An answered call for aid? Cannabinoid clinical framework for the opioid epidemic.

BACKGROUND: The opioid crisis continues in full force, as physicians and caregivers are desperate for resources to help patients with opioid use and chronic pain disorders find safer and more accessible non-opioid tools. MAIN BODY: The purpose of this article is to review the current state of the opioid epidemic; the shifting picture of cannabinoids; and the research, policy, and current events that make opioid risk reduction an urgent public health challenge. The provided table contains an evidence-based clinical framework for the utilization of cannabinoids to treat patients with chronic pain who are dependent on opioids, seeking alternatives to opioids, and tapering opioids. CONCLUSION: Based on a comprehensive review of the literature and epidemiological evidence to date, cannabinoids stand to be one of the most interesting, safe, and accessible tools available to attenuate the devastation resulting from the misuse and abuse of opioid narcotics. Considering the urgency of the opioid epidemic and broadening of cannabinoid accessibility amidst absent prescribing guidelines, the authors recommend use of this clinical framework in the contexts of both clinical research continuity and patient care.

The need for establishing best practices and gold standards in psychedelic medicine.

Psychedelic substances are under investigation in several drug development programs. Controlled clinical trials are providing evidence for safe and effective use of psychedelic therapies for treating mental health conditions. With the anticipated FDA approval of MDMA-assisted therapy for posttraumatic stress disorder in 2023 and psilocybin therapy for depression disorders soon after, now is the time for the medical community to become informed on best practices and to actively participate in developing standards of care for these new treatments. Given the emergence of numerous drug sponsors and other companies developing therapeutic modalities for combination with psychedelic medications, it is essential that the medical professional field is at the forefront of communicating unbiased information related to safety and effectiveness. Gold standards have long been a part of medicine and serve to distinguish treatments and assessments as the highest quality by which all others can be compared to. For a treatment to be established as a gold standard, several factors are considered including the quantity and quality of the supporting data, the rigor of trials, and the safety and efficacy compared to other treatments. In this article, we review the origins of psychedelic-assisted therapy (PAT), minimum requirements for safe use of psychedelics, criteria for gold standards in mental health, and the nuances regarding how to establish gold standards in psychedelic medicine and guide clinical decision making.

Virtual Care Team Guided Management of Patients With Heart Failure During Hospitalization.

BACKGROUND: Scalable and safe approaches for heart failure guideline-directed medical therapy (GDMT) optimization are needed. OBJECTIVES: The authors assessed the safety and effectiveness of a virtual care team guided strategy on GDMT optimization in hospitalized patients with heart failure with reduced ejection fraction (HFrEF). METHODS: In a multicenter implementation trial, we allocated 252 hospital encounters in patients with left ventricular ejection fraction ≤40% to a virtual care team guided strategy (107 encounters among 83 patients) or usual care (145 encounters among 115 patients) across 3 centers in an integrated health system. In the virtual care team group, clinicians received up to 1 daily GDMT optimization suggestion from a physician-pharmacist team. The primary effectiveness outcome was in-hospital change in GDMT optimization score (+2 initiations, +1 dose up-titrations, -1 dose down-titrations, -2 discontinuations summed across classes). In-hospital safety outcomes were adjudicated by an independent clinical events committee. RESULTS: Among 252 encounters, the mean age was 69 ± 14 years, 85 (34%) were women, 35 (14%) were Black, and 43 (17%) were Hispanic. The virtual care team strategy significantly improved GDMT optimization scores vs usual care (adjusted difference: +1.2; 95% CI: 0.7-1.8; P < 0.001). New initiations (44% vs 23%; absolute difference: +21%; P = 0.001) and net intensifications (44% vs 24%; absolute difference: +20%; P = 0.002) during hospitalization were higher in the virtual care team group, translating to a number needed to intervene of 5 encounters. Overall, 23 (21%) in the virtual care team group and 40 (28%) in usual care experienced 1 or more adverse events (P = 0.30). Acute kidney injury, bradycardia, hypotension, hyperkalemia, and hospital length of stay were similar between groups. CONCLUSIONS: Among patients hospitalized with HFrEF, a virtual care team guided strategy for GDMT optimization was safe and improved GDMT across multiple hospitals in an integrated health system. Virtual teams represent a centralized and scalable approach to optimize GDMT.

Pilot study suggests DNA methylation of the glucocorticoid receptor gene (NR3C1) is associated with MDMA-assisted therapy treatment response for severe PTSD.

Background: Previous research has demonstrated that epigenetic changes in specific hypothalamic-pituitary-adrenal (HPA) genes may predict successful psychotherapy in post-traumatic stress disorder (PTSD). A recent Phase 3 clinical trial reported high efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for treating patients with severe PTSD compared to a therapy with placebo group (NCT03537014). This raises important questions regarding potential mechanisms of MDMA-assisted therapy. In the present study, we examined epigenetic changes in three key HPA axis genes before and after MDMA and placebo with therapy. As a pilot sub-study to the parent clinical trial, we assessed potential HPA epigenetic predictors for treatment response with genomic DNA derived from saliva (MDMA, n = 16; placebo, n = 7). Methylation levels at all 259 CpG sites annotated to three HPA genes (CRHR1, FKBP5, and NR3C1) were assessed in relation to treatment response as measured by the Clinician-Administered PTSD Scale (CAPS-5; Total Severity Score). Second, group (MDMA vs. placebo) differences in methylation change were assessed for sites that predicted treatment response. Results: Methylation change across groups significantly predicted symptom reduction on 37 of 259 CpG sites tested, with two sites surviving false discovery rate (FDR) correction. Further, the MDMA-treatment group showed more methylation change compared to placebo on one site of the NR3C1 gene. Conclusion: The findings of this study suggest that therapy-related PTSD symptom improvements may be related to DNA methylation changes in HPA genes and such changes may be greater in those receiving MDMA-assisted therapy. These findings can be used to generate hypothesis driven analyses for future studies with larger cohorts.

Under the ACA Higher Deductibles and Medical Debt Cause Those Most Vulnerable to Defer Needed Care.

OBJECTIVE: Study occurrence and consequences of deductibles and medical debt among privately insured under the Affordable Care Act. METHODS: Analysis of 2012-2016 National Health Interview Survey data on privately insured adults younger than age 65 on the effect of deductibles on medical debt, deferred medical care, and office visits, by demographic characteristics, and treatable chronic diseases. RESULTS: Rates of medical debt and deferred care decreased. Medical debt is greater for those with any type of high deductible (HD) insurance, and among those more vulnerable (lower income, minority, treatable chronic diseases). Medical debt with HD's increased deferred needed medical care 6 fold and is highest for those with more treatable chronic diseases. CONCLUSION: While medical debt and deferred care decreased for all privately insured, those HD-insured and vulnerable report higher medical debt rates markedly increasing deferred needed medical care. Highdeductible insurance risks adverse health and social consequences for those vulnerable.

Privately insured adults in HDHP with higher deductibles reduce rates of primary care and preventive services.

Rates of insurance coverage in high deductible health plans (HDHP) and deductible size have been increasing. Over-time, financial barriers can lead to a substantial reduction in opportunities for health promotion and care coordination. We investigated the impact of different types of HDHPs on primary and specialty services utilization and receipt of preventive services among adult (18-64 years) privately insured respondents using pooled 2011-2014 Medical Expenditure Panel Survey (MEPS). The sample (n = 25,965) was divided into four insurance types (1) no deductible (ND) (2) low deductible (LD), (3) high deductible with health savings account (HD-HSA), and (4) high deductible without health savings account (HD-NoHSA). Multivariable regression models were estimated, adjusting for demographic characteristics and health status. Number of visits to primary care physicians and specialists were lowest for persons in the HD-NoHSA group (IRR 0.88 95% CI [0.81-0.96]). HD-NoHSA beneficiaries had lower rates of receiving hypertension screening (IRR 0.97 95% CI [0.94-0.99]) and flu vaccination (IRR 0.92 95% CI [0.86-1.00]) when compared to ND enrollees. Female respondents in the HD-NoHSA group were 7% less likely to receive mammograms (IRR 0.93 95% CI [0.89-0.98]) compared to the ND group. There was no significant association between insurance type and the other preventive service measures. Higher deductibles significantly decrease opportunities for early detection and management of chronic diseases, immunizations and care coordination. Fiscal barriers to essential medical care should be eliminated at least for those most vulnerable.

Validity of an automated algorithm using diagnosis and procedure codes to identify decompensated cirrhosis using electronic health records.

Viral hepatitis-induced cirrhosis can progress to decompensated cirrhosis. Clinical decompensation represents a milestone event for the patient with cirrhosis, yet there remains uncertainty regarding precisely how to define this important phenomenon. With the development of broader treatment options for cirrhotic hepatitis patients, efficient identification of liver status before evolving to decompensated cirrhosis could be life-saving, but research on the topic has been limited by inconsistencies across studies, populations, and case-confirmation methods. We sought to determine whether diagnosis/procedure codes drawn from electronic health records (EHRs) could be used to identify patients with decompensated cirrhosis. In our first step, chart review was used to determine liver status (compensated cirrhosis, decompensated cirrhosis, non-cirrhotic) in patients from the Chronic Hepatitis Cohort Study. Next, a hybrid approach between Least Absolute Shrinkage and Selection Operator regression and Classification Regression Trees models was used to optimize EHR-based identification of decompensated cirrhosis, based on 41 diagnosis and procedure codes. These models were validated using tenfold cross-validation; method accuracy was evaluated by positive predictive values (PPVs) and area under receiver operating characteristic (AUROC) curves. Among 296 patients (23 with hepatitis B, 268 with hepatitis C, and 5 co-infected) with a 2:1 ratio of biopsy-confirmed cirrhosis to noncirrhosis, chart review identified 127 cases of decompensated cirrhosis (Kappa=0.88). The algorithm of five liver-related conditions-liver transplant, hepatocellular carcinoma, esophageal varices complications/procedures, ascites, and cirrhosis-yielded a PPV of 85% and an AUROC of 92%. A hierarchical subset of three conditions (hepatocellular carcinoma, ascites, and esophageal varices) demonstrated a PPV of 81% and an AUROC of 86%. Given the excellent predictive ability of our model, this EHR-based automated algorithm may be used to successfully identify patients with decompensated cirrhosis. This algorithm may contribute to timely identification and treatment of viral hepatitis patients who have progressed to decompensated cirrhosis.

Among Low-Income Respondents With Diabetes, High-Deductible Versus No-Deductible Insurance Sharply Reduces Medical Service Use.

OBJECTIVE: To contrast the effect of private insurance and deductibles (by size) on medical service use, health status, and medical debt for adult respondents with diabetes with low and high incomes. RESEARCH DESIGN AND METHODS: Using the 2011-2013 Medical Expenditure Panel Survey, bivariate and regression analyses were conducted to compare demographic characteristics, medical service use, diabetes care, and health status among privately insured adult respondents with diabetes, aged 18-64 years (N = 1,461) by lower (<200% of the federal poverty level) and higher (≥200% of the federal poverty level) income and deductible vs. no deductible (ND), low deductible ($1,000/$2,400) (LD), and high deductible (>$1,000/$2,400) (HD). The National Health Interview Survey 2012-2014 was used to analyze differences in medical debt and delayed/avoided needed care among adult respondents with diabetes (n = 4,058) by income. RESULTS: Compared with privately insured respondents with diabetes with ND, privately insured lower-income respondents with diabetes with an LD report significant decreases in service use for primary care, checkups, and specialty visits (27%, 39%, and 77% lower, respectively), and respondents with an HD decrease use by 42%, 65%, and 86%, respectively. Higher-income respondents with an LD report significant decreases in specialty (28%) and emergency department (37%) visits. Diabetes care measures are similar by income and insurance; there were no changes in physical health status. Medical debt is similar by income, but deferred service use is two times greater for those indebted and with lower income. CONCLUSIONS: Private insurance with a deductible substantially and problematically reduces medical service use for lower-income insured respondents with diabetes who have an HD; these patients are more likely to report forgoing needed medical services.

The impact of insurance and a usual source of care on emergency department use in the United States.

Background. Finding a usual source of care (USC) is difficult for certain populations. This analysis determines how insurance type and having a USC affect the settings in which patients seek care. Methods. In this cross-sectional study of the 2000-2011 Medical Expenditure Panel Surveys, we assessed the percentage of low-income persons with half or more of their ambulatory visits to the emergency department (ED). Respondents were stratified based on insurance type and presence of a USC. Results. In 2011, among Medicaid enrollees without USCs, 21.6% had half or more of their ambulatory visits to EDs compared to 8.1% for those with USCs. Among the uninsured without USCs, 24.1% went to an ED for half or more of their ambulatory visits compared to 8.8% for those with USCs in 2011. Among the privately insured without USCs, 7.8% went to an ED for half or more of their ambulatory visits compared to 5.0% for those with USCs in 2011. These differences remained in multivariate analyses. Conclusions. Those who lack USCs, particularly the uninsured and Medicaid enrollees, are more likely to rely on EDs.

Effectiveness and feasibility study of routine HIV rapid testing in an urban methadone maintenance treatment program.

BACKGROUND: Universal Human Immunodeficiency Virus (HIV) testing and treatment are strategies to decrease AIDS-related morbidity and mortality and to reduce HIV transmission. OBJECTIVE: This study examined the feasibility and effectiveness of routine HIV rapid testing implemented in the largest New York City (NYC) Methadone Maintenance Treatment Program (MMTP). METHODS: A routine HIV rapid testing program performed by medical providers without pretest counseling or the provision of incentives was compared to HIV rapid testing done by referral to HIV counselors with pretest counseling and incentives over the prior 12 months. RESULTS: Routine HIV rapid testing proved feasible and effective when performed by the medical staff in the setting of a large urban MMTP. The program increased HIV testing in all genders, race/ethnicities, and ages. HIV-positive individuals were diagnosed and successfully linked to care. The elimination of HIV prevention counseling may have facilitated expanded testing. CONCLUSION: This study confirms that routine HIV rapid testing without HIV-prevention counseling or the provision of incentives for patients is feasible on a large scale in a busy, urban methadone clinic.

Chronic oxidative stress upregulates Drusen-related protein expression in adult human RPE stem cell-derived RPE cells: a novel culture model for dry AMD.

PURPOSE: The goal of this study was to examine changes in the expression of transcripts and proteins associated with drusen in Age-related Macular Degeneration (AMD) after exposing human retinal pigment epithelium (hRPE) cells to chronic oxidative stress. METHODS: Primary adult human RPE cells were isolated from cadaveric donor eyes. The subpopulation of RPE stem cells (RPESCs) was activated, expanded, and then differentiated into RPE progeny. Confluent cultures of RPESC-derived hRPE and ARPE-19 cells were exposed to a regimen of tert-butylhydroperoxide (TBHP) for 1-5 days. After treatment, gene expression was measured by quantitative PCR (qPCR), protein expression was assessed by immunocytochemistry and transepithelial resistance and cell toxicity were measured. RESULTS: hRPE cells exposed to a regimen of TBHP for 5 days upregulate expression of several molecules identified in drusen, including molecular chaperones and pro-angiogenic factors. 5-day TBHP treatment was significantly more effective than 1-day treatment at eliciting these effects. The extent of hRPE response to 5-day treatment varied significantly between individual donors, nevertheless, 6 transcripts were reliably significantly upregulated. ARPE-19 cells treated with the same 5-day stress regime did not show the same pattern of response and did not upregulate this group of transcripts. CONCLUSIONS: RPESC-derived hRPE cells change significantly when exposed to repeated oxidative stress conditions, upregulating expression of several drusen-related proteins and transcripts. This is consistent with the hypothesis that hRPE cells are competent to be a source of proteins found in drusen deposits. Our results suggest that donor-specific genetic and environmental factors influence the RPE stress response. ARPE-19 cells appear to be less representative of AMD-like changes than RPESC-derived hRPE. This adult stem cell-based system using chronic TBHP treatment of hRPE represents a novel in vitro model useful for the study of drusen formation and dry AMD pathophysiology.

Projecting US primary care physician workforce needs: 2010-2025.

PURPOSE: We sought to project the number of primary care physicians required to meet US health care utilization needs through 2025 after passage of the Affordable Care Act. METHODS: In this projection of workforce needs, we used the Medical Expenditure Panel Survey to calculate the use of office-based primary care in 2008. We used US Census Bureau projections to account for demographic changes and the American Medical Association's Masterfile to calculate the number of primary care physicians and determine the number of visits per physician. The main outcomes were the projected number of primary care visits through 2025 and the number of primary care physicians needed to conduct those visits. RESULTS: Driven by population growth and aging, the total number of office visits to primary care physicians is projected to increase from 462 million in 2008 to 565 million in 2025. After incorporating insurance expansion, the United States will require nearly 52,000 additional primary care physicians by 2025. Population growth will be the largest driver, accounting for 33,000 additional physicians, while 10,000 additional physicians will be needed to accommodate population aging. Insurance expansion will require more than 8,000 additional physicians, a 3% increase in the current workforce. CONCLUSIONS: Population growth will be the greatest driver of expected increases in primary care utilization. Aging and insurance expansion will also contribute to utilization, but to a smaller extent.

Adult human RPE can be activated into a multipotent stem cell that produces mesenchymal derivatives.

The retinal pigment epithelium (RPE) is a monolayer of cells underlying and supporting the neural retina. It begins as a plastic tissue, capable, in some species, of generating lens and retina, but differentiates early in development and remains normally nonproliferative throughout life. Here we show that a subpopulation of adult human RPE cells can be activated in vitro to a self-renewing cell, the retinal pigment epithelial stem cell (RPESC) that loses RPE markers, proliferates extensively, and can redifferentiate into stable cobblestone RPE monolayers. Clonal studies demonstrate that RPESCs are multipotent and in defined conditions can generate both neural and mesenchymal progeny. This plasticity may explain human pathologies in which mesenchymal fates are seen in the eye, for example in proliferative vitroretinopathy (PVR) and phthisis bulbi. This study establishes the RPESC as an accessible, human CNS-derived multipotent stem cell, useful for the study of fate choice, replacement therapy, and disease modeling.

Prevalence of diverticulosis in recurrent Clostridium difficile infection.

AIM: To re-evaluate the theory that colonic diverticulosis is associated with relapse of Clostridium difficile associated disease (CDAD) in light of data suggesting increasing rates of CDAD infection and relapse. METHODS: Charts were reviewed for patients with recurrent CDAD who had also had a prior colonoscopy or flexible sigmoidoscopy. An age and gender matched control group was used to compare the prevalence of diverticulosis. RESULTS: Twenty-two patients met the study criteria, and the prevalence of diverticulosis in patients with CDAD relapse was 23% compared to 32% in age and sex matched controls (P = 0.44). A significant proportion of patients with CDAD relapse had co-morbidities associated with immune suppression. CONCLUSION: Diverticulosis does not appear to be associated with CDAD relapse.

Decreasing self-perceived health status despite rising health expenditures.

Despite steady increases in U.S. health care spending, the population's self-perceived health status has been in a long-term decline. Increased support for public health, prevention, and primary care could reduce growth in spending and improve actual and perceived health.

Having a usual source of care reduces ED visits.

The recent growth in the use of emergency departments (EDs) is costly, undesirable, and unnecessary. This trend is partly due to a growing proportion of persons who lack a usual source of care. This group is increasingly likely to rely on EDs for their health care needs compared with those who have a usual source of care.

Human retinal pigment epithelium cell changes and expression of alphaB-crystallin: a biomarker for retinal pigment epithelium cell change in age-related macular degeneration.

OBJECTIVE: To examine changes in the retinal pigment epithelium (RPE) in eyes with age-related macular degeneration (AMD) and specifically to characterize alphaB-crystallin expression in RPE cells as a biomarker in this disease. METHODS: Maculae from human patients diagnosed as having AMD or from age-matched control eyes were isolated, cryosectioned, and analyzed immunohistochemically for alphaB-crystallin and for cell type-specific markers. RESULTS: In eyes with dry and wet AMD, alphaB-crystallin was heterogeneously expressed by a subpopulation of RPE cells in the macular region (frequently in cells adjacent to drusen) and in areas of RPE hypertrophy associated with wet AMD. In contrast, alphaB-crystallin was not detected at significant levels in control RPE. CONCLUSION: Accompanying the formation of drusen in early-stage and late-stage AMD, RPE cells undergo change to express alphaB-crystallin. CLINICAL RELEVANCE: The detection of alphaB-crystallin in the RPE of patients with early and advanced AMD implicates this as an AMD biomarker. Sporadic expression of alphaB-crystallin by RPE cells localized adjacent to drusen in early AMD indicates that changes in the gene expression of RPE cells accompany early stages of the disease and introduces novel potential targets for AMD therapy.

Comparison of sarcoidosis phenotypes among affected African-American siblings.

STUDY OBJECTIVE: To test the hypothesis that sibling pairs, who share genes and environmental exposures, might have similar phenotypic expressions of sarcoidosis beyond what would be expected by chance alone. DESIGN: Multicenter family study with study subjects recruited from 11 clinical centers. SUBJECTS: Subjects were African-American sibling pairs with sarcoidosis. Sarcoidosis and organ pattern involvement were defined according to specific criteria. Fifteen different organ systems were evaluated. RESULTS: For full-sibling pairs, ocular involvement was found in both siblings more often than expected by chance alone (p < 0.05), but the concordance was weak (kappa = 0.18). When analyzing full-sibling and half-sibling pairs, ocular and liver involvement showed a significant concordance between sibling pairs (p < 0.05), but again the agreement was poor (kappa = 0.16 for both). Concordance in pulmonary function change over time was also weak. Clinical outcomes of sibling pairs were not significantly correlated except for whether treatment was prescribed, and this level of agreement was poor (kappa = 0.14 for full-sibling and half-sibling pairs; kappa = 0.15 for full-sibling pairs only). Modeling phenotypic expression in sibling pairs using logistic regression did show that the presence of ocular and liver sarcoidosis in the first affected sibling conferred a statistically significant increased risk to the second affected sibling for having those organs involved (odds ratio [OR], 3; 95% confidence interval [CI], 1.7 to 5.4 for ocular; OR, 3.3; 95% CI, 1.5 to 7.4 for liver). CONCLUSIONS: The phenotypic features and clinical outcomes of sarcoidosis in sibling pairs show minimal concordance, with the possible exception that the presence of ocular or liver involvement in the first sibling with a diagnosis of sarcoidosis makes involvement of these organs more likely in other affected siblings.

A sarcoidosis genetic linkage consortium: the sarcoidosis genetic analysis (SAGA) study.

BACKGROUND: Sarcoidosis, a systemic granulomatous disease of unknown etiology, likely results from an environmental insult in a genetically susceptible host. In the United States of America, African Americans have a higher sarcoidosis incidence and suffer greater morbidity than Caucasians. METHODS: A sarcoidosis genetic linkage study consortium was established to recruit African-American affected sib pair (ASP) families to identify chromosomal regions that may harbor sarcoidosis susceptibility genes and to determine if environmental factors modify any genetic effects. RESULTS: We successfully met our goal of enrolling 359 ASPs using a multifaceted recruitment approach. In the total 559 sib pairs that were enrolled, genetic analyses revealed incorrectly specified relationships that required reclassification or removal from the analysis dataset of 10.4% of reported full and 1.4% of reported half sib pairs. The final study sample comprised 415 full and 104 half sib pairs with complete data. This included 338 ASPs. Within sib pairs, affection status was not associated with sex. Only 15 per cent of the 229 families had three or more affected sibs, but they contributed 42 per cent of the ASP total. CONCLUSIONS: The SAGA study experience should provide useful lessons and information to serve others in conducting genetic studies of complex diseases in African-American families.