting MH or SU disorders diagnoses. From the onset of diabetes to 7 years later, patients' mean estimated DCSI scores
Although the tachykinins substance P (SP) and neurokinin A (NKA) are coreleased from primary affe... more Although the tachykinins substance P (SP) and neurokinin A (NKA) are coreleased from primary afferent nociceptors and act via neurokinin (NK) receptors, their differential effects in vivo are not known. Despite pharmacological evidence that NKA preferentially binds NK-2 receptors, this receptor is not found in spinal cord neurons. Thus, in the present studies, we compared the extent to which SP and NKA contribute to spinal nociceptive processing via the NK-1 receptor. We found that SP and NKA induce NK-1 receptor internalization with identical dose dependence and induce increases in intracellular calcium at the same concentrations, suggesting that SP and NKA equally activate the NK-1 receptor. We found, however, that the selective NK-1 receptor antagonist GR 205171 blocked NKA but not SP-induced NK-1 receptor internalization in the rat spinal cord in vivo and in embryonic day 19 rat spinal neurons in vitro. Using this selectivity of GR 205171 for NKA-induced NK-1 receptor activation, we examined the relative contribution of SP and NKA to noxious stimulusinduced activation of spinal NK-1 receptors. We estimate that NKA contributes to at least 50% of the NK-1 receptor activation in lamina I. Under inflammatory conditions, all noxious stimulus-induced NK-1 receptor internalization in deep dorsal horn neurons was blocked by GR 205171, suggesting that it is entirely NKA-mediated. Substance P-mediated NK-1 receptor internalization was focused at the site of termination of stimulated nociceptors but NKA also activated NK-1 receptors at more distant sites. We conclude that NKA not only targets the NK-1 receptor but may be a predominant pronociceptive primary afferent neurotransmitter.
Mental health treatment access and quality are influenced by the interplay of structural, organiz... more Mental health treatment access and quality are influenced by the interplay of structural, organizational, and performance factors-including the number of mental health staff providing direct clinical care relative to patients treated (i.e., staffing ratio), mental health staff productivity, and wait times for scheduled mental health appointments. With no industry standards to follow, the Veterans Health Administration (VHA) developed an outpatient mental health staffing model and a recommended minimum total staffing ratio. At the level of VHA health care facility (N=140), we conducted cross-sectional regression analyses to examine the relative importance of outpatient mental health staffing and productivity and mental health patient wait times in predicting measures of mental health treatment access and quality. Outpatient mental health staffing ratios (especially total and therapist staffing ratios) had substantial, positive relationships with overall mental health treatment access and quality, broadly and in specific domains. Staffing ratios generally had stronger relationships with treatment access and quality than did staff productivity and patient wait times. Mental health staffing ratios should be a primary consideration when trying to improve mental health treatment access and quality at the facility level. Having more mental health staff of all types is associated with better overall access to and quality of mental health services, and multiple staff types are needed to provide high-quality mental health care. Knowledge gained may guide efforts to address challenges in improving access to and quality of mental health services within and outside of VHA.
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Papers by Jodie Trafton