Publications by authors named "Christina A Mikosz"

15 Publications

  • Page 1 of 1

Assessment of Annual Cost of Substance Use Disorder in US Hospitals.

JAMA Netw Open 2021 03 1;4(3):e210242. Epub 2021 Mar 1.

National Center for Injury Prevention and Control, Centers for Disease Control and Prevention, Atlanta, Georgia.

Importance: A persistently high US drug overdose death toll and increasing health care use associated with substance use disorder (SUD) create urgency for comprehensive estimates of attributable direct costs, which can assist in identifying cost-effective ways to prevent SUD and help people to receive effective treatment.

Objective: To estimate the annual attributable medical cost of SUD in US hospitals from the health care payer perspective.

Design, Setting, And Participants: This economic evaluation of observational data used multivariable regression analysis and mathematical modeling of hospital encounter costs, controlling for patient demographic, clinical, and insurance characteristics, and compared encounters with and without secondary SUD diagnosis to statistically identify the total attributable cost of SUD. Nationally representative hospital emergency department (ED) and inpatient encounters from the 2017 Healthcare Cost and Utilization Project Nationwide Emergency Department Sample and National Inpatient Sample were studied. Statistical analysis was performed from March to June 2020.

Exposures: International Statistical Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) principal or secondary SUD diagnosis on the hospital discharge record according to the Clinical Classifications Software categories (disorders related to alcohol, cannabis, hallucinogens, inhalants, opioids, sedatives, stimulants, and other substances).

Main Outcomes And Measures: Annual attributable SUD medical cost in hospitals overall and by substance type (eg, alcohol). The number of encounters (ED and inpatient) with SUD diagnosis (principal or secondary) and the mean cost attributable to SUD per encounter by substance type are also reported.

Results: This study examined a total of 124 573 175 hospital ED encounters and 33 648 910 hospital inpatient encounters from the 2017 Healthcare Cost and Utilization Project Nationwide Emergency Department Sample and National Inpatient Sample. Total annual estimated attributable SUD medical cost in hospitals was $13.2 billion. By substance type, the cost ranged from $4 million for inhalant-related disorders to $7.6 billion for alcohol-related disorders.

Conclusions And Relevance: This study's results suggest that the cost of effective prevention and treatment may be substantially offset by a reduction in the high direct medical cost of SUD hospital care. The findings of this study may inform the treatment of patients with SUD during hospitalization, which presents a critical opportunity to engage patients who are at high risk for overdose. Aligning incentives such that prevention cost savings accrue to payers and practitioners that are otherwise responsible for SUD-related medical costs in hospitals and other health care settings may encourage prevention investment.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.0242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936257PMC
March 2021

Indication-Specific Opioid Prescribing for US Patients With Medicaid or Private Insurance, 2017.

JAMA Netw Open 2020 05 1;3(5):e204514. Epub 2020 May 1.

National Center for Injury Prevention and Control, Centers for Disease Control and Prevention, Atlanta, Georgia.

Importance: Although opioids can be effective medications in certain situations, they are associated with harms, including opioid use disorder and overdose. Studies have revealed unexplained prescribing variation and prescribing mismatched with patient-reported pain for many indications.

Objective: To summarize opioid prescribing frequency, dosages, and durations, stratified across numerous painful medical indications.

Design, Setting, And Participants: Retrospective cross-sectional analysis of 2017 US administrative claims data among outpatient clinical settings, including postsurgical discharge. Participants had any of 41 different indications associated with nonsurgical acute or chronic pain or postsurgical pain or pain associated with sickle cell disease or active cancer and were enrolled in either private insurance (including Medicare Advantage) in the OptumLabs Data Warehouse data set (n = 18 016 259) or Medicaid in the IBM MarketScan Multi-State Medicaid Database (n = 11 453 392). OptumLabs data were analyzed from October 2018 to March 2019; MarketScan data were analyzed from January to April 2019.

Exposures: Nonsurgical acute or chronic pain or postsurgical pain; pain related to sickle cell disease or active cancer.

Main Outcomes And Measures: Indication-specific opioid prescribing rates; days' supply per prescription; daily opioid dosage in morphine milligram equivalents; and for chronic pain indications, the number of opioid prescriptions.

Results: During the study period, of 18 016 259 eligible patients with private insurance, the mean (95% CI) age was 42.7 (42.7-42.7) years, and 50.3% were female; of 11 453 392 eligible Medicaid enrollees, the mean (95% CI) age was 20.4 (20.4-20.4) years, and 56.1% were female. A pain-related indication under study occurred in at least 1 visit among 6 380 694 patients with private insurance (35.4%) and 3 169 831 Medicaid enrollees (27.7%); 2 270 596 (35.6% of 6 380 694) privately insured patients and 1 126 508 (35.5% of 3 169 831) Medicaid enrollees had 1 or more opioid prescriptions. Nonsurgical acute pain opioid prescribing rates were lowest for acute migraines (privately insured, 4.6% of visits; Medicaid, 6.6%) and highest for rib fractures (privately insured, 44.8% of visits; Medicaid, 56.3%), with variable days' supply but similar daily dosage across most indications. Opioid prescribing for a given chronic pain indication varied depending on a patient's opioid use history. Days' supply for postoperative prescriptions was longest for combined spinal decompression and fusion (privately insured, 9.5 days [95% CI, 9.4-9.7 days]) or spinal fusion (Medicaid, 9.1 days [95% CI, 8.9-9.2 days]) and was shortest for vaginal delivery (privately insured, 4.1 days [95% CI, 4.1-4.1 days] vs Medicaid, 4.2 days [95% CI, 4.2-4.2 days]).

Conclusions And Relevance: Indication-specific opioid prescribing rates were not always aligned with existing guidelines. Potential inconsistencies between prescribing practice and clinical recommendations, such as for acute and chronic back pain, highlight opportunities to enhance pain management and patient safety.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.4514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215258PMC
May 2020

Severe Pulmonary Disease Associated with Electronic-Cigarette-Product Use - Interim Guidance.

MMWR Morb Mortal Wkly Rep 2019 Sep 13;68(36):787-790. Epub 2019 Sep 13.

On September 6, 2019, this report was posted as an MMWR Early Release on the MMWR website (https://www.cdc.gov/mmwr). As of August 27, 2019, 215 possible cases of severe pulmonary disease associated with the use of electronic cigarette (e-cigarette) products (e.g., devices, liquids, refill pods, and cartridges) had been reported to CDC by 25 state health departments. E-cigarettes are devices that produce an aerosol by heating a liquid containing various chemicals, including nicotine, flavorings, and other additives (e.g., propellants, solvents, and oils). Users inhale the aerosol, including any additives, into their lungs. Aerosols produced by e-cigarettes can contain harmful or potentially harmful substances, including heavy metals such as lead, volatile organic compounds, ultrafine particles, cancer-causing chemicals, or other agents such as chemicals used for cleaning the device (1). E-cigarettes also can be used to deliver tetrahydrocannabinol (THC), the principal psychoactive component of cannabis, or other drugs; for example, "dabbing" involves superheating substances that contain high concentrations of THC and other plant compounds (e.g., cannabidiol) with the intent of inhaling the aerosol. E-cigarette users could potentially add other substances to the devices. This report summarizes available information and provides interim case definitions and guidance for reporting possible cases of severe pulmonary disease. The guidance in this report reflects data available as of September 6, 2019; guidance will be updated as additional information becomes available.
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http://dx.doi.org/10.15585/mmwr.mm6836e2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755818PMC
September 2019

Pulmonary Illness Related to E-Cigarette Use in Illinois and Wisconsin - Final Report.

N Engl J Med 2020 03 6;382(10):903-916. Epub 2019 Sep 6.

From the Illinois Department of Public Health, Springfield (J.E.L., I.G., L.N., M.T.P., L.S.-H.); the Epidemic Intelligence Service, Center for Surveillance, Epidemiology, and Laboratory Services (I.G., I.P., A.K., M.W.T., P.P.S.), National Center for Environmental Health (M.L.), the Division of State and Local Readiness, Center for Preparedness and Response (L.N.), the Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control (B.H., J.G.S., C.A.M.), and the Office on Smoking and Health, National Center for Chronic Disease Prevention and Health Promotion (B.A.K.), Centers for Disease Control and Prevention, and Emory University School of Medicine (M.L.) - all in Atlanta; and the Wisconsin Department of Health Services (I.P., M.E., J.M.), the Wisconsin Division of Public Health, Bureau of Communicable Disease (T.H.), and the Department of Radiology, University of Wisconsin School of Medicine and Public Health (J.K.) - all in Madison.

Background: E-cigarettes are battery-operated devices that heat a liquid and deliver an aerosolized product to the user. Pulmonary illnesses related to e-cigarette use have been reported, but no large series has been described. In July 2019, the Wisconsin Department of Health Services and the Illinois Department of Public Health received reports of lung injury associated with the use of e-cigarettes (also called vaping) and launched a coordinated public health investigation.

Methods: We defined case patients as persons who reported use of e-cigarette devices and related products in the 90 days before symptom onset and had pulmonary infiltrates on imaging and whose illnesses were not attributed to other causes. Medical record abstraction and case patient interviews were conducted with the use of standardized tools.

Results: There were 98 case patients, 79% of whom were male; the median age of the patients was 21 years. The majority of patients presented with respiratory symptoms (97%), gastrointestinal symptoms (77%), and constitutional symptoms (100%). All case patients had bilateral infiltrates on chest imaging. A total of 95% of the patients were hospitalized, 26% underwent intubation and mechanical ventilation, and two deaths were reported. A total of 89% of the patients reported having used tetrahydrocannabinol products in e-cigarette devices, although a wide variety of products and devices was reported. Syndromic surveillance data from Illinois showed that the mean monthly rate of visits related to severe respiratory illness in June through August of 2019 was twice the rate that was observed in the same months in 2018.

Conclusions: Case patients presented with similar clinical characteristics. Although the definitive substance or substances contributing to injury have not been determined, this initial cluster of illnesses represents an emerging clinical syndrome or syndromes. Additional work is needed to characterize the pathophysiology and to identify the definitive causes.
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http://dx.doi.org/10.1056/NEJMoa1911614DOI Listing
March 2020

U.S. National 90-Day Readmissions After Opioid Overdose Discharge.

Am J Prev Med 2019 06 17;56(6):875-881. Epub 2019 Apr 17.

National Center for Injury Prevention and Control, Centers for Disease Control and Prevention, Atlanta, Georgia.

Introduction: U.S. hospital discharges for opioid overdose increased substantially during the past two decades. This brief report describes 90-day readmissions among patients discharged from inpatient stays for opioid overdose.

Methods: In 2018, survey-weighted analysis of hospital stays in the 2016 Healthcare Cost and Utilization Project National Readmissions Database yielded the national estimated proportion of patients with opioid overdose stays that had all-cause readmissions within ≤90 days. A multivariable logistic regression model assessed index stay factors associated with readmission by type (opioid overdose or not). Number of readmissions per patient was assessed.

Results: More than 24% (n=14,351/58,850) of patients with non-fatal index stays for opioid overdose had at least one all-cause readmission ≤90 days of index stay discharge and 3% (n=1,658/58,850) of patients had at least one opioid overdose readmission. Less than 0.2% (n=104/58,850) of patients had more than one readmission for opioid overdose. Patient demographic characteristics (e.g., male, older age), comorbidities diagnosed during the index stay (e.g., drug use disorder, chronic pulmonary disease, psychoses), and other index stay factors (Medicare or Medicaid primary payer, discharge against medical advice) were significantly associated with both opioid overdose and non-opioid overdose readmissions. Nearly 30% of index stays for opioid overdose included heroin, which was significantly associated with opioid overdose readmissions.

Conclusions: A quarter of opioid overdose patients have ≤90 days all-cause readmissions, although opioid overdose readmission is uncommon. Effective strategies to reduce readmissions will address substance use disorder as well as comorbid physical and mental health conditions.
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http://dx.doi.org/10.1016/j.amepre.2018.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527476PMC
June 2019

Trends and Patterns of Geographic Variation in Opioid Prescribing Practices by State, United States, 2006-2017.

JAMA Netw Open 2019 03 1;2(3):e190665. Epub 2019 Mar 1.

Division of Public Health Information and Dissemination, Center for Surveillance, Epidemiology, and Laboratory Sciences, Centers for Disease Control and Prevention, Atlanta, Georgia.

Importance: Risk of opioid use disorder, overdose, and death from prescription opioids increases as dosage, duration, and use of extended-release and long-acting formulations increase. States are well suited to respond to the opioid crisis through legislation, regulations, enforcement, surveillance, and other interventions.

Objective: To estimate temporal trends and geographic variations in 6 key opioid prescribing measures in 50 US states and the District of Columbia.

Design, Setting, And Participants: Population-based cross-sectional analysis of opioid prescriptions filled nationwide at US retail pharmacies between January 1, 2006, and December 31, 2017. Data were obtained from the IQVIA Xponent database. All US residents who had an opioid prescription filled at a US retail pharmacy were included.

Main Outcomes And Measures: Primary outcomes were annual amount of opioids prescribed in morphine milligram equivalents (MME) per person; mean duration per prescription in days; and 4 separate prescribing rates-for prescriptions 3 or fewer days, those 30 days or longer, those with a high daily dosage (≥90 MME), and those with extended-release and long-acting formulations.

Results: Between 2006 and 2017, an estimated 233.7 million opioid prescriptions were filled in retail pharmacies in the United States each year. For all states combined, 4 measures decreased: (1) mean (SD) amount of opioids prescribed (mean [SD] decrease, 12.8% [12.6%]) from 628.4 (178.0) to 543.4 (158.6) MME per person, a statistically significant decrease in 23 states; (2) high daily dosage (mean [SD] decrease, 53.1% [13.6%]) from 12.3 (3.4) to 5.6 (1.7) per 100 persons, a statistically significant decrease in 49 states; (3) short-term (≤3 days) duration (mean [SD] decrease, 43.1% [9.4%]) from 18.0 (5.4) to 10.0 (2.5) per 100 persons, a statistically significant decrease in 48 states; and (4) extended-release and long-acting formulations (mean [SD] decrease, 14.7% [13.7%]) from 7.2 (1.9) to 6.0 (1.7) per 100 persons, a statistically significant decrease in 27 states. Two measures increased, each associated with the duration of prescription dispensed: (1) mean (SD) prescription duration (mean [SD] increase, 37.6% [6.9%]) from 13.0 (1.2) to 17.9 (1.4) days, a statistically significant increase in every state; and (2) prescriptions for a term of 30 days or longer (mean [SD] increase, 37.7% [28.9%]) from 18.3 (7.7) to 24.9 (10.7) per 100 persons, a statistically significant increase in 39 states. Two- to 3-fold geographic differences were observed across states, measured by comparing the ratio of each state's 90th to 10th percentile for each measure.

Conclusions And Relevance: In this study, across 12 years, the mean duration and prescribing rate for long-term prescriptions of opioids increased, whereas the amount of opioids prescribed per person and prescribing rate for high-dosage prescriptions, short-term prescriptions, and extended-release and long-acting formulations decreased. Some decreases were significant, but results were still high. Two- to 3-fold state variation in 5 measures occurred in most states. This information may help when state-specific intervention programs are being designed.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.0665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484643PMC
March 2019

Prevalence of Nonopioid and Opioid Prescriptions Among Commercially Insured Patients with Chronic Pain.

Pain Med 2019 10;20(10):1948-1954

Divisions of Analysis, Research, and Practice Integration.

Objective The increased use of opioids to treat chronic pain in the past 20 years has led to a drastic increase in opioid prescribing in the United States. The Centers for Disease Control and Prevention's (CDC's) Guideline for Prescribing Opioids for Chronic Pain recommends the use of nonopioid therapy as the preferred treatment for chronic pain. This study analyzes the prevalence of nonopioid prescribing among commercially insured patients with chronic pain. Design Data from the 2014 IBM® MarketScan® databases representing claims for commercially insured patients were used. International Classification of Diseases, Ninth Revision, codes were used to identify patients with chronic pain. Nonopioid prescriptions included nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics/antipyretics (e.g., acetaminophen), anticonvulsants, and antidepressant medications. The prevalence of nonopioid and opioid prescriptions was calculated by age, sex, insurance plan type, presence of a depressive or seizure disorder, and region. Results In 2014, among patients with chronic pain, 16% filled only an opioid, 17% filled only a nonopioid prescription, and 28% filled both a nonopioid and an opioid. NSAIDs and antidepressants were the most commonly prescribed nonopioids among patients with chronic pain. Having prescriptions for only nonopioids was more common among patients aged 50-64 years and among female patients. Conclusions This study provides a baseline snapshot of nonopioid prescriptions before the release of the CDC Guideline and can be used to examine the impact of the CDC Guideline and other evidence-based guidelines on nonopioid use among commercially insured patients with chronic pain.
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http://dx.doi.org/10.1093/pm/pny247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536362PMC
October 2019

US hospital discharges documenting patient opioid use disorder without opioid overdose or treatment services, 2011-2015.

J Subst Abuse Treat 2018 09 20;92:35-39. Epub 2018 Jun 20.

National Center for Injury Prevention and Control, Centers for Disease Control and Prevention (CDC), Atlanta, GA, USA.

Background: Understanding more about circumstances in which patients receive an opioid use disorder (OUD) diagnosis might illuminate opportunities for intervention and ultimately prevent opioid overdoses. This study aimed to describe patient and clinical characteristics of hospital discharges documenting OUD among patients not being treated for opioid overdose, detoxification, or rehabilitation.

Methods: We assessed patient, payer, and clinical characteristics of nationally-representative 2011-2015 National Inpatient Sample discharges documenting OUD, excluding opioid overdose, detoxification, and rehabilitation. Discharges were clinically classified by Diagnostic Related Group (DRG) for analysis.

Results: Annual discharges grew 38%, from 347,137 (2011) to 478,260 (2015), totaling 2 million discharges during the study period. The annual discharge rate increased among all racial/ethnic groups, but was highest among the non-Hispanic black population until 2015, when non-Hispanic whites had a slightly higher rate (164 versus 162 per 100,000 population). Female patients and Medicaid and Medicare as primary payer accounted for an increasing annual proportion of discharges. Just 14 DRGs accounted for nearly 50% of discharges over the study period. The most prevalent primary treatment received during OUD inpatient stays was for psychoses (DRG 885; 16% of discharges) and drug and alcohol abuse or dependence symptoms (including withdrawal) or (non-opioid) poisoning (DRG 894, 897, 917, 918; 12% of discharges).

Conclusions: Now nearly half a million yearly US hospital discharges for a range of primary treatment include patients' diagnosis of OUD without opioid overdose, detoxification, or rehabilitation services. Inpatient stays present an important opportunity to link OUD patients to treatment to reduce opioid-related morbidity and mortality.
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http://dx.doi.org/10.1016/j.jsat.2018.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6084454PMC
September 2018

Fungal endophthalmitis associated with compounded products.

Emerg Infect Dis 2014 Feb;20(2):248-56

Fungal endophthalmitis is a rare but serious infection. In March 2012, several cases of probable and laboratory-confirmed fungal endophthalmitis occurring after invasive ocular procedures were reported nationwide. We identified 47 cases in 9 states: 21 patients had been exposed to the intraocular dye Brilliant Blue G (BBG) during retinal surgery, and the other 26 had received an intravitreal injection containing triamcinolone acetonide. Both drugs were produced by Franck's Compounding Lab (Ocala, FL, USA). Fusarium incarnatum-equiseti species complex mold was identified in specimens from BBG-exposed case-patients and an unopened BBG vial. Bipolaris hawaiiensis mold was identified in specimens from triamcinolone-exposed case-patients. Exposure to either product was the only factor associated with case status. Of 40 case-patients for whom data were available, 39 (98%) lost vision. These concurrent outbreaks, associated with 1 compounding pharmacy, resulted in a product recall. Ensuring safety and integrity of compounded medications is critical for preventing further outbreaks associated with compounded products.
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http://dx.doi.org/10.3201/eid2002.131257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3901475PMC
February 2014

Rocky mountain spotted fever hospitalizations among American Indians.

Am J Trop Med Hyg 2006 Sep;75(3):537-41

Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA.

To describe the epidemiology of Rocky Mountain spotted fever (RMSF) among American Indians/Alaska Natives (AI/ANs), we conducted a retrospective analysis of hospitalization records with an RMSF diagnosis using Indian Health Service (IHS) hospital discharge data for calendar years 1980-2003. A total of 261 RMSF hospitalizations were reported among AIs, for an average annual hospitalization rate of 1.21 per 100,000 persons; two deaths were reported (0.8%). Most hospitalizations (88.5%) occurred in the Southern Plains region, where the rate was 4.23 per 100,000 persons. Children 1-4 years of age had the highest age-specific hospitalization rate of 2.50 per 100,000 persons. The overall annual RMSF hospitalization rate declined during the study period. Understanding the epidemiology of RMSF among AI/ANs and educating IHS/tribal physicians on the diagnosis of tick-borne diseases remain important for the prompt treatment of RMSF and the reduction of the disease occurrence among AI/ANs, particularly in high-risk areas.
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September 2006

Comparison of two major emergency department-based free-text chief-complaint coding systems.

MMWR Suppl 2004 Sep;53:101-5

Rush University Medical Center, 1653 W. Congress Parkway, Chicago, IL, 60612, USA.

Introduction: Emergency departments (EDs) using free-text chief-complaint data for syndromic surveillance face a unique challenge because a complaint might be described and coded in multiple ways.

Objective: Two major ED-based free-text chief-complaint coding systems were compared for agreement between free-text interpretation and syndrome coding.

Methods: Chief-complaint data from 21,736 patients at an urban ED were processed through both the New York City Department of Health and Mental Hygiene (DOHMH) syndrome coding system as modified by the Chicago Department of Public Health and the Real-Time Outbreak Detection System Complaint Coder (CoCo, version 2.1, University of Pittsburgh). To account for differences in each system's specified syndromes, relevant syndromes from the DOHMH system were collapsed into the corresponding CoCo categories so that a descriptive comparison could be made. DOHMH classifications were combined to match existing CoCo categories as follows: 1) vomit+diarrhea = Gastrointestinal; 2) cold+respiratory+asthma = Respiratory; 3) fevflu = Constitutional; 4) rash = Rash; 5) sepsis+other = Other, 6) unknown = Unknown.

Results: Overall agreement between DOHMH and CoCo syndrome coding was optimal (0.614 kappa). However, agreement between individual syndromes varied substantially. Rash and Respiratory had the highest agreement (0.711 and 0.594 kappa, respectively). Other and Constitutional had an intermediate level of agreement (0.453 and 0.419 kappa, respectively), but less than optimal agreement was identified for Gastrointestinal and Unknown (0.270 and 0.002 kappa, respectively).

Conclusions: Although this analysis revealed optimal overall agreement between the two systems evaluated, substantial differences in classification schemes existed, highlighting the need for a consensus regarding chief-complaint classification.
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September 2004

Ubiquitin modification of serum and glucocorticoid-induced protein kinase-1 (SGK-1).

J Biol Chem 2002 Nov 5;277(45):43064-70. Epub 2002 Sep 5.

Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois 60637, USA.

The serum and glucocorticoid-induced protein kinase gene (sgk-1) encodes a multifunctional kinase that can be phosphorylated and activated through a phosphatidylinositol 3-kinase-dependent signaling pathway. In many cell types, endogenous SGK-1 steady-state protein levels are very low but can be acutely up-regulated after glucocorticoid receptor-mediated transcriptional activation; in breast epithelial and cancer cell lines, this up-regulation is associated with promotion of cell survival. We and others have noted that ectopically introduced full-length SGK-1 is poorly expressed, although SGK-1 lacking the first 60 amino acids (delta60SGK-1) is expressed at much higher-fold protein levels than wild-type SGK-1 in both human embryonic kidney 293T and MCF10A mammary epithelial cells. In this report, we demonstrate for the first time that the low steady-state expression level of SGK-1 is due to polyubiquitination and subsequent degradation by the 26S proteasome. Deletion of the amino-terminal 60 amino acids of SGK-1 results in a mutant SGK-1 protein that is neither efficiently polyubiquitinated nor degraded by the 26S proteasome, accounting for the higher steady-state levels of the truncated protein. We also demonstrate that a subset of SGK-1 localizes to the plasma membrane and that the polyubiquitin-modified SGK-1 localizes to a membrane-associated fraction of the cell. Taken together, these data suggest that a significant fraction of SGK-1 is membrane-associated and ubiquitinated. These findings are consistent with the recently described role of SGK-1 in phosphorylating the membrane-associated protein Nedd4-2 and the integral membrane Na+/H+ exchanger isoform 3 (NHE3) and suggest a novel mechanism of regulation of SGK-1.
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http://dx.doi.org/10.1074/jbc.M207604200DOI Listing
November 2002
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