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Aims: Higher body mass index (BMI) is associated with higher bone mass and bone serves as a buffer during the development of metabolic acidosis. The authors sought to examine the relationship between BMI and metabolic acidosis in patients with chronic kidney disease (CKD)., Materials and Methods: The study utilized a large US longitudinal data repository including over 103 million patients from healthcare provider organizations to evaluate the relationship between the exposure variable (BMI) and the prevalence and incidence of metabolic acidosis among patients with estimated glomerular filtration rate <60 ml/min/1.73 m 2 . Incident metabolic acidosis was identified at the first of two consecutive post-index serum bicarbonate values, 10-365 days apart, between 12 and <22 mEq/L in patients with normal index serum bicarbonate. Cox proportional hazard models were adjusted for multiple variables including demographics, comorbidities, income, education, and kidney function., Results: 103,766 patients qualified for this study; 6472 (6.2%) had metabolic acidosis at index. An inverse association between BMI category and metabolic acidosis was observed for both baseline (prevalence) and new-onset (incidence) metabolic acidosis. Compared to BMI category of 18.5 to <25 kg/m 2 , each category of incrementally higher BMI was associated with a decreasing risk of incident metabolic acidosis; the adjusted hazard ratios (95% confidence interval) were 0.866 (0.824-0.911), 0.770 (0.729-0.813), 0.664 (0.622-0.709), and 0.612 (0.571-0.655) for BMI 25 to <30, 30 to <35, 35 to <40, and 40+ kg/m 2 , respectively., Conclusions: Among patients with CKD, an incremental increase in BMI was inversely associated with both the prevalence and incidence of metabolic acidosis. These associations suggest that increased body weight may protect against the development of metabolic acidosis, a risk factor for progressive loss of kidney function., Competing Interests: Vandana Mathur, Nancy L. Reaven, Susan E. Funk, Thomas W. Ferguson, Navdeep Tangri were paid consultants to Tricida, Inc. in connection with the development of this manuscript. Vandana Mathur, Nancy L. Reaven, Navdeep Tangri report consultancy, personal fees, and equity ownership from Tricida, Inc., related to the submitted work. Susan E. Funk and Thomas W. Ferguson report consultancy and personal fees from Tricida, Inc. Vandana Mathur, Navdeep Tangri are members of advisory boards at Tricida. Vandana Mathur is listed on patents related to work for Tricida. Vandana Mathur reports additional consulting fees from Tricida, Equillium, Myovant, Rigel, Corvidia, Acuta, Frazier, Intarcia, PTC Bio, Escient, RallyBio, Unicycive, Lilac, Galderma, and Sanifit outside the submitted work., (© 2023 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.)

Background: Guidelines recommend treatment of metabolic acidosis (MA) in patients with chronic kidney disease (CKD), but the diagnosis and treatment rates in real-world settings are unknown. We investigated the frequency of MA treatment and diagnosis in patients with CKD., Methods: In this retrospective cohort study, we examined administrative health data from two US databases [Optum's de-identified Integrated Claims + Clinical Electronic Health Record Database (US EMR cohort; 1 January 2007 to 30 June 2019) and Symphony Health Solutions IDV® (US claims cohort; 1 May 2016 to 30 April 2019)] and population-level databases from Manitoba, Canada (1 April 2006 to 31 March 2018). Patients who met laboratory criteria indicative of CKD and chronic MA were included: two consecutive estimated glomerular filtration results <60 mL/min/1.73 m2 and two serum bicarbonate results 12 to <22 mEq/L over 28-365 days. Outcomes included treatment of MA (defined as a prescription for oral sodium bicarbonate) and a diagnosis of MA (defined using administrative records). Outcomes were assessed over a 3-year period (1 year pre-index, 2 years post-index)., Results: A total of 96 184 patients were included: US EMR, 6179; Manitoba, 3223; US Claims, 86 782. Sodium bicarbonate treatment was prescribed for 17.6%, 8.7% and 15.3% of patients, and a diagnosis was found for 44.7%, 20.9% and 20.9% of patients, for the US EMR, Manitoba and US Claims cohorts, respectively., Conclusions: This analysis of 96 184 patients with laboratory-confirmed MA from three independent cohorts of patients with CKD and MA highlights an important diagnosis and treatment gap for this disease-modifying complication., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Introduction: The Kidney Failure Risk Equations (KFRE) are accurate and validated to predict the risk of kidney failure in individuals with chronic kidney disease (CKD), but their potential to predict health care costs in the US health care system is unknown. We assessed the association of kidney failure risk from the 4-variable and 8-variable 2-year KFRE models with monthly health care costs in US patients with CKD stages G3 and G4., Methods: This was an ancillary study to a larger observational, retrospective cohort study examining the association between serum bicarbonate and adverse kidney outcomes. Monthly medical costs were calculated from individual health care insurance claims. Generalized linear regression models were used to examine the association of KFRE score with health care costs., Results: A total of 1721 patients qualified for the study (1475 and 246 with CKD stages G3 and G4, respectively). For 8-variable KFRE, each 1% (absolute) increase in risk was associated with 13.5% ( P  < 0.001) and 4.1% ( P  < 0.001) higher monthly costs for patients with CKD stage G3 and G4, respectively. For 4-variable KFRE, a 1% increase in risk was associated with 6.7% ( P  = 0.016) and 2.9% ( P = 0.014) increase in monthly costs for patients with CKD stage G3 and G4, respectively., Conclusion: Higher risks of kidney failure as predicted by the 4-variable or 8-variable KFRE were associated with higher 2-year medical costs for patients with CKD stages G3 and G4. The KFRE may be a useful tool to anticipate medical costs and target cost-reducing interventions for patients at risk of kidney failure., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)

Background: Epidemiological studies demonstrate an association between kidney stones and risk of chronic kidney disease (CKD) and CKD progression. Metabolic acidosis, as a consequence of CKD, results in a reduced urine pH which promotes the formation of some types of kidney stones and inhibits the formation of others. While metabolic acidosis is a risk factor for CKD progression, the association of serum bicarbonate with risk of incident kidney stones is not well understood., Methods: We used an Integrated Claims-Clinical dataset of US patients to generate a cohort of patients with non-dialysis-dependent CKD with two serum bicarbonate values of 12 to <22 mmol/L (metabolic acidosis) or 22 to <30 mmol/L (normal serum bicarbonate). Primary exposure variables were baseline serum bicarbonate and change in serum bicarbonate over time. Cox proportional hazards models evaluated time to first occurrence of kidney stones during a median 3.2-year follow-up., Results: A total of 142 884 patients qualified for the study cohort. Patients with metabolic acidosis experienced post-index date kidney stones at greater frequency than patients with normal serum bicarbonate at the index date (12.0% vs 9.5%, P  < .0001). Both lower baseline serum bicarbonate [hazard ratio (HR) 1.047; 95% confidence interval (CI) 1.036-1.057] and decreasing serum bicarbonate over time (HR 1.034; 95% CI 1.026-1.043) were associated with increased risk of kidney stone development., Conclusions: Metabolic acidosis was associated with a higher incidence of kidney stones and shorter time to incident stone formation in patients with CKD. Future studies may investigate the role of correcting metabolic acidosis to prevent stone formation., Competing Interests: N.T., V.M., N.L.R., S.E.F., D.E.W. and D.A.B. were paid consultants to Tricida, Inc. in connection with the development of this manuscript. N.T., V.M., N.L.R., D.E.W. and D.A.B. report consultancy, personal fees and equity ownership from Tricida, Inc., related to the submitted work. S.E.F. reports consultancy and personal fees from Tricida, Inc. N.T., V.M., D.E.W. and D.A.B. are members of advisory boards at Tricida. V.M. is listed on patents related to work for Tricida. V.M. reports additional consulting fees from Tricida, Equillium, Myovant, Rigel, Corvidia, Acuta, Frazier, Intarcia, PTC Bio, Escient, RallyBio, Unicycive, Galderma, Lilac Therapeutics and Sanifit outside the submitted work. D.A.B. also reports consulting fees from Amgen, Sanofi/Genzyme and Fresenius/Relypsa/Vifor, personal fees as a medical advisory board member from Sanifit, speaker fees from Sanofi/Genzyme, and stock ownership in Amgen and past stock ownership in Relypsa, all outside this work., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Rationale & Objective: Metabolic acidosis is a risk factor for progression of chronic kidney disease (CKD), but little is known about its effect on health care costs and resource utilization. We describe the associations between metabolic acidosis, adverse kidney outcomes, and health care costs in patients with CKD stages G3-G5 and not receiving dialysis., Study Design: Retrospective cohort study., Setting & Participants: An integrated claims-clinical data set of US patients with CKD stages G3-G5, with serum bicarbonate values of 12 to <22 mEq/L (metabolic acidosis group) or 22 to 29 mEq/L (normal serum bicarbonate level group)., Predictor: The primary exposure variable was the baseline serum bicarbonate level., Outcomes: The primary clinical outcome was the composite of all-cause mortality, maintenance dialysis, kidney transplant, or a decline in the estimated glomerular filtration rate of ≥40% (DD40). The primary cost outcome was all-cause predicted per-patient per-year cost, assessed over a 2-year outcome period., Analytical Approach: Logistic and generalized linear regression models, adjusted for key covariates such as age, sex, race, kidney function, comorbidities, and pharmacy insurance coverage, were used to assess serum bicarbonate levels as a predictor of DD40 and health care costs, respectively., Results: 51,558 patients qualified. The metabolic acidosis group experienced higher rates of DD40 (48.3% vs. 16.7%, P  < 0.001) and higher all-cause yearly costs ($65,172 vs. $24,681, P  < 0.001). Two-year adjusted odds ratio of DD40 per 1-mEq/L increase in serum bicarbonate levels was 0.873 (95% CI, 0.866-0.879); the parameter estimate (±SE) for costs was -0.070 ± 0.0075 ( P  < 0.001)., Limitations: Possible residual confounding., Conclusions: Patients with CKD and metabolic acidosis had higher costs and rates of adverse kidney outcomes compared with patients with normal serum bicarbonate levels. Each 1-mEq/L increase in serum bicarbonate levels was associated with a 13% decrease in 2-year DD40 events and a 7% decrease in per-patient per-year cost., (© 2023 The Authors.)

Polycythemia vera (PV) is a myeloproliferative neoplasm associated with increased risk of thrombotic events (TE) and death. Therapeutic interventions, phlebotomy and cytoreductive medications, are targeted to maintain hematocrit levels < 45% to prevent adverse outcomes. This retrospective observational study examined medical and pharmacy claims of 28,306 PV patients initiating treatment for PV in a data period inclusive of 2011 to 2019. Study inclusion required ≥ 2 PV diagnosis codes in the full data period, at least 1 year of PV treatment history, and ≥ 1 prescription claim and medical claim in both 2018 and 2019. Patients having ≥ 2 hematocrit (HCT) test results in linked outpatient laboratory data (2018-2019) were designated as the HCT subgroup (N = 4246). Patients were characterized as high- or low-risk at treatment initiation based on age and prior thrombotic history. The majority of patients in both risk groups (60% of high-risk and 83% of low-risk) initiated treatment with phlebotomy monotherapy, and during a median follow-up period of 808 days, the vast majority (81% low-risk, 74% high-risk) maintained their original therapy during the follow-up period. Hematocrit control was suboptimal in both risk groups; 54% of high-risk patients initiating with phlebotomy monotherapy sometimes/always had HCT levels > 50%; among low-risk patients, 64% sometimes/always had HCT levels above 50%. Overall, 16% of individuals experienced at least 1 TE subsequent to treatment initiation, 20% (n = 3920) among high-risk and 8% (n = 629) among low-risk patients. This real-world study suggests that currently available PV treatments may not be used to full advantage., (© 2023. The Author(s).)

Introduction: Low serum bicarbonate at a single point in time is associated with accelerated kidney decline in patients with chronic kidney disease (CKD). We modeled how changes in serum bicarbonate over time affect incidence of adverse kidney outcomes., Methods: We analyzed data from Optum's deidentified Integrated Claims-Clinical data set of US patients (2007-2019) with ≥1 year of prior medical record data, CKD stages G3 to G5, and metabolic acidosis (i.e., index serum bicarbonate 12 to <22 mmol/l). The primary predictor of interest was the change in serum bicarbonate, evaluated at each postindex outpatient serum bicarbonate test as a time-dependent continuous variable. The primary outcome was a composite of either a ≥40% decline in estimated glomerular filtration rate (eGFR) from index or evidence of dialysis or transplantation, evaluated using Cox proportional hazards models., Results: A total of 24,384 patients were included in the cohort with median follow-up of 3.7 years. A within-patient increase in serum bicarbonate over time was associated with a lower risk of the composite kidney outcome. The unadjusted hazard ratio (HR) per 1-mmol/l increase in serum bicarbonate was 0.911 (95% confidence interval [CI]: 0.905-0.917; P  < 0.001). After adjustment for baseline eGFR and serum bicarbonate, the time-adjusted effect of baseline eGFR and other covariates, the HR per 1-mmol/l increase in serum bicarbonate was largely unchanged (0.916 [95% CI: 0.910-0.922; P  < 0.001])., Conclusion: In a real-world population of US patients with CKD and metabolic acidosis, a within-patient increase in serum bicarbonate over time independent of changes in eGFR, was associated with a lower risk of CKD progression., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)

Rationale & Objective: Identification of treatable risk factors for kidney allograft failure is necessary to improve graft longevity. Metabolic acidosis with either low serum bicarbonate or normal serum bicarbonate (eubicarbonatemic metabolic acidosis) is implicated in native kidney disease progression but its effects in kidney transplant recipients are unclear., Study Design: Retrospective cohort study., Setting & Participants: An Integrated Claims-Clinical dataset of US patients with chronic kidney disease (estimated glomerular filtration rates <60 mL/min/1.73 m 2 ) and serum bicarbonate data were used to generate a cohort of kidney transplant recipients with data from ≥1 year before and after transplantation., Primary Predictor: The primary independent variable was a change in serum bicarbonate from baseline., Outcomes: The primary outcomes were graft failure and all-cause mortality. The secondary outcomes were major adverse cardiac events and all-cause hospitalization., Analytical Approach: We used adjusted time-dependent Cox proportional hazards models to assess the risk of graft failure, all-cause mortality, major adverse cardiac events, and time to first hospitalization., Results: In this US community-based cohort of 1,915 kidney transplant recipients with a median follow-up of ∼2.5 years, each 1-mEq/L increase in serum bicarbonate was associated with significantly lower hazard of graft loss, death, major adverse cardiac events, and hospitalization by 10%, 8%, 4%, and 8%, respectively., Limitations: Possible residual confounding., Conclusions: In a US community-based population of kidney transplant recipients, even small incremental increases in serum bicarbonate (1 mEq/L) were significantly associated with reduced hazard of graft loss, all-cause mortality, cardiovascular events, and hospitalization. Interventional trials evaluating the potential benefits of treating metabolic acidosis in kidney transplant recipients are warranted., (© 2022 The Authors.)

Introduction: Metabolic acidosis in patients with chronic kidney disease (CKD) results from a loss of kidney function. It has been associated with CKD progression, all-cause mortality, and other adverse outcomes. We aimed to determine whether metabolic acidosis is associated with a higher risk of acute kidney injury (AKI)., Methods: This was a retrospective cohort study. Using electronic health records and administrative data, we enrolled 2 North American cohorts of patients with CKD Stages G3-G5 as follows: (i) 136,067 patients in the US electronic medical record (EMR) based cohort; and (ii) 34,957 patients in the Manitoba claims-based cohort. The primary exposure was metabolic acidosis (serum bicarbonate between 12 mEq/l and <22 mEq/l). The primary outcome was the development of AKI (defined using ICD-9 and 10 codes at hospital admission or a laboratory-based definition based on Kidney Disease: Improving Global Outcomes guidelines). We applied Cox proportional hazards regression models adjusting for relevant demographic and clinical characteristics., Results: In both cohorts, metabolic acidosis was associated with AKI: hazard ratio (HR) 1.57 (95% confidence interval [CI] 1.52-1.61) in the US EMR cohort, and HR 1.65 (95% CI 1.58-1.73) in the Manitoba claims cohort. The association was consistent when serum bicarbonate was treated as a continuous variable, and in multiple subgroups, and sensitivity analyses including those adjusting for albuminuria., Conclusion: Metabolic acidosis is associated with a higher risk of AKI in patients with CKD. AKI should be considered as an outcome in studies of treatments for patients with metabolic acidosis., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Background: The risk of adverse geriatric outcomes such as falls and fractures is high among patients with chronic kidney disease (CKD). Metabolic acidosis is associated with protein catabolism and bone loss in experimental animal and human studies. We sought to quantify the independent association of metabolic acidosis with adverse muscle, bone and functional outcomes in a large US community-based cohort., Methods: The Optum's de-identified Integrated Claims-Clinical dataset of US patients (2007-2017) was used to generate a cohort of patients with nondialysis-dependent CKD who had estimated glomerular filtration rate >10 to <60 mL/min/1.73 m 2 and two serum bicarbonate values 12 to <22 mmol/L or 22-29 mmol/L. The primary outcomes were failure to thrive, protein-calorie malnutrition, and fall or fracture. Cox proportional hazards models were used for the primary outcomes for up to 10 years, while logistic regression models were used at 2 years., Results: A total of 51 558 patients qualified for the study, with a median [Interquartile Range (IQR)] follow-up time of 4.2 (2.5-5.8) years. Over a ≤10-year period, for each 1 mmol/L increase in serum bicarbonate, the hazard ratios (adjusted for age, sex, race, estimated glomerular filtration rate, serum albumin, hemoglobin, diabetes and cardiovascular comorbidities) for failure to thrive, protein-calorie malnutrition and fall or fracture were 0.91 [95% confidence interval (CI): 0.90-0.92], 0.91 (95% CI: 0.90-0.92) and 0.95 (95% CI: 0.95-0.96), all P < 0.001, respectively., Conclusions: The presence and severity of metabolic acidosis was a significant, independent risk factor for failure to thrive, protein-calorie malnutrition and fall or fracture in this large community cohort of patients with stage 3-5 CKD., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Introduction: Metabolic acidosis is associated with chronic kidney disease (CKD) progression and mortality, but the association of race/ethnicity with incident metabolic acidosis and/or its adverse outcomes in patients with CKD is unknown., Methods: We used deidentified medical records data (2007-2019) to generate a cohort of 136,067 patients with nondialysis-dependent CKD stages 3-5 and ≥2 years' postindex data or death within 2 years. We grouped participants into those with and without metabolic acidosis (serum bicarbonate 12 to <22 mEq/L vs. 22 to <30 mEq/L) as Asian, Black, Hispanic, non-Hispanic White individuals, or unknown. Cox proportional hazards models examined factors associated with (1) incident metabolic acidosis; and (2) time to the composite outcome of death, dialysis, transplant, or ≥40% decline from baseline eGFR (DD40) within each race/ethnic group., Results: Metabolic acidosis incidence was higher for Asian, Black, and Hispanic versus non-Hispanic White individuals (p values for adjusted hazard ratios [HR] all <0.001), but this higher hazard was mitigated in all groups with increasing community education. During the median follow-up of 4.2 years, 47,032 of 136,607 (34.6%) experienced a DD40 event. There was an independent association of metabolic acidosis with DD40 within each race/ethnic group. Adjusted HRs (95% confidence interval) for DD40 were 1.806 (1.312, 2.486), 1.420 (1.313, 1.536), 1.409 (1.211, 1.641), and 1.561 (1.498, 1.626) in Asian, Black, Hispanic, and non-Hispanic White groups, respectively (all p < 0.0001), for metabolic acidosis versus normal serum bicarbonate., Discussion/conclusion: The higher incidence of metabolic acidosis observed in Asian, Black, and Hispanic individuals was mitigated by residing in higher education zip codes. Once established, metabolic acidosis was independently associated with DD40 in patients with CKD in all racial/ethnic groups examined., (© 2022 S. Karger AG, Basel.)

Rationale & Objective: Metabolic acidosis related to chronic kidney disease (CKD) is associated with an accelerated decline in glomerular filtration rate (GFR) and the development of end-stage kidney disease. Whether metabolic acidosis is associated with cardiovascular (CV) events in patients with CKD is unclear., Study Design: Retrospective cohort study., Setting & Participants: The Optum De-identified Electronic Health Records Dataset, 2007-2017, was used to generate a cohort of patients with non-dialysis-dependent CKD who had at least 3 estimated GFR < 60 mL/min/1.73 m 2 . Patients with metabolic acidosis (serum bicarbonate 12 to <22 mEq/L) or normal serum bicarbonate (22‒29 mEq/L) at baseline were identified by 2 consecutive measurements 28‒365 days apart., Predictor: Serum bicarbonate as a continuous variable., Outcome: Primary outcome was a composite of major adverse cardiovascular events (MACE+). Secondary outcomes included individual components of the composite outcome., Analytical Approach: Cox proportional hazards models to evaluate the association between 1-mEq/L increments in serum bicarbonate and MACE+., Results: A total of 51,558 patients were evaluated, 34% had metabolic acidosis. The median follow-up period was 3.9-4.5 years, depending on the outcome assessed. The adjusted hazard ratio (HR) for MACE+ was 0.964 (95% CI, 0.961-0.968). For the individual components of incident heart failure (HF), stroke, myocardial infarction (MI), and CV death, HRs were 0.98 (95% CI, 0.97-0.98), 0.98 (95% CI, 0.97-0.99), 0.96 (95% CI, 0.96-0.97), and 0.94 (95% CI, 0.93-0.94), respectively, for every 1-mEq/L increase in serum bicarbonate., Limitations: Possible residual confounding., Conclusions: Metabolic acidosis in CKD is associated with an increased risk of MACE+ as well as the individual components of incident HF, stroke, MI, and CV death. Randomized controlled trials evaluating treatments for the correction of metabolic acidosis in CKD to prevent CV events are needed., (© 2021 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.)

Background: Management of chronic kidney disease (CKD) requires the management of risk factors, such as hypertension and albuminuria, that affect CKD progression. Identification of additional modifiable risk factors is necessary to develop new treatment strategies for CKD. We sought to quantify the association of metabolic acidosis with CKD progression and mortality in a large U.S. community-based cohort., Methods: In this longitudinal, retrospective cohort study we identified non-dialysis-dependent patients with stage 3‒5 CKD from Optum's de-identified integrated electronic health records. We selected cohorts of patients with confirmed metabolic acidosis or normal serum bicarbonate levels based on 2 consecutive serum bicarbonate values: 12 to < 22 mEq/L or 22-29 mEq/L, respectively, 28‒365 days apart. The primary composite outcome was ≥ 40 % decline in estimated glomerular filtration rate (eGFR), renal replacement therapy (chronic dialysis or kidney transplant), or all-cause mortality (DD40). Secondary outcomes included each component of the composite outcome. Cox proportional hazards models were used for the DD40 outcome and secondary outcomes, while logistic regression models were used for the DD40 outcome at 2 years., Results: A total of 51,558 patients qualified for the study. The unadjusted 2-year incidence of adverse renal and fatal outcomes was significantly worse among patients in the metabolic acidosis group vs. those who had normal serum bicarbonate levels: 48 % vs. 17 % for DD40, 10 % vs. 4 % for ≥ 40 % decline in eGFR, 20 % vs. 6 % for renal replacement therapy, and 31 % vs. 10 % for all-cause mortality (all P < 0.001). Over a ≤ 10-year period, for each 1-mEq/L increase in serum bicarbonate, the adjusted hazard ratio for DD40 was 0.926 (95 % confidence interval [CI], 0.922-0.930; P < 0.001); over a ≤ 2-year period, the adjusted odds ratio for DD40 was 0.873 (95 % CI, 0.866-0.879; P < 0.001)., Conclusions: In this large community cohort of patients with stage 3‒5 CKD, the presence of metabolic acidosis was a significant, independent risk factor for the composite adverse outcome of CKD progression, renal replacement therapy, and all-cause mortality (DD40).

Objective: The objective of the study was to assess the direct cost of medically treated seizure events in severe childhood-onset epilepsies. Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC) are representative conditions associated with frequent intractable seizures., Methods: Commercial and Medicaid insurance claims from 2010 to 2015 were queried to identify patients with possible LGS, possible DS, or TSC, having ≥2 years of continuous insurance from the date of first epilepsy/seizure diagnosis or antiepileptic drug (AED) fill (index date). Utilization and cost data in patients with and without seizure events requiring acute treatment were evaluated for two years postindex. Medically treated seizure events resulting in minor, moderate, severe, and no injury were included. Average costs were normalized to 2017 dollars at 3% per annum and reported for each cohort, by insurance type and degree of injury., Results: Among 9754 patients, 55.4-58.8% of LGS, 47.7-55.8% of DS, and 13.7-28.0% of TSC cohorts had ≥1 medically treated seizure event, depending on insurance type. Events during two-year postindex averaged 2.8-3.3 in LGS, 3.1-3.3 in DS, and 1.9-2.2 in TSC; cost per event averaged $8147-$14,759 in LGS, $4637-$8751 in DS, and $5335-$9672 in TSC. In patients with events, average all-cause costs per-patient-per-year (PPPY) were $71,512-$84,939 in LGS; $31,278-$43,758 in DS; and $42,997-$48,330 in TSC., Conclusions: Patients with intractable seizures having at least one medically treated seizure event incur substantial all-cause costs. Our results can be used to inform cost effectiveness and budget impact models to estimate the value of existing and future treatments for these and similar conditions., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Lennox-Gastaut syndrome (LGS) is a severe and treatment-resistant epilepsy syndrome characterized by multiple subtypes of intractable seizures, moderate to severe cognitive impairment, and slow spike-wave complexes on electroencephalographic (EEG) recordings. Lennox-Gastaut syndrome is also associated with increased risk for injury, reduced quality of life, long-term disability, and early mortality. By evaluating private and public US medical insurance claims, we quantified healthcare utilization and direct costs in patients with possible LGS., Methods: Commercial and Medicaid insurance claims (Truven Health Analytics) from October 2010 to September 2015 were queried to identify patients with intractable epilepsy, intellectual disability, ≥1 prescription for selected antiepileptic drugs (AEDs), and ≥2 years of continuous enrollment. To identify patients with LGS in the absence of a specific International Classification of Diseases ICD-9 diagnosis code, current or prior rufinamide use was selected as a disease indicator of LGS per previously published methodology. Characteristics significantly predictive of rufinamide use were identified with multivariate regression by comparing groups with and without LGS, then assessed in non-rufinamide users fulfilling all other inclusion criteria. Controls without epilepsy, seizures, or prescriptions for selected AEDs were matched to patients with possible LGS by age, gender, US region, and dates of insurance coverage. Average healthcare utilization and costs per patient per year (PPPY) were evaluated for a 2-year postindex period and compared between the cohort with LGS and controls by insurance type. Costs were normalized to 2017 dollars at 3% per annum., Results: In the study, 6019 patients with possible LGS (53% male, mean age of 13 years, in both insurance groups) were identified: 2270 with commercial insurance and 3749 with Medicaid. The cohort with LGS used >8 times more services and >7 times more drugs than controls (all p < 0.001) in both insurance groups. The biggest contributors to service use PPPY were outpatient physician visits and home health services in the commercial-insured cohort with LGS and other outpatient visits and home health services in the Medicaid-insured cohort with LGS. Average total costs PPPY (services + drugs) were significantly higher for the cohort with LGS vs. controls: $65,026 (SD $34,324) vs. $2442 (SD $10,670) for commercial-insured and $63,930 (SD $45,761) vs. $3849 (SD $13849) for Medicaid-insured patients. The biggest cost contributors PPPY were inpatient care in the commercial-insured cohort with LGS and home health services in the Medicaid-insured cohort with LGS., Conclusions: Patients with possible LGS have significantly higher healthcare utilization and costs than patients without epilepsy or seizures. Our results suggest that direct costs associated with LGS are substantial and highlight the need for new and effective treatments., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

X-linked severe combined immunodeficiency (X-SCID) has been successfully treated by hematopoietic stem cell (HSC) transduction with retroviral vectors expressing the interleukin-2 receptor subunit gamma gene (IL2RG), but several patients developed malignancies due to vector integration near cellular oncogenes. This adverse side effect could in principle be avoided by accurate IL2RG gene editing with a vector that does not contain a functional promoter or IL2RG gene. Here, we show that adeno-associated virus (AAV) gene editing vectors can insert a partial Il2rg cDNA at the endogenous Il2rg locus in X-SCID murine bone marrow cells and that these ex vivo-edited cells repopulate transplant recipients and produce CD4 + and CD8 + T cells. Circulating, edited lymphocytes increased over time and appeared in secondary transplant recipients, demonstrating successful editing in long-term repopulating cells. Random vector integration events were nearly undetectable, and malignant transformation of the transplanted cells was not observed. Similar editing frequencies were observed in human hematopoietic cells. Our results demonstrate that therapeutically relevant HSC gene editing can be achieved by AAV vectors in the absence of site-specific nucleases and suggest that this may be a safe and effective therapy for hematopoietic diseases where in vivo selection can increase edited cell numbers., (Copyright © 2018 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Healthcare utilization and the cost implications associated with undiagnosed and/or misdiagnosed narcolepsy have not been evaluated, and there is scant literature characterizing the newly diagnosed population with narcolepsy with respect to treatment patterns and resource utilization., Objective: To analyze the changes in medication use, healthcare utilization, and the associated costs after a new diagnosis of narcolepsy., Methods: In this retrospective cohort study, we used data from the Truven Health Analytics MarketScan Research Databases, between January 2006 and March 2013, to identify patients who had a probable new diagnosis of narcolepsy-defined as a de novo medical claim for a multiple sleep latency test-which was preceded by ≥6 months of continuous insurance and was followed by a de novo diagnosis of narcolepsy. The utilization and cost of medical services and the percentage of patients filling prescriptions for narcolepsy-related medications were evaluated in 3 consecutive 1-year periods from the date of a positive multiple sleep latency test result (ie, index date), and each year's findings were compared with the annualized results from the 6-month preindex period., Results: A total of 3757 patients who met the definition of a new diagnosis of narcolepsy were identified. The total medical service utilization decreased each year from a preindex average of 28.2 visits per patient per year (PPPY) to 26.9 visits ( P <.05), 23.1 visits ( P <.0001), and 22.5 visits ( P <.0001) PPPY in years 1, 2, and 3 postdiagnosis, respectively. In each outpatient service category, the medical services utilization decreased from preindex to year 3 postdiagnosis, including hospital outpatient and physician visits ( P <.0001), and other outpatient and emergency department visits ( P <.05). The percentage of patients receiving narcolepsy-related medications increased from 54.0% preindex to 77.4%, 70.0%, and 66.9% for years 1, 2, and 3 postindex (all P <.0001 vs preindex). The total medical service cost PPPY was $12,159 preindex and decreased to $10,708, $8543, and $9136 in years 1, 2, and 3 postindex (all P <.0001 vs preindex)., Conclusions: In this study, the confirmation of a diagnosis of narcolepsy was associated with decreasing utilization and associated costs of medical services in the first 3 years after diagnosis. The total costs encompassing medical services and pharmacy costs were relatively stable during this period.

Polymorphisms in the human leukocyte antigen (HLA) class I genes can cause the rejection of pluripotent stem cell (PSC)-derived products in allogeneic recipients. Disruption of the Beta-2 Microglobulin (B2M) gene eliminates surface expression of all class I molecules, but leaves the cells vulnerable to lysis by natural killer (NK) cells. Here we show that this 'missing-self' response can be prevented by forced expression of minimally polymorphic HLA-E molecules. We use adeno-associated virus (AAV)-mediated gene editing to knock in HLA-E genes at the B2M locus in human PSCs in a manner that confers inducible, regulated, surface expression of HLA-E single-chain dimers (fused to B2M) or trimers (fused to B2M and a peptide antigen), without surface expression of HLA-A, B or C. These HLA-engineered PSCs and their differentiated derivatives are not recognized as allogeneic by CD8 + T cells, do not bind anti-HLA antibodies and are resistant to NK-mediated lysis. Our approach provides a potential source of universal donor cells for applications where the differentiated derivatives lack HLA class II expression.

Objective: To evaluate the economic impact of chronic kidney disease (CKD) on US health plans., Study Design: A retrospective analysis identified patients with a renin-angiotensin-aldosterone system inhibitor (RAASi) prescription from an electronic medical record (EMR) database (Humedica); those with =90 days in =1 CKD stage were selected based on estimated glomerular filtration rate or diagnosis code, and a cohort on RAASi medications without CKD was selected. Costs for specific services obtained from OptumInsight were applied to services in EMR data of patients aged <65 years (commercial) and =65 years (Medicare). Dialysis costs were excluded., Results: The study included 106,050 patients with CKD and 56,761 no-CKD controls (90,302 commercial and 72,509 Medicare overall). Mean annualized all-cause costs increased exponentially with advancing stage, from $7537 (no CKD) to $76,969 (CKD stages 4-5) in the commercial group, and $8091 (no CKD) to $46,178 (CKD stages 4-5) in the Medicare group (P <.001; all comparisons with preceding disease stage). Mean costs for end-stage renal disease (ESRD) patients were $121,948 and $87,339 in the commercial and Medicare groups, respectively. Inpatient costs were the largest contributor to total costs, and their relative contribution increased with advancing CKD., Conclusions: Cost to US health plans increases exponentially with each CKD stage progression. ESRD costs are even higher. Because readmissions lead to higher costs, efforts to reduce readmissions would result in cost reductions. Furthermore, healthcare reengineering paradigms that manage increasing comorbidities with advancing CKD, including heart failure, diabetes, and hyperkalemia, should offer additional potential for cost reductions.

Objective/background: The objective of this study was to evaluate medical comorbidity patterns in patients with a narcolepsy diagnosis in the United States., Patients/methods: This was a retrospective medical claims data analysis. Truven Health Analytics MarketScan® Research Databases were accessed to identify individuals ≥18 years of age with ≥1 diagnosis code for narcolepsy (International Classification of Diseases (ICD)-9, 347.0, 347.00, 347.01, 347.1, 347.10, or 347.11) continuously insured between 2006 and 2010, and controls without narcolepsy matched 5:1 on age, gender, region, and payer. Narcolepsy and control subjects were compared for frequency of comorbid conditions, identified by the appearance of >1 diagnosis code(s) mapped to a Clinical Classification System (CCS) level 1 category any time during the study period, and on specific subcategories, including recognized narcolepsy comorbidities of obstructive sleep apnea (OSA) and depression., Results: The final study group included 9312 subjects with narcolepsy and 46,559 controls (each group: average age, 46.1 years; 59% female). As compared with controls, patients with narcolepsy showed a statistically significant excess prevalence in all the CCS multilevel categories, the only exceptions being conditions originating in the perinatal period and pregnancy/childbirth complications. The greatest excess prevalence in the narcolepsy cohort was seen for mental illness (31.1% excess prevalence; odds ratio (OR) 3.8, 95% confidence interval (CI) 3.6, 4.0), followed by diseases of the digestive system (21.4% excess prevalence; OR 2.7, 95% CI 2.5, 2.8) and nervous system/sense organs (excluding narcolepsy; 20.7% excess prevalence; OR 3.7, 95% CI 3.4, 3.9)., Conclusions: In this claims analysis, a narcolepsy diagnosis was associated with a wide range of comorbid medical illness claims, at significantly higher rates than matched controls., (Copyright © 2016. Published by Elsevier B.V.)

Objective: To evaluate psychiatric comorbidity patterns in patients with a narcolepsy diagnosis in the United States., Methods: Truven Health Analytics MarketScan Research Databases were accessed to identify individuals ≥ 18 years of age with ≥ 1 ICD-9 diagnosis code(s) for narcolepsy continuously insured between 2006 and 2010 and non-narcolepsy controls matched 5:1 (age, gender, region, payer). Extensive subanalyses were conducted to confirm the validity of narcolepsy definitions. Narcolepsy subjects and controls were compared for frequency of psychiatric comorbid conditions (based on ICD-9 codes/Clinical Classification Software [CCS] level 2 categories) and psychiatric medication use., Results: The final population included 9,312 narcolepsy subjects and 46,559 controls (each group, mean age = 46.1 years; 59% female). All categories of mental illness were significantly more prevalent in patients with narcolepsy versus controls, with the highest excess prevalence noted for CCS 5.8 Mood disorders (37.9% vs 13.8%; odds ratio [OR] = 4.0; 95% CI, 3.8-4.2), CCS 5.8.2 Depressive disorders (35.8% vs 13.0%; OR = 3.9; 95% CI, 3.7-4.1), and CCS 5.2 Anxiety disorders (25.1% vs 11.9%; OR = 2.5; 95% CI, 2.4-2.7). Excess prevalence of anxiety and mood disorders (narcolepsy vs controls) was higher in younger age groups versus older age groups. Psychiatric medication usage was higher in the narcolepsy group versus controls in the following categories: selective serotonin reuptake inhibitors (36% vs 17%), anxiolytic benzodiazepines (34% vs 19%), hypnotics (29% vs 13%), serotonin-norepinephrine reuptake inhibitors (21% vs 6%), and tricyclic antidepressants (13% vs 4%) (all P values < .0001)., Conclusions: Narcolepsy is associated with significant comorbid psychiatric illness burden and higher psychiatric medication usage compared with the non-narcolepsy population., (© Copyright 2016 Physicians Postgraduate Press, Inc.)

Objectives: This study examined renin-angiotensin-aldosterone system (RAAS) inhibitor dose levels in a US patient population and investigated the impact of hyperkalemia on RAAS inhibitor dose and the association between dose levels and clinical outcomes., Study Design: De-identified medical records from a large database of electronic health records (Humedica) for patients 5 years of age or older with at least 2 serum potassium readings were analyzed (N = 205,108 patients; 1.7 million records)., Methods: Inclusion criteria required 1 RAAS inhibitor prescription and 12 months' data prior to July 1, 2009 (index date). Patients were classified by comorbidities (chronic kidney disease, heart failure, or diabetes) and RAAS inhibitor dose level at index date, as determined by prescription information. Additional analyses examined RAAS inhibitor dose changes following hyperkalemia and the frequency of cardiorenal adverse outcome/mortality or mortality alone by post index dose level., Results: Dose level was similarly distributed irrespective of patient comorbidity status, with RAAS inhibitors prescribed at maximum dose in 19% to 26% of patients and submaximum dose in 58% to 65% of patients; RAAS inhibitors were discontinued in 14% to 16% of patients. RAAS inhibitor dose was down-titrated after 16% to 21% of hyperkalemia events and discontinued after 22% to 27% of hyperkalemia events. Cardiorenal adverse event/mortality and mortality occurred in 34.3% and 11.0% of patients who discontinued RAAS inhibitors, 24.9% and 8.2% of patients on submaximum doses, and 24.9% and 4.1% of patients on maximum doses, respectively., Conclusions: Relatively few patients were prescribed maximum doses of RAAS inhibitors, and dose and usage declined following hyperkalemia. Patients on submaximum doses or who discontinued RAAS inhibitors had worse outcomes than patients on maximum doses.

Objective: Our objective was to estimate 4-year healthcare costs associated with the metabolic profile of patients before and after 1 year of treatment with phentermine (15 mg) and topiramate extended-release (92 mg) [phentermine-topiramate ER]., Design and Methods: Using a medical records database, we created two patient cohorts reflecting metabolic profiles of subjects before and after phentermine-topiramate ER therapy during the 1-year CONQUER trial. We matched database patients with trial subjects by age, sex, body mass index (BMI), and hypertension, glycemic, and triglyceride status. We collected real-world data on emergency department and outpatient visits, hospitalizations, and drug prescriptions over 4 years, linking them to reimbursements to estimate US private insurance costs for post-trial (n = 2295) versus pre-trial intention-to-treat (ITT) patients (n = 2295). Secondary analysis assessed responders (completers losing ≥5 % body weight [n = 1285])., Results: Over 4 years, the mean cost per patient in the post- versus pre-trial ITT-group was $US32,432 versus $US34,725 (mean difference -2292; 95 % confidence interval [CI] -4776 to 209). In responders, corresponding costs were $US30,558 versus $US33,936 (mean difference -3378; 95 % CI -6496 to -464). Costs for post- versus pre-trial responders were lower for outpatient visits, emergency visits, and medications (all P < 0.05)., Conclusion: Excluding treatment cost and potential side effects, patients matched to profiles of phentermine-topiramate ER responders had lower costs than patients matched to pre-treatment profiles.

Objectives: The aim of this study was to characterize health-care utilization, costs, and productivity in a large population of patients diagnosed with narcolepsy in the United States., Methods: This retrospective, observational study using data from the Truven Health Analytics MarketScan Research Databases assessed 5 years of claims data (2006-2010) to compare health-care utilization patterns, productivity, and associated costs among narcolepsy patients (identified by International Classification of Diseases, Ninth Revision (ICD9) narcolepsy diagnosis codes) versus matched controls. A total of 9312 narcolepsy patients (>18 years of age, continuously insured between 2006 and 2010) and 46,559 matched controls were identified., Results: Compared with controls, narcolepsy subjects had approximately twofold higher annual rates of inpatient admissions (0.15 vs. 0.08), emergency department (ED) visits w/o admission (0.34 vs. 0.17), hospital outpatient (OP) visits (2.8 vs. 1.4), other OP services (7.0 vs. 3.2), and physician visits (11.1 vs. 5.6; all p<0.0001). The rate of total annual drug transactions was doubled in narcolepsy versus controls (26.4 vs. 13.3; p<0.0001), including a 337% and 72% higher usage rate of narcolepsy drugs and non-narcolepsy drugs, respectively (both p<0.0001). Mean yearly costs were significantly higher in narcolepsy compared with controls for medical services ($8346 vs. $4147; p<0.0001) and drugs ($3356 vs. $1114; p<0.0001)., Conclusions: Narcolepsy was found to be associated with substantial personal and economic burdens, as indicated by significantly higher rates of health-care utilization and medical costs in this large US group of narcolepsy patients., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: The use of flexible endoscopes is growing rapidly around the world. Dominant approaches to high-level disinfection among resource-constrained countries include fully manual cleaning and disinfection and the use of automated endoscope reprocessors (AERs). Suboptimal reprocessing at any step can potentially lead to contamination, with consequences to patients and healthcare systems., Aim: To compare the potential results of guideline-recommended AERs to manual disinfection along three dimensions - productivity, need for endoscope repair, and infection transmission risk in India, China, and Russia., Methods: Financial modelling using data from peer-reviewed published literature and country-specific market research., Findings: In countries where revenue can be gained through productivity improvements, conversion to automated reprocessing has a positive direct impact on financial performance, paying back the capital investment within 14 months in China and seven months in Russia. In India, AER-generated savings and revenue offset nearly all of the additional operating costs needed to support automated reprocessing., Conclusion: Among endoscopy facilities in India and China, current survey-reported practices in endoscope reprocessing using manual soaking may place patients at risk of exposure to pathogens leading to infections. Conversion from manual soak to use of AERs, as recommended by the World Gastroenterology Organization, may generate cost and revenue offsets that could produce direct financial gains for some endoscopy units in Russia and China., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Currently, >200 meshes are commercially available in the United States. To help guide appropriate mesh selection, the investigators examined the postsurgical experiences of all patients undergoing ventral hernia repair at their facility from 2008 to 2011 with ≥12 months of follow-up., Methods: A retrospective review of prospectively collected data was conducted. All returns (surgical readmission, office or emergency visit) for complications or recurrences were examined. The impact of demographics (age, gender, and body mass index [BMI]), risk factors (hernia grade, hernia size, concurrent and past bariatric surgery, concurrent and past organ transplantation, any concurrent surgery, and American Society of Anesthesiologists score), and prosthetic type (polypropylene, other synthetic, human acellular dermal matrix, non-cross-linked porcine-derived acellular dermal matrix, other biologic, or none) on the frequency of return was evaluated., Results: A total of 564 patients had 12 months of follow-up, and 417 patients had 18 months of follow-up. In a univariate regression analysis, study arm (biologic, synthetic, or primary repair), hernia grade, hernia size, past bariatric surgery, and American Society of Anesthesiologists score were significant predictors of recurrence (P < .05). Multivariate analysis, stepwise regression, and interaction tests identified three variables with significant predictive power: hernia grade, hernia size, and BMI. The adjusted odds ratios vs hernia grade 2 for surgical readmission were 2.6 (95% confidence interval [CI], 1.3 to 5.1) for grade 3 and 2.6 (95% CI, 1.1 to 6.4) for grade 4 at 12 months and 2.3 (95% CI, 1.1 to 4.6) for grade 3 and 4.2 (95% CI, 1.7 to 10.0) for grade 4 at 18 months. Large hernia size (adjusted odds ratio vs small size, 3.2; 95% CI, 1.6 to 6.2) and higher BMI (adjusted odds ratio for BMI ≥50 vs 30 to 34.99 kg/m(2), 5.7; 95% CI, 1.2 to 26.2) increased the likelihood of surgical readmission within 12 months., Conclusions: The present data support the hypothesis that careful matching of patient characteristics to choice of prosthetic will minimize complications, readmissions, and the number of postoperative office visits., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: Growing acceptance of nipple-sparing mastectomy and rising rates of prophylactic mastectomy due to genetic findings make immediate one-stage implant breast reconstruction an attractive option for many American women facing post-mastectomy breast reconstruction. We compared medical services utilization and cost of immediate one-stage reconstruction with that of the more common tissue-expander (TE) breast reconstruction., Design: Retrospective administrative claims database analysis., Methods: We obtained commercial insurance claims on patients in the U.S. who had undergone one-stage or TE post-mastectomy implant breast reconstructions in 2008, and we compared 18-month results in terms of the frequency and cost of return visits for additional procedures and/or for the treatment of complications. Return visits were categorized as planned, planned with revision, or unplanned., Results: Among 1,316 immediate implant breast reconstructions, 95 (7%) were one-stage procedures and 1,221 (93%) were TE reconstructions. The data showed a modest, nonsignificant trend toward fewer return visits after one-stage reconstruction versus TE reconstruction (191 vs. 242 visits per 100 patients, respectively; relative risk [RR]: 0.95). Patients with TE reconstructions returned more often for planned returns and planned returns with revisions. Patients with one-stage reconstructions returned more often for unplanned events. The total costs over 18 months were $34,839 and $39,062 for one-stage and TE reconstructions, respectively, for a difference of -$4,223 (P = 0.38). The initial reconstruction, including the mastectomy, accounted for 64% of the 18-month costs with one-stage reconstructions and for 54% of the 18-month costs for TE reconstructions., Conclusion: Costs and utilization trended lower over 18 months for one-stage versus TE reconstructions following post-mastectomy breast reconstructions but did not achieve statistical significance.

Background: Postmastectomy implant breast reconstruction is typically accomplished in a two-stage process involving a tissue expander that is later exchanged for a permanent implant. Adoption of an immediate one stage reconstruction (1-stage) approach, where feasible, has been slowed by surgeon perception that this method is less likely to achieve acceptable results., Methods: To compare outcomes of these approaches in actual practice, we obtained commercial insurance claims on 1,316 patients throughout the United States who had immediate 1-stage or tissue expander (TE) postmastectomy implant breast reconstructions in 2008, without flaps, and compared results of these two reconstructive approaches over 18 months in terms of patient complication rates and return visits for additional procedures and/or treatment of complications., Results: Immediate 1-stage reconstructions were identified in 95 patients (7.2 percent), mean age 49.3 years, while 1,221 (92.8 percent), mean age 49.1 years, had TE reconstructions. Data shows a modest, non-significant trend toward fewer return visits after 1-stage reconstructions vs. TE reconstructions (191 vs. 242/100 patients, respectively); RR 0.95, NS. Complications of the implant, graft or mesh were the most common complication, experienced by 28.4 percent of 1-stage and 27.4 percent of TE reconstruction patients (RR 1.03, NS). Complications involving skin or connective tissue were also common, occurring in 20.0 percent of 1-stage and 26.4 percent of TE reconstruction patients (RR 0.76, NS). The average time to expander exchange was 189 days in patients without radiation and 288 days among irradiated patients., Conclusions: The results show that surgeons in the United States achieved substantially similar results in immediate postmastectomy implant breast reconstructions with 1-stage and TE approaches in terms of patient complications and returns for reconstruction-related services over 18 months. As evolving mastectomy techniques make 1-stage implant reconstructions more attractive, we hope these findings will motivate researchers to compare the approaches in more strictly controlled clinical studies., (Copyright © 2012 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Objective: To perform risk analysis of tracheal injuries caused by endotracheal intubation (ETI) and to estimate the financial impact of these sequelae., Study Design: Cost analysis using a national database., Settings: The Agency for Healthcare Research and Quality (AHRQ) 2006 National Inpatient Sample., Subjects and Methods: We identified clinical manifestations and treatments of complications associated with endotracheal tubes and codified them into International Classification of Disease-ninth revision diagnosis and procedure codes, intentionally excluding alternative etiologies of tracheal injury. Using the AHRQ 2006 National Inpatient Sample, we then compared patients with tracheal injury coded during the medical or surgical stay for length of stay (LOS) and mean hospital cost with diagnosis-related group (DRG)-matched controls; we also examined readmissions treating tracheal injury., Results: Tracheal injury presents as tracheal stenosis, tracheomalacia, tracheoesophageal fistula, laryngotracheal ulceration, and vocal cord paralysis. A total of 3232 discharge records met criteria for tracheal injury from ETI within the index hospital stay. Average LOS for patients with tracheal injury (6.3 days; 95% confidence interval [CI] 6.0-6.3) exceeded LOS in the uncomplicated sample (5.2 days; CI 5.1-5.3) by 1.1 days. The average hospital cost was $1888 higher with tracheal injury ($10,375 [CI $9762-$10,988] vs $8487 [CI $8266-$8669]). LOS for procedures treating prior tracheal injury averaged 4.7 days and cost an average of $11,025 per discharge., Conclusion: Tracheal injury from ETI is associated with a significant increase in healthcare costs that accrue both during the index admission and during subsequent hospitalizations required to treat the injury., (2010 American Academy of Otolaryngology-Head and Neck Surgery Foundation. Published by Mosby, Inc. All rights reserved.)

Fever has been shown to be related to extended hospital stays in neurologically injured patients. We performed meta-analyses of the impact of fever on length of stay (LOS) in the Intensive Care Unit (ICU) and for total hospital length of stay, including all recent scholarship published since 1/1/1995 pertaining to thermoregulation of neurogenic fever and length of hospital stay. We also developed estimates of the financial impact on hospital costs. Fever was shown to have a large, statistically significant impact on both ICU and hospital LOS. For ICU LOS, combined effect size g = .88, Z = 4.24, P < .0001. For hospital LOS, g = .79, Z = 2.2, P = .0278. Mean additional ICU days = 5.7 days; mean additional hospital days = 8.5 days. We estimate that fever added an average of $17,414 in hospital cost to total hospital stays; mean $13,672 (95% Confidence Interval [CI]: $10,074, $17,270) in additional ICU costs and mean $3,742 (CI: -$1,203, $8,820) in additional routine costs.

The appropriate progression of diagnostic testing for acute angina has been the topic of several recommendations by the American College of Cardiology and American Heart Association (ACC/AHA). We measured how frequently electrocardiography (ECG) is provided as the initial cardiac diagnostic test, as recommended for patients with new angina. Using an insurance database representing 2% of the U.S. adult population, we identified patients undergoing a new cardiac diagnostic process for angina. Rates of initial ECG were stratified by age, gender, co-morbid disease, and care setting. Of 4.4 million patients, 18,139 met the entry criteria by presenting with anginal symptoms for testing. A substantial portion (35%, 95% confidence interval [CI] 34% to 35%) did not receive the initial ECG recommended by expert guidelines. Patients treated in emergency departments received an initial ECG more frequently (91%, CI 90% to 92%) than patients tested in outpatient settings (61%, CI 60% to 62%; risk ratio [RR] 0.67, CI for RR 0.65 to 0.68) or in inpatient hospital settings (34%, CI 32% to 37%; RR 0.38, CI for RR 0.36 to 0.40). Slightly lower rates of initial ECG were observed in men (RR 0.93 vs women, CI for RR 0.91 to 0.95) and patients over 64 years (RR 0.93 vs younger patients, CI for RR 0.91 to 0.95). Total diagnostic costs averaged $954 when testing began with the recommended ECG versus $1,233 when testing did not. In conclusion, ECG is not universally obtained as the initial test for patients presenting with anginal symptoms despite evidence-based recommendations for such use. Clinicians should be aware that suboptimal use of ECG in certain settings may hinder investigations of heart disease.

The commonly deleted region (CDR) for the 5q- syndrome has been identified as a 1.5-megabase interval on human chromosome 5q32. We studied, by real-time reverse-transcription (RT)-PCR, the expression of 33 genes within the CDR that are known to be expressed in CD34+ hematopoietic stem cells. Genes in the 5q- samples that showed the most pronounced decrease in expression compared to non-5q- samples were: solute carrier family 36, member 1 (SLC36A1; 89% downregulated), Ras-GTPase-activating protein SH3 domain-binding (G3BP; 79%), antioxidant protein 1 (ATOX1; 76%), colony-stimulating factor-1 receptor precursor (CSF1R; 76%), ribosomal protein S14 (RPS14; 74%), platelet-derived growth factor receptor-beta (PDGFRB; 73%), Nef-associated factor 1 (TNIP1; 72%), secreted protein, acidic and rich in cysteine (SPARC; 71%), annexin VI (ANAX6; 69%), NSDT (66%) and TIGD (60%). We further studied the hematopoietic system in SPARC-null mice. These mice showed significantly lower platelet counts compared to wild-type animals (P=0.008). Although hemoglobin, hematocrit and mean corpuscular volume (MCV) were lower in mice lacking SPARC, differences were not statistically significant. SPARC-null mice showed a significantly impaired ability to form erythroid burst-forming units (BFU-E). However, no significant differences were found in the formation of erythroid colony-forming units (CFU-E), granulocyte/monocyte colony-forming units (CFU-GM) or megakaryocyte colony-forming units (CFU-Mk) in these animals. We conclude that many of the genes within the CDR associated with the 5q- syndrome exhibit significantly decreased expression and that SPARC, as a potential tumor suppressor gene, may play a role in the pathogenesis of this disease.

Eristostatin, an RGD-containing disintegrin isolated from the venom of Eristicophis macmahoni, inhibits lung or liver colonization of melanoma cells in a mouse model. In this study, transwell migration and in vitro wound closure assays were used to determine the effect of eristostatin on the migration of melanoma cells. Eristostatin significantly impaired the migration of five human melanoma cell lines. Furthermore, it specifically inhibited cell migration on fibronectin in a concentration-dependent manner, but not that on collagen IV or laminin. In contrast, eristostatin was found to have no effect on cell proliferation or angiogenesis. These results indicate that the interaction between eristostatin and melanoma cells may involve fibronectin-binding integrins that mediate cell migration. Mutations to alanine of seven residues within the RGD loop of eristostatin and four residues outside the RGD loop of eristostatin resulted in significantly less potency in both platelet aggregation and wound closure assays. For six of the mutations, however, decreased activity was found only in the latter assay. We conclude that a different mechanism and/or integrin is involved in these two cell activities.

Matricellular proteins such as SPARC, thrombospondin 1 and 2, and tenascin C and X subserve important functions in extracellular matrix synthesis and cellular adhesion to extracellular matrix. By virtue of its reported interaction with collagen I and deadhesive activity on cells, we hypothesized that hevin, a member of the SPARC gene family, regulates dermal extracellular matrix and collagen fibril formation. We present evidence for an altered collagen matrix and levels of the proteoglycan decorin in the normal dermis and dermal wound bed of hevin-null mice. The dermal elastic modulus was also enhanced in hevin-null animals. The levels of decorin protein secreted by hevin-null dermal fibroblasts were increased by exogenous hevin in vitro, data indicating that hevin might regulate both decorin and collagen fibrillogenesis. We also report a decorin-independent function for hevin in collagen fibrillogenesis. In vitro fibrillogenesis assays indicated that hevin enhanced fibril formation kinetics. Furthermore, cell adhesion assays indicated that cells adhered differently to collagen fibrils formed in the presence of hevin. Our observations support the capacity of hevin to modulate the structure of dermal extracellular matrix, specifically by its regulation of decorin levels and collagen fibril assembly.

Secreted protein acidic and rich in cysteine (SPARC) and thrombospondin-2 (TSP-2) are structurally unrelated matricellular proteins that have important roles in cell-extracellular matrix (ECM) interactions and tissue repair. SPARC-null mice exhibit accelerated wound closure, and TSP-2-null mice show an overall enhancement in wound healing. To assess potential compensation of one protein for the other, we examined cutaneous wound healing and fibrovascular invasion of subcutaneous sponges in SPARC-TSP-2 (ST) double-null and wild-type (WT) mice. Epidermal closure of cutaneous wounds was found to occur significantly faster in ST-double-null mice, compared with WT animals: histological analysis of dermal wound repair revealed significantly more mature phases of healing at 1, 4, 7, 10, and 14 days after wounding, and electron microscopy showed disrupted ECM at 14 days in these mice. ST-double-null dermal fibroblasts displayed accelerated migration, relative to WT fibroblasts, in a wounding assay in vitro, as well as enhanced contraction of native collagen gels. Zymography indicated that fibroblasts from ST-double-null mice also produced higher levels of matrix metalloproteinase (MMP)-2. These data are consistent with the increased fibrovascular invasion of subcutaneous sponge implants seen in the double-null mice. The generally accelerated wound healing of ST-double-null mice reflects that described for the single-null animals. Importantly, the absence of both proteins results in elevated MMP-2 levels. SPARC and TSP-2 therefore perform similar functions in the regulation of cutaneous wound healing, but fine-tuning with respect to ECM production and remodeling could account for the enhanced response seen in ST-double-null mice.

Implanted foreign materials, used to restore or assist tissue function, elicit an initial acute inflammatory response followed by chronic fibrosis that leads to the entrapment of the biomaterial in a thick, poorly vascularized collagenous capsule. Matricellular proteins, secreted macromolecules that interact with extracellular matrix proteins but do not in themselves serve structural roles, have been identified as important mediators of the foreign body response that includes inflammation, angiogenesis, and collagen synthesis and assembly. In this report we delineate functions of hevin and SPARC, two homologs of the SPARC family of matricellular proteins, in the foreign body response. Despite their sequence similarity, hevin and SPARC mediate different aspects of this fibrotic response. Using mice with targeted gene deletions, we show that hevin is central to the progression of biomaterial-induced inflammation whereas SPARC regulates the formation of the collagenous capsule. Although vascular density within the capsule is unaltered in the absence of either protein, SPARC-hevin double-null capsules show substantially increased numbers of vessels, indicating compensatory functions for these two proteins in the inhibition of angiogenesis. These results provide important information for further development of implant technology.

SPARC, a matricellular protein that affects cellular adhesion and proliferation, is produced in remodeling tissue and in pathologies involving fibrosis and angiogenesis. In this study we have asked whether peptides generated from cleavage of SPARC in the extracellular milieu can regulate angiogenesis. Matrix metalloproteinase (MMP)-3, but not MMP-1 or 9, showed significant activity toward SPARC. Limited digestion of recombinant human (rhu)SPARC with purified catalytic domain of rhuMMP-3 produced three major fragments, which were sequenced after purification by HPLC. Three synthetic peptides (Z-1, Z-2, and Z-3) representing motifs from each fragment were tested in distinct assays of angiogenesis. Peptide Z-1 (3.9 kDa, containing a Cu2+-binding sequence KHGK) exhibited a biphasic effect on [3H]thymidine incorporation by cultured endothelial cells and stimulated vascular growth in the chick chorioallantoic membrane (CAM). In contrast, peptides Z-2 (6.1 kDa, containing Ca2+-binding EF hand-1) and Z-3 (2.2 kDa, containing neither Cu2+-binding motifs nor EF hands), inhibited cell proliferation in a concentration-dependent manner and exhibited no effects on vessel growth in the CAM. Reciprocal results were obtained in a migration assay in native collagen gels: peptide Z-1 was ineffective over a range of concentrations, whereas Z-2 or Z-3 stimulated cell migration. Therefore, proteolysis of SPARC by MMP-3 produced peptides that regulate endothelial cell proliferation and/or migration in vitro in a mutually exclusive manner. One of these peptides containing KHGK also demonstrated a concentration-dependent effect on angiogenesis.

Interactions among growth factors, cells, and extracellular matrix regulate proliferation during normal development and in pathologies such as atherosclerosis. SPARC (secreted protein, acidic, and rich in cysteine) is a matrix-associated glycoprotein that modulates the adhesion and proliferation of vascular cells. In this study, we demonstrate that SPARC inhibits human arterial smooth muscle cell proliferation stimulated by platelet-derived growth factor or by adhesion to monomeric type I collagen. Binding studies with SPARC and SPARC peptides indicate specific and saturable interaction with smooth muscle cells that involves the C-terminal Ca2+-binding region of the protein. We also report that SPARC arrests monomeric collagen-supported smooth muscle cell proliferation in the late G1-phase of the cell cycle in the absence of an effect on cell shape or on levels of cyclin-dependent kinase inhibitors. Cyclin-dependent kinase-2 activity, p107 and cyclin A levels, and retinoblastoma protein phosphorylation are markedly reduced in response to the addition of exogenous SPARC and/or peptides derived from specific domains of SPARC. Thus, SPARC, previously characterized as an inhibitor of platelet-derived growth factor binding to its receptor, also antagonizes smooth muscle cell proliferation mediated by monomeric collagen at the level of cyclin-dependent kinase-2 activity., (Copyright 2002 Wiley-Liss, Inc.)

Studies of therapeutic angiogenesis have generally focused on single growth factor strategies. However, multiple factors participate in angiogenesis. We evaluated the angiogenic potential of a growth factor mixture (GFm) derived from bovine bone. The major components of GFm (SDS-polyacrylamide gel electrophoresis, mass spectrometry, and Western blot) include transforming growth factor-beta1-3, bone morphogenic protein-2-7, and fibroblast growth factor-1. GFm was first shown to induce an angiogenic response in chorioallantoic membranes. Next, myocardial ischemia was induced in 21 dogs (ameroid) that were randomized 3 weeks later to received GFm 1 mg/ml (I), GFm 10 mg/ml (II), or placebo (P) (with investigators blinded to conditions) injected in and adjacent to ischemic myocardium. Dogs were assessed 6 weeks later using quantitative and semiquantitative measures. There were GFm concentration-dependent improvements in distal left anterior descending artery (LAD) opacification by angiography (P: 0.4 +/- 0.2, I: 1.1 +/- 0.14, II: 1.6 +/- 0.3, angiographic score p = 0.014). Histologically, there was also concentration-dependent vascular growth response of relatively large vessels (P: 0.21 +/- 0.15, I: 1.00 +/- 0.22, II: 1.71 +/- 0.18, vascular growth score p = 0.001). Resting myocardial blood flow (colored microspheres) was not significantly impaired in any group. However, maximum blood flow (adenosine) was reduced in ischemic territories and did not improve in GFm-treated hearts. GFm, a multiple growth factor mixture, is a potent angiogenic agent that stimulates large vessel growth. Although blood flow did not improve during maximal vasodilatory stress, large intramyocardial collateral vessels developed and angiographic visualization of the occluded distal LAD improved significantly. The use of multiple growth factors may be an effective strategy for therapeutic angiogenesis provided a more effective delivery strategy is devised that can achieve improved maximum blood flow potential.

SPARC (secreted protein, acidic and rich in cysteine), also called osteonectin or BM-40, is a collagen-binding glycoprotein secreted by a variety of cells and is associated with functional responses involving tissue remodeling, cell movement and proliferation. Because SPARC and monocytes/macrophages are prevalent at sites of inflammation and remodeling in which there is connective tissue turnover, we examined the effect of SPARC on monocyte matrix metalloproteinase (MMP) production. Treatment of human peripheral blood monocytes with SPARC stimulated the production of gelatinase B (MMP-9) and interstitial collagenase (MMP-1). Experiments with synthetic peptides indicated that peptide 3.2, belonging to the alpha helical domain III of SPARC, is the major peptide mediating the MMP production by monocytes. SPARC and peptide 3.2 were also shown to induce prostaglandin synthase (PGHS)-2 as determined by Western and Northern blot analyses. The increase in PGHS-2 stimulated by SPARC or peptide 3.2 correlated with substantially elevated levels of prostaglandin E2 (PGE2) and other arachidonic acid metabolites as measured by radioimmunoassay and high performance liquid chromatography (HPLC), respectively. Moreover, the synthesis of MMP was dependent on the generation of PGE2 by PGHS-2, since indomethacin inhibited the production of these enzymes and their synthesis was restored by addition of exogenous PGE2 or dibutyryl cAMP (Bt2cAMP). These results demonstrate that SPARC might play a significant role in the modulation of connective tissue turnover due to its stimulation of PGHS-2 and the subsequent release of PGE2, a pathway that leads to the production of MMP by monocytes.

Human SPARC has been cloned by the polymerase chain reaction from an endothelial cell cDNA library and expressed in Escherichia coli as a biologically active protein. Transcriptional expression of the insert cDNA was dependent on the activation of the T7 RNA polymerase promoter by isopropylgalactopyranoside. Two forms of recombinant SPARC (rSPARC) protein were recovered from BL21 (DE3) E. coli after transformation with the plasmid pSPARCwt: a soluble, monomeric form of rSPARC and an insoluble, aggregated form sequestered in inclusion bodies. The isolation of the soluble form of rSPARC was accomplished by anion-exchange, nickel-chelate affinity, and gel filtration chromatographies. The isolated protein was an intact, full-length polypeptide of 293 amino acids by the following criteria: N-terminal amino acid sequence, reaction with anti-SPARC immunoglobulins specific for N-terminal and C-terminal sequences, and interaction of the C-terminal histidine tag of rSPARC with a nickel-chelate affinity resin. Circular dichroism and intrinsic fluorescence spectroscopy indicated that the conformation of rSPARC was dependent on interaction with Ca2- ions. The recombinant protein inhibited cell spreading and bound specifically to bovine aortic endothelial cells. Levels of bacterial endotoxin (< 18 pg/microgram rSPARC) present in rSPARC preparations were below the threshold that affects the behavior of these endothelial cells. These conformational and biological properties of rSPARC are consistent with previously described characteristics of the native protein. The purification of biologically active rSPARC, as well as mutated forms of the protein, will provide sufficient quantities of protein for the determination of structure/function relationships.

SPARC (Secreted Protein, Acidic and Rich in Cysteine)/osteonectin is a secreted glycoprotein that exhibits restricted expression in murine adult and embryonic tissues and is associated with cell migration, matrix mineralization, steroid hormone production, cell cycle regulation, and angiogenesis. We produced a monoclonal antibody, MAb SSP2, against a Ca(2+)-binding region of SPARC and evaluated the immunoreactivity of normal and malignant tissue from 118 human samples. In normal tissue we found restricted and moderate reactivity with SSP2 in steroidogenic cells, chondrocytes, placental trophoblasts, vascular smooth muscle cells, and endothelial cells. Strong reactivity was found in fibrocytes and endothelial cells involved in tissue repair and in invasive malignant tumors, including those of the gastrointestinal tract, breast, lung, kidney, adrenal cortex, ovary, and brain. We conclude that SSP2 is a useful reagent for detection of SPARC in human tissue. Given the broad reactivity of malignant tissues, we propose that SPARC expression might contribute to some aspects of tumor progression.

SPARC (secreted protein acidic and rich in cysteine) can be selectively expressed by the endothelium in response to certain types of injury and induces rounding in adherent endothelial cells in vitro. To determine whether SPARC might influence endothelial permeability, we studied the effect of exogenous SPARC on the movement of 14C-labeled bovine serum albumin across postconfluent bovine pulmonary artery endothelial cells. SPARC increased (P < 0.02) transendothelial albumin flux in a dose-dependent manner at concentrations > or = 0.5 microgram/ml. At a fixed dose (15 micrograms/ml), exposure times > or = 1 h augmented (P < 0.005) albumin flux by 1.3- to 3.6-fold; this increase was blocked by anti-SPARC antibodies but not by inhibition of protein synthesis. Barrier dysfunction was not associated with loss of cell viability. Monolayers exposed to SPARC exhibited a rounded morphology and intercellular gaps. Prior stabilization of F-actin with phallicidin protected against the changes in barrier function (P = 0.0001) that were otherwise induced by SPARC. Bovine aortic and retinal microvascular endothelia also responded to SPARC. We propose that SPARC regulates endothelial barrier function through F-actin-dependent changes in cell shape, coincident with the appearance of intercellular gaps, that provide a paracellular pathway for extravasation of macromolecules.