High-Dose Opioid Prescribing in Individuals with Acute Pain: Assessing the Effects of US State Opioid Policies.

BACKGROUND: How state opioid policy environments with multiple concurrent policies affect opioid prescribing to individuals with acute pain is unknown. OBJECTIVE: To examine how prescription drug monitoring programs (PDMPs), pain management clinic regulations, initial prescription duration limits, and mandatory continued medical education affected total and high-dose prescribing. DESIGN: A county-level multiple-policy difference-in-difference event study framework. SUBJECTS: A total of 2,425,643 individuals in a large national commercial insurance deidentified claims database (aged 12-64 years) with acute pain diagnoses and opioid prescriptions from 2007 to 2019. MAIN MEASURES: The total number of acute pain opioid treatment episodes and number of episodes containing high-dose (> 90 morphine equivalent daily dosage (MEDD)) prescriptions. KEY RESULTS: Approximately 7.5% of acute pain episodes were categorized as high-dose episodes. Prescription duration limits were associated with increases in the number of total episodes; no other policy was found to have a significant impact. Beginning five quarters after implementation, counties in states with pain management clinic regulations experienced a sustained 50% relative decline in the number of episodes containing > 90 MEDD prescriptions (95 CIs: (Q5: - 0.506, - 0.144; Q12: - 1.000, - 0.290)). Mandated continuing medical education regarding the treatment of pain was associated with a 50-75% relative increase in number of high-dose episodes following the first year-and-a-half of enactment (95 CIs: (Q7: 0.351, 0.869; Q12: 0.413, 1.107)). Initial prescription duration limits were associated with an initial relative reduction of 25% in high-dose prescribing, with the effect increasing over time (95 CI: (Q12: - 0.967, - 0.335). There was no evidence that PDMPs affected high-dose opioids dispensed to individuals with acute pain. Other high-risk prescribing indicators were explored as well; no consistent policy impacts were found. CONCLUSIONS: State opioid policies may have differential effects on high-dose opioid dispensing in individuals with acute pain. Policymakers should consider effectiveness of individual policies in the presence of other opioid policies to address the ongoing opioid crisis.

A Longitudinal Multivariable Analysis: State Policies and Opioid Dispensing in Medicare Beneficiaries Undergoing Surgery.

BACKGROUND: States have implemented policies to decrease clinically unnecessary opioid prescribing, but few studies have examined how state policies affect opioid dispensing rate trends for surgical patients. OBJECTIVE: To examine trends in the perioperative opioid dispensing rates for fee-for-service Medicare beneficiaries and the effects of select state policies. DESIGN AND PARTICIPANTS: A retrospective cohort study using 2006 to 2018 Medicare claims data for individuals undergoing surgical procedures for which opioid analgesic treatment is common. EXPOSURES: State policies mandating prescription drug monitoring program (PDMP; PDMP policies) use, initial opioid prescription duration limit (duration limit policies), and mandated continuing medical education (CME; CME pain policies) on pain management. MAIN MEASURES: Opioid dispensing rates, days' supply, and the daily morphine milligram equivalent dose (MMED). KEY RESULTS: The percentage of Medicare beneficiaries dispensed opioids in the perioperative period increased from 2007 to 2018; MMED and days' supply decreased over the same period, with significant variation by age, sex, and race. None of the three state policies affected the likelihood of Medicare beneficiaries being dispensed perioperative opioids. However, CME pain policies and duration limit policies were associated with decreased days' supply and decreased MMED in the several years following implementation, respectively. CONCLUSION: While we observed a slight increase in the rate of Medicare beneficiaries dispensed opioids perioperatively and a substantial decrease in MMED and days' supply for those receiving opioids, state policies examined had relatively modest effects on the main measures. Our findings suggest that these state policies may have a limited impact on opioid dispensing for a patient population that is commonly dispensed opioid analgesics to help control surgical pain, and as a result may have little direct effect on clinical outcomes for this population. Changes in opioid dispensing for this population may be the result of broader societal trends than such state policies.

Insurance-based Disparities in Outcomes and Extracorporeal Membrane Oxygenation Utilization for Hospitalized COVID-19 Patients.

BACKGROUND: The objective of this study was to examine insurance-based disparities in mortality, nonhome discharges, and extracorporeal membrane oxygenation utilization in patients hospitalized with COVID-19. METHODS: Using a national database of U.S. academic medical centers and their affiliated hospitals, the risk-adjusted association between mortality, nonhome discharge, and extracorporeal membrane oxygenation utilization and (1) the type of insurance coverage (private insurance, Medicare, dual enrollment in Medicare and Medicaid, and no insurance) and (2) the weekly hospital COVID-19 burden (0 to 5.0%; 5.1 to 10%, 10.1 to 20%, 20.1 to 30%, and 30.1% and greater) was evaluated. Modeling was expanded to include an interaction between payer status and the weekly hospital COVID-19 burden to examine whether the lack of private insurance was associated with increases in disparities as the COVID-19 burden increased. RESULTS: Among 760,846 patients hospitalized with COVID-19, 214,992 had private insurance, 318,624 had Medicare, 96,192 were dually enrolled in Medicare and Medicaid, 107,548 had Medicaid, and 23,560 had no insurance. Overall, 76,250 died, 211,702 had nonhome discharges, 75,703 were mechanically ventilated, and 2,642 underwent extracorporeal membrane oxygenation. The adjusted odds of death were higher in patients with Medicare (adjusted odds ratio, 1.28 [95% CI, 1.21 to 1.35]; P < 0.0005), dually enrolled (adjusted odds ratio, 1.39 [95% CI, 1.30 to 1.50]; P < 0.0005), Medicaid (adjusted odds ratio, 1.28 [95% CI, 1.20 to 1.36]; P < 0.0005), and no insurance (adjusted odds ratio, 1.43 [95% CI, 1.26 to 1.62]; P < 0.0005) compared to patients with private insurance. Patients with Medicare (adjusted odds ratio, 0.47; [95% CI, 0.39 to 0.58]; P < 0.0005), dually enrolled (adjusted odds ratio, 0.32 [95% CI, 0.24 to 0.43]; P < 0.0005), Medicaid (adjusted odds ratio, 0.70 [95% CI, 0.62 to 0.79]; P < 0.0005), and no insurance (adjusted odds ratio, 0.40 [95% CI, 0.29 to 0.56]; P < 0.001) were less likely to be placed on extracorporeal membrane oxygenation than patients with private insurance. Mortality, nonhome discharges, and extracorporeal membrane oxygenation utilization did not change significantly more in patients with private insurance compared to patients without private insurance as the COVID-19 burden increased. CONCLUSIONS: Among patients with COVID-19, insurance-based disparities in mortality, nonhome discharges, and extracorporeal membrane oxygenation utilization were substantial, but these disparities did not increase as the hospital COVID-19 burden increased.

Towards molecular-pathology informed clinical trials in childhood arthritis to achieve precision medicine in juvenile idiopathic arthritis.

In childhood arthritis, collectively known as Juvenile idiopathic arthritis (JIA), the rapid rise of available licensed biological and targeted small molecule treatments in recent years has led to improved outcomes. However, real-world data from multiple countries and registries show that despite a large number of available drugs, many children and young people continue to suffer flares and experience significant periods of time with active disease for many years. More than 50% of young people with JIA require ongoing immune suppression well into adult life, and they may have to try multiple different treatments in that time. There are currently no validated tools with which to select specific treatments, nor biomarkers of response to assist in such choices, therefore, current management uses essentially a trial-and-error approach. A further consequence of recent progress is a reducing pool of available children or young people who are eligible for new trials. In this review we consider how progress towards a molecular based approach to defining treatment targets and informing trial design in JIA, combined with novel approaches to clinical trials, could provide strategies to maximise discovery and progress, in order to move towards precision medicine for children with arthritis.

An Exploratory Analysis of Differential Prescribing of High-Risk Opioids by Insurance Type Among Patients Seen by the Same Clinician.

BACKGROUND: Insurance status may influence quality of opioid analgesic (OA) prescribing among patients seen by the same clinician. OBJECTIVE: To explore how high-risk OA prescribing varies by payer type among patients seeing the same prescriber and identify clinician characteristics associated with variable prescribing DESIGN: Retrospective cohort study using the 2016-2018 IQVIA Real World Data - Longitudinal Prescription PARTICIPANTS: New OA treatment episodes for individuals ≥ 12 years, categorized by payer and prescriber. We created three dyads: prescribers with ≥ 10 commercial insurance episodes and ≥ 10 Medicaid episodes; ≥ 10 commercial insurance episodes and ≥ 10 self-pay episodes; and ≥ 10 Medicaid episodes and ≥ 10 self-pay episodes. MAIN OUTCOME(S) AND MEASURE(S): Rates of high-risk episodes (initial opioid episodes with > 7-days' supply or prescriptions with a morphine milliequivalent daily dose >90) and odds of being an unbalanced prescriber (prescribers with significantly higher percentage of high-risk episodes paid by one payer vs. the other payer) KEY RESULTS: There were 88,352 prescribers in the Medicaid/self-pay dyad, 172,392 in the Medicaid/commercial dyad, and 122,748 in the self-pay/commercial dyad. In the Medicaid/self-pay and the commercial-self-pay dyads, self-pay episodes had higher high-risk episode rates than Medicaid (16.1% and 18.4%) or commercial (22.7% vs. 22.4%). In the Medicaid/commercial dyad, Medicaid had higher high-risk episode rates (21.1% vs. 20.4%). The proportion of unbalanced prescribers was 11-12% across dyads. In adjusted analyses, surgeons and pain specialists were more likely to be unbalanced prescribers than adult primary care physicians (PCPs) in the Medicaid/self-paydyad (aOR 1.2, 95% CI 1.16-1.34 and aOR 1.2, 95% CI 1.03-1.34). For Medicaid/commercial and self-pay/commercial dyads, surgeons had lower odds of being unbalanced compared to PCPs (aOR 0.6, 95% CI 0.57-0.66 and aOR 0.6, 95% CI 0.61-0.68). CONCLUSIONS: Clinicians prescribe high-risk OAs differently based on insurance type. The relationship between insurance and opioid prescribing quality goes beyond where patients receive care.

Buprenorphine Treatment Episodes During the First Year of COVID: a Retrospective Examination of Treatment Initiation and Retention.

BACKGROUND: During the COVID pandemic, overall buprenorphine treatment appeared to remain relatively stable, despite some studies suggesting a decrease in patients starting buprenorphine. There is a paucity of empirical information regarding patterns of buprenorphine treatment during the pandemic. OBJECTIVE: To better understand the patterns of buprenorphine episodes during the pandemic and how those patterns compared to pre-pandemic patterns. DESIGN: Pharmacy claims representing approximately 92% of all prescriptions filled at retail pharmacies in all 50 US states and the District of Columbia. PARTICIPANTS: Individuals filling buprenorphine prescriptions indicated for treatment of opioid use disorder. MAIN MEASURES: The number of active, starting, and ending buprenorphine treatment episodes March 13 to December 1, 2020, and the expected number of such episodes in 2020 based on the growth in treatment episodes from March 13 to December 1, 2019. KEY RESULTS: The observed number of active buprenorphine episodes in December 2020 was comparable to the expected number, but new treatment episodes starting between March 13 and December 1, 2020, were 17.2% fewer than expected based on the 2019 experience. Similarly, the number of episodes that ended between March 13 and December 1, 2020, was 16.0% fewer than expected. Decreases from expected episode starts and ends occurred throughout the period but were greatest in the 2 months after the declaration of the public health emergency. CONCLUSIONS AND RELEVANCE: Beneath the apparent stability of buprenorphine patient numbers during the pandemic, the flow of individuals receiving buprenorphine treatment changed substantially. Our findings shed light on how policy changes meant to support buprenorphine prescribing influenced prescribing dynamics during that period, suggesting that while policy efforts may have been successful in maintaining existing patients in treatment, that success did not extend to individuals not yet in treatment.

Medical marijuana access and prolonged opioid use among adolescents and young adults.

BACKGROUND AND OBJECTIVES: Laws liberalizing access to medical marijuana are associated with reduced opioid analgesic use among adults, but little is known about the impact of such policies on adolescents and young adults. METHODS: This retrospective cohort study used 2005 to 2014 claims from MarketScan® Commercial database, which covers all 50 states and Washington D.C. The sample included 195,204 adolescent and young adult patients (aged 12-25) who underwent one of 13 surgical procedures. RESULTS: Of the 195,204 patients, 4.8% had prolonged opioid use. Several factors were associated with a higher likelihood of prolonged opioid use, including being female (adjusted odds ratio [aOR], 1.27; 95% confidence interval [CI], 1.21-1.33), longer hospital stay (aOR, 1.04; 95% CI, 1.02-1.06), greater days of index opioid supply (8-14 days: aOR, 1.39, 95% CI, 1.33-1.45; greater than 14 days: aOR, 2.42, 95% CI, 2.26-2.59), rural residence (aOR, 1.07; 95% CI, 1.01-1.14), and cholecystectomy (aOR, 1.16; 95% CI, 1.08-1.25). There was not a significant association of medical marijuana dispensary laws on prolonged opioid use (aOR, 0.98; 95% CI, 0.81-1.18). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Medical marijuana has been suggested as a substitute for opioids, but our results focusing on adolescents and young adults provide new evidence that this particularly vulnerable population does not exhibit reductions in prolonged use of opioids after surgery when they have legal access to medical marijuana. These findings are the first to demonstrate potentially important age differences in sustained use of opioids, and point to the need for prescriber oversight and management with this vulnerable population.

Elastin Layer in Bruch's Membrane as a Target for Immunization or Tolerization to Modulate Pathology in the Mouse Model of Smoke-Induced Ocular Injury.

Age-related macular degeneration (AMD) is associated with an overactive complement system and an increase in circulating antibodies. Our search for potential neoantigens that can trigger complement activation in disease has led us to investigate elastin. A loss of the elastin layer (EL) of Bruch's membrane (BrM) has been reported in aging and AMD together with an increase of serum elastin-derived peptides and α-elastin antibodies. In the mouse model of cigarette smoke exposure (CSE), damage in BrM, loss of the EL, and vision loss are dependent on complement activation. We have examined the hypothesis that CSE generates immunogenic elastin neoepitopes that trigger an increase in α-elastin IgG and IgM antibodies, which can then bind to the neoepitopes in the target cells or membranes, triggering complement activation. Specifically, we showed that immunization with elastin peptide oxidatively modified by cigarette smoke (ox-elastin) exacerbated ocular pathology and vision loss in CSE mice. In contrast, mice receiving peptide immunotherapy (PIT) with ox-elastin did not lose vision over the smoking period and exhibited a more preserved BrM. Immunization and PIT correlated with humoral immunity and complement activation and IgG/IgM deposition in the RPE/BrM/choroid. Finally, PIT modulated immune markers IFNγ and IL-4. The data further support the hypothesis that complement activation, triggered by immune complex formation in target tissues, plays a role in ocular damage in the CSE model. As PIT with ox-elastin peptides reduces damage, we discuss the possibility that AMD progression might be preventable.

National Trends in Buprenorphine Treatment for Opioid Use Disorder From 2007 to 2018.

BACKGROUND: Buprenorphine is a key medication to treat opioid use disorder (OUD). Since its approval in 2002, buprenorphine access has grown markedly, spurred by major federal and state policy changes. This study characterizes buprenorphine treatment episodes during 2007 to 2018 with respect to payer, provider specialty, and patient demographics. METHODS: In this observational cohort study, IQVIA Real World pharmacy claims data were used to characterize trends in buprenorphine treatment episodes across four time periods: 2007-2009, 2010-2012, 2013-2015, and 2016-2018. RESULTS: In total, we identified more than 4.1 million buprenorphine treatment episodes among 2 540 710 unique individuals. The number of episodes doubled from 652 994 in 2007-2009 to 1 331 980 in 2016-2018. Our findings indicate that the payer landscape changed dramatically, with the most pronounced growth observed for Medicaid (increased from 17% of episodes in 2007-2009 to 37% of episodes in 2016-2018), accompanied by relative declines for both commercial insurance (declined from 35 to 21%) and self-pay (declined from 27 to 11%). Adult primary care providers (PCPs) were the dominant prescribers throughout the study period. The number of episodes among adults older than 55 increased more than 3-fold from 2007-2009 to 2016-2018. In contrast, youth under age 18 experienced an absolute decline in buprenorphine treatment episodes. Buprenorphine episodes increased in length from 2007-2018, particularly among adults over age 45. CONCLUSIONS: Our findings demonstrate that the U.S. experienced clear growth in buprenorphine treatment-particularly for older adults and Medicaid beneficiaries-reflecting some key health policy and implementation success stories. Yet, since the prevalence of OUD and fatal overdose rate have also approximately doubled during this period, the observed growth in buprenorphine treatment did not demonstrably impact the pronounced treatment gap. To date, only a minority of individuals with OUD currently receive treatment, indicating continued need for systemic efforts to equitably improve treatment uptake.

Spatial and temporal trends in the diagnosis of opioid-related problems in commercially-insured adolescents and young adults.

Little is known about the extent to which the prevalence of opioid-related problems (ORPs) varies among U.S. adolescents and young adults across geographic regions and over time, information that can help to guide policies that aim to curb the opioid epidemic. A retrospective, cross-sectional design was used to analyze longitudinal claims data from privately insured individuals aged 12-64 years who had an outpatient or inpatient diagnosis of an ORP in the years 2005-2018. The prevalence of opioid-related problem diagnoses (per 10,000) varied considerably across census divisions, both over time and between age groups. Knowledge of the origin of and variation in diagnosed opioid-related problems in terms of age group and census division is important so that interventions and policies can be more targeted and effective.

Sociodemographic differences in quality of treatment to Medicaid enrollees receiving buprenorphine.

Background: Buprenorphine is a key medication to treat opioid use disorder, but little is known about how treatment quality varies across sociodemographic groups. Objective: We examined measures of treatment quality and explored variation by sociodemographic factors. Methods: We used Medicaid MAX data from 50 states from 2006 to 2014 to identify buprenorphine treatment episodes (N = 317,494). We used multivariable logistic regression to examine the quality of buprenorphine treatment along four dimensions: (1) sufficient duration, (2) effective dosage, and concurrent prescribing of (3) opioid analgesics and (4) benzodiazepines. We explored how quality varied by race/ethnicity, age, sex, and urbanicity. Results: In adjusted models, compared to non-Hispanic White individuals, non-Hispanic Black and Hispanic individuals had lower odds of receiving effective dosage (aORs = 0.79 and 0.89, respectively) and sufficient duration (aORs = 0.64 and 0.71, respectively), and lower odds of concurrent prescribing of opioid analgesics (aORs = 0.86 and 0.85, respectively) and benzodiazepines (aORs = 0.51 and 0.59, respectively). Older individuals had higher odds of sufficient duration (aORs from 1.21-1.33), but also had higher odds of concurrent opioid analgesics prescribing (aORs from 1.29-1.56) and benzodiazepines (aORs from 1.44-1.99). Females had higher odds of sufficient duration (aOR = 1.12), but lower odds of effective dosage (aOR = 0.77) and higher odds of concurrent prescribing of opioid analgesics (aOR = 1.25) and benzodiazepines (aOR = 1.16). Compared to individuals living in metropolitan areas, individuals living in non-metropolitan areas had higher odds of sufficient duration (aORs = 1.11 and 1.24) and effective dosage (aORs = 1.06 and 1.33), and lower odds of concurrent prescribing (aORs from 0.81-0.98). Conclusions: Black and Hispanic individuals were less likely to receive effective buprenorphine dosage and sufficient duration. Quality results were mixed for older and female individuals; although these individuals were more likely to receive treatment of sufficient duration, they were also more likely to be concurrently prescribed potentially contraindicated medications, and females were less likely to receive effective dosage. Findings raise concerns about adequacy of care for minority and other at-risk populations.

Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration.

Age-related macular degeneration (AMD), a degenerative disease in the central macula area of the neuroretina and the supporting retinal pigment epithelium, is the most common cause of vision loss in the elderly. Although advances have been made, treatment to prevent the progressive degeneration is lacking. Besides the association of innate immune pathway genes with AMD susceptibility, environmental stress- and cellular senescence-induced alterations in pathways such as metabolic functions and inflammatory responses are also implicated in the pathophysiology of AMD. Cellular senescence is an adaptive cell process in response to noxious stimuli in both mitotic and postmitotic cells, activated by tumor suppressor proteins and prosecuted via an inflammatory secretome. In addition to physiological roles in embryogenesis and tissue regeneration, cellular senescence is augmented with age and contributes to a variety of age-related chronic conditions. Accumulation of senescent cells accompanied by an impairment in the immune-mediated elimination mechanisms results in increased frequency of senescent cells, termed "chronic" senescence. Age-associated senescent cells exhibit abnormal metabolism, increased generation of reactive oxygen species, and a heightened senescence-associated secretory phenotype that nurture a proinflammatory milieu detrimental to neighboring cells. Senescent changes in various retinal and choroidal tissue cells including the retinal pigment epithelium, microglia, neurons, and endothelial cells, contemporaneous with systemic immune aging in both innate and adaptive cells, have emerged as important contributors to the onset and development of AMD. The repertoire of senotherapeutic strategies such as senolytics, senomorphics, cell cycle regulation, and restoring cell homeostasis targeted both at tissue and systemic levels is expanding with the potential to treat a spectrum of age-related diseases, including AMD.

Treatment of psoriatic arthritis with biologic and targeted synthetic DMARDs: British Society for Rheumatology guideline scope.

The aim of this guideline is to provide an update on evidence-based recommendations for treatment of adult patients with PsA. The previous BSR guidelines for PsA were published in 2012 and since that time, there have been many new advanced therapies licensed for PsA. This update will provide practical guidance for clinicians on the optimal selection of advanced therapies taking into account different domains of PsA (arthritis, enthesitis, dactylitis, axial disease and psoriasis) and key associated comorbidities. It will also update guidance on treatment strategy including the use of a treat-to-target approach. The guideline will be developed using the methods and processes outlined in Creating Clinical Guidelines: Our Protocol. (1) This development process to produce guidance, advice and recommendations for practice has National Institute for Health and Care Excellence (NICE) accreditation.

Long-Term Safety and Efficacy of Adalimumab in Patients with Noninfectious Intermediate Uveitis, Posterior Uveitis, or Panuveitis.

PURPOSE: To evaluate long-term efficacy and safety of extended treatment with adalimumab in patients with noninfectious intermediate, posterior, or panuveitis. DESIGN: Open-label, multicenter, phase 3 extension study (VISUAL III). PARTICIPANTS: Adults who had completed a randomized, placebo-controlled phase 3 parent trial (VISUAL I or II) without treatment failure (inactive uveitis) or who discontinued the study after meeting treatment failure criteria (active uveitis). METHODS: Patients received subcutaneous adalimumab 40 mg every other week. Data were collected for ≤ 362 weeks. Adverse events (AEs) were recorded until 70 days after the last dose. MAIN OUTCOME MEASURES: Long-term safety and quiescence; other efficacy variables included inflammatory lesions, anterior chamber cell and vitreous haze grade, macular edema, visual acuity, and dose of uveitis-related systemic corticosteroids. RESULTS: At study entry, 67% of patients (283/424) showed active uveitis and 33% (141/424) showed inactive uveitis; 60 patients subsequently met exclusion criteria, and 364 were included in the intention-to-treat analysis. Efficacy variables were analyzed through week 150, when approximately 50% of patients (214/424) remained in the study. Patients showing quiescence increased from 34% (122/364) at week 0 to 85% (153/180) at week 150. Corticosteroid-free quiescence was achieved by 54% (66/123) and 89% (51/57) of patients with active or inactive uveitis at study entry. Mean daily dose of systemic corticosteroids was reduced from 9.4 ± 17.1 mg/day at week 0 (n = 359) to 1.5 ± 3.9 mg/day at week 150 (n = 181). The percentage of patients who achieved other efficacy variables increased over time for those with active uveitis at study entry and was maintained for those with inactive uveitis. The most frequently reported treatment-emergent AEs of special interest were infections (n = 275; 79 events/100 patient-years [PY]); AEs and serious AEs occurred at a rate of 396 events/100 PY and 15 events/100 PY, respectively. CONCLUSIONS: Long-term treatment with adalimumab led to quiescence and reduced corticosteroid use for patients who entered VISUAL III with active uveitis and led to maintenance of quiescence for those with inactive uveitis. AEs were comparable with those reported in the parent trials and consistent with the known safety profile of adalimumab.

The Unequal Burden of COVID-19 Deaths in Counties With High Proportions of Black and Hispanic Residents.

BACKGROUND: Understanding the current burden of coronavirus disease 2019 (COVID-19) deaths in vulnerable populations will help inform efforts by policymakers to address disparities in COVID-19 outcomes. OBJECTIVE: The objective of this study was to examine the association between COVID-19 deaths and the county-level proportions of non-Hispanic Black and Hispanic residents. RESEARCH DESIGN AND METHODS: A retrospective study using COVID-19 mortality data from USA Facts linked to data from the US Census Bureau, the Health Resources & Services Administration Area Health Resources file, and the US Census Bureau. Negative binomial regression was used to estimate the association between the total county COVID-19 deaths during consecutive 30-day intervals and the proportion of non-Hispanic Blacks and Hispanic residents after adjusting for resident demographics, comorbidity burden, rurality, social determinants of health, and health care resources. RESULTS: In April, counties (n=179) with >40% Blacks had 6-fold higher death rates than counties (n=1521) with <2% Blacks [incident rate ratio (IRR)=6.58, 95% confidence interval (CI): 3.29-13.2, P<0.001]. These counties had higher death rates until October, but were no different than referent counties in November. In April, death rates in counties with >40% Hispanic residents were similar to death rates in counties with <2% Hispanic residents. Death rates in these counties peaked in August (IRR=3.14, 95% CI: 1.69-5.82, P<0.001) but were also no different than referent counties in November. These effects were robust after adjusting for county-level characteristics. Before August, death rates differed little by insurance status, but since then, counties with >15% uninsurance rates had up to 2-fold higher mortality rates (IRR=1.97, 95% CI: 1.19-3.27, P<0.001) than counties with <5% uninsurance rates. CONCLUSION: Counties with high concentrations of non-Hispanic Blacks were disproportionately affected by COVID-19 throughout most of the pandemic, but other social determinants of health such as health insurance are now playing a more prominent role than race and ethnicity.

Outcomes Associated With State Policies Enabling Provision of Oral Health Services in Medical Offices Among Medicaid-enrolled Children.

BACKGROUND: To increase receipt of preventive oral health services (POHS), all state Medicaid programs have enacted policies to encourage nondental providers to deliver POHS in medical offices. This study examined if these Medicaid policies improved oral health, as measured by reductions in dental visits with treatment and preventable emergency department (ED) visits for nontraumatic dental conditions (NTDC). METHODS: Using data on children aged 6 months to up to 6 years from 38 state Medicaid programs during 2006-2014, we used a generalized difference-in-differences estimation approach to examine the probability of a child having, in a year, any dental visits with caries-related treatment and any ED visits for NTDC, conditional on length of policy enactment. Models included additional child-level and county-level characteristics, state and year fixed effects, probability weights, and clustered standard errors. RESULTS: Among a weighted sample of 45,107,240 child/year observations, 11.7% had any dental visits with treatment and 0.2% had any ED visits for NTDC annually. Children in states with and without medical POHS policies had similar odds of having any dental visits with treatment, regardless of length of policy enactment. Children in states with medical POHS policies enacted for one or more years had significantly greater odds of having any ED visits for NTDC (P<0.05). CONCLUSIONS: State policies making POHS available in medical offices did not affect rates of dental visits with caries-related treatment, but were associated with increased rates of potentially avoidable ED visits for NTDC. Findings suggest that many young Medicaid-enrollees lack access to dentists.

Peptide-based immunotherapy against oxidized elastin ameliorates pathology in mouse model of smoke-induced ocular injury.

PURPOSE: Age-related macular degeneration (AMD), the leading cause of blindness in western populations, is associated with an overactive complement system, and an increase in circulating antibodies against certain epitopes, including elastin. As loss of the elastin layer of Bruch's membrane (BrM) has been reported in aging and AMD, we previously showed that immunization with elastin peptide oxidatively modified by cigarette smoke (ox-elastin), exacerbated ocular pathology in the smoke-induced ocular pathology (SIOP) model. Here we asked whether ox-elastin peptide-based immunotherapy (PIT) ameliorates damage. METHODS: C57BL/6J mice were injected with ox-elastin peptide at two doses via weekly subcutaneous administration, while exposed to cigarette smoke for 6 months. FcγR-/- and uninjected C57BL/6J mice served as controls. Retinal morphology was assessed by electron microscopy, and complement activation, antibody deposition and mechanisms of immunological tolerance were assessed by Western blotting and ELISA. RESULTS: Elimination of Fcγ receptors, preventing antigen/antibody-dependent cytotoxicity, protected against SIOP. Mice receiving PIT with low dose ox-elastin (LD-PIT) exhibited reduced humoral immunity, reduced complement activation and IgG/IgM deposition in the RPE/choroid, and largely a preserved BrM. While there is no direct evidence of ox-elastin pathogenicity, LD-PIT reduced IFNγ and increased IL-4 within RPE/choroid. High dose PIT was not protective. CONCLUSIONS: These data further support ox-elastin role in ocular damage in part via elastin-specific antibodies, and support the corollary that PIT with ox-elastin attenuates ocular pathology. Overall, damage is associated with complement activation, antibody-dependent cell-mediated cytotoxicity, and altered cytokine signature.

Gene Therapy for Glaucoma by Ciliary Body Aquaporin 1 Disruption Using CRISPR-Cas9.

Glaucoma is a common cause of blindness, yet current therapeutic options are imperfect. Clinical trials have invariably shown that reduction in intraocular pressure (IOP) regardless of disease subtype prevents visual loss. Reducing ciliary body aqueous humor production can lower IOP, and the adeno-associated virus ShH10 serotype was identified as able to transduce mouse ciliary body epithelium following intravitreal injection. Using ShH10 to deliver a single vector CRISPR-Cas9 system disrupting Aquaporin 1 resulted in reduced IOP in treated eyes (10.4 ± 2.4 mmHg) compared with control (13.2 ± 2.0 mmHg) or non-injected eyes (13.1 ± 2.8 mmHg; p < 0.001; n = 12). Editing in the aquaporin 1 gene could be detected in ciliary body, and no off-target increases in corneal or retinal thickness were identified. In experimental mouse models of corticosteroid and microbead-induced ocular hypertension, IOP could be reduced to prevent ganglion cell loss (32 ± 4 /mm2) compared with untreated eyes (25 ± 5/mm2; p < 0.01). ShH10 could transduce human ciliary body from post-mortem donor eyes in ex vivo culture with indel formation detectable in the Aquaporin 1 locus. Clinical translation of this approach to patients with glaucoma may permit long-term reduction of IOP following a single injection.

Advanced cognitive impairment among older nursing home residents.

BACKGROUND: Though work has been done studying nursing home (NH) residents with either advanced Alzheimer's disease (AD) or Alzheimer's disease related dementia (ADRD), none have distinguished between them; even though their clinical features affecting survival are different. In this study, we compared mortality risk factors and survival between NH residents with advanced AD and those with advanced ADRD. METHODS: This is a retrospective observational study, in which we examined a sample of 34,493 U.S. NH residents aged 65 and over in the Minimum Data Set (2011-2013). Incident assessment of advanced disease was defined as the first MDS assessment with severe cognitive impairment (Cognitive Functional Score equals to 4) and diagnoses of AD or ADRD. Demographics, functional limitations, and comorbidities were evaluated as mortality risk factors using Cox models. Survival was characterized with Kaplan-Maier functions. RESULTS: Of those with advanced cognitive impairment, 35 % had AD and 65 % ADRD. At the incident assessment of advanced disease, those with AD had better health compared to those with ADRD. Mortality risk factors were similar between groups (shortness of breath, difficulties eating, substantial weight-loss, diabetes mellitus, heart failure, chronic obstructive pulmonary disease, and pneumonia; all p < 0.01). However, stroke and difficulty with transfer (for women) were significant mortality risk factors only for those with advanced AD. Urinary tract infection, and hypertension (for women) only were mortality risk factors for those with advanced ADRD. Median survival was significantly shorter for the advanced ADRD group (194 days) compared to the advanced AD group (300 days). CONCLUSIONS: There were distinct mortality and survival patterns of NH residents with advanced AD and ADRD. This may help with care planning decisions regarding therapeutic and palliative care.

Trends in personal and family member opioid prescriptions prior to a diagnosis of an opioid-related problem among adolescents and young adults.

Background: Efforts to reduce the risk of opioid misuse are often focused on reducing unnecessary prescriptions for opioid medications or reducing the dose prescribed; however, not all misuse occurs in individuals with a personal prescription. This study examined trends in the proportion of adolescents and young adults (AYAs) who had an opioid-related problem (ORP) and who also had a personal opioid prescription drug claim or had a family member with an opioid prescription drug claim prior to the ORP diagnosis. Methods: A retrospective cohort design was used to analyze longitudinal claims data. We identified individuals aged 12 to 25 years who had a newly diagnosed ORP in the years 2006 to 2014. Trends over time in personal or family opioid prescription drug claims within 1 year prior to ORP diagnosis were examined. Results: We identified 53,560 AYAs with an ORP diagnosis. Over the entire study period, 40% of AYAs with an ORP diagnosis had a personal opioid prescription in the year prior to diagnosis, and 48% had a family member with an opioid prescription in the prior year. While the proportion of AYAs with a family prescription remained constant, the proportion with a personal prescription fell from 77.1% in 2006 to 27.3% in 2014. Conclusions: The number of AYAs with an ORP increased over time, yet the proportion with a personal opioid prescription claim prior to their diagnosis decreased over time. This suggests that providers are paying greater attention to prescribing opioids to AYAs directly, although prescriptions to family members may still remain a point of access.