Emergency Department Visits due to Scabies in the United States: A Retrospective Analysis of a Nationally Representative Emergency Department Sample.

BACKGROUND: Limited information exists regarding the burden of emergency department (ED) visits due to scabies in the United States. The goal of this study was to provide population-level estimates regarding scabies visits to American EDs. METHODS: This study was a retrospective analysis of the nationally representative National Emergency Department Sample from 2013 to 2015. Outcomes included adjusted odds for scabies ED visits, adjusted odds for inpatient admission due to scabies in the ED scabies population, predictors for cost of care, and seasonal/regional variation in cost and prevalence of scabies ED visits. RESULTS: Our patient population included 416 017 218 ED visits from 2013 to 2015, of which 356 267 were due to scabies (prevalence = 85.7 per 100 000 ED visits). The average annual expenditure for scabies ED visits was $67 125 780.36. The average cost of care for a scabies ED visit was $750.91 (±17.41). Patients visiting the ED for scabies were most likely to be male children from lower income quartiles and were most likely to present to the ED on weekdays in the fall, controlling for all other factors. Scabies ED patients that were male, older, insured by Medicare, from the highest income quartile, and from the Midwest/West were most likely to be admitted as inpatients. Older, higher income, Medicare patients in large Northeastern metropolitan cities had the greatest cost of care. CONCLUSION: This study provides comprehensive nationally representative estimates of the burden of scabies ED visits on the American healthcare system. These findings are important for developing targeted interventions to decrease the incidence and burden of scabies in American EDs.

Characteristics of Patients Hospitalized for Cutaneous Squamous Cell Carcinoma.

BACKGROUND: Knowledge regarding the inpatient burden of cutaneous squamous cell carcinoma (cSCC) is limited. OBJECTIVE: To provide nationally representative estimates for hospitalization characteristics due to cSCC and determine predictors for increased length of stay (LOS) and cost of care. METHODS/MATERIALS: A retrospective cohort study of the 2009 to 2015 National Inpatient Sample. Weighted multivariate logistic/linear regression models were created to evaluate sociodemographic factors associated with cSCC hospitalization and to assess characteristics associated with cost of care and LOS. RESULTS: This study included 15,784 cSCC and 255,244,626 non-SCC inpatients (prevalence = 6.2/100,000 inpatients). On average, cSCC hospitalizations lasted 5.8 days and cost $66,841.00. Cutaneous squamous cell carcinoma most often occurred on the scalp (30.57%), face (21.08%), and lower limb (11.93%). Controlling for all other factors, cSCC inpatients presented to larger/urban/teaching hospitals and were most often older non-Hispanic white women. More chronic conditions/diagnoses/procedures and nonwhite race were associated with greater cost of care and LOS. Cost of care and LOS significantly differed between cSCCs of different anatomical sites. The most common procedures performed were skin grafts (27.96%), excisions (25.83%), and lymph node biopsies (11.39%). CONCLUSION: This study highlights the substantial burden of inpatient cSCC in the United States. Further research is necessary to prevent cSCC hospitalizations and improve inpatient dermatologic care for cSCC.

Are There Nationwide Socioeconomic and Demographic Disparities in the Use of Outpatient Orthopaedic Services?

BACKGROUND: Although disparities in the use of healthcare services in the United States have been well-documented, information examining sociodemographic disparities in the use of healthcare services (for example, office-based and emergency department [ED] care) for nonemergent musculoskeletal conditions is limited. QUESTIONS/PURPOSES: This study was designed to answer two important questions: (1) Are there identifiable nationwide sociodemographic disparities in the use of either office-based orthopaedic care or ED care for common, nonemergent musculoskeletal conditions? (2) Is there a meaningful difference in expenditures associated with these same conditions when care is provided in the office rather than the ED? METHODS: This study analyzed data from the 2007 to 2015 Medical Expenditure Panel Survey (MEPS). The MEPS is a nationally representative database administered by the Agency for Healthcare Research and Quality that tracks patient interactions with the healthcare system and expenditures associated with each visit, making it an ideal data source for our study. Differences in the use of office-based and ED care were assessed across different socioeconomic and demographic groups. Healthcare expenditures associated with office-based and ED care were tabulated for each of the musculoskeletal conditions included in this study. The MEPS database defines expenditures as direct payments, including out-of-pocket payments and payments from insurances. In all, 63,514 participants were included in our study. Fifty-one percent (32,177 of 63,514) of patients were aged 35 to 64 years and 29% were older than 65 years (18,445 of 63,514). Women comprised 58% (37,031 of 63,514) of our population, while men comprised 42% (26,483 of 63,514). Our study was limited to the following eight categories of common, nonemergent musculoskeletal conditions: osteoarthritis (40%, 25,200 of 63,514), joint derangement (0.5%, 285 of 63,514), other joint conditions (43%, 27,499 of 63,514), muscle or ligament conditions (6%, 3726 of 63,514), bone or cartilage conditions (8%, 5035 of 63,514), foot conditions (1%, 585 of 63,514), fractures (7%, 4189 of 63,514), and sprains or strains (18%, 11,387 of 63,514). Multivariable logistic regression was used to ascertain which demographic, socioeconomic, and health-related factors were independently associated with differences in the use of office-based orthopaedic services and ED care for musculoskeletal conditions. Furthermore, expenditures over the course of our study period for each of our musculoskeletal categories were calculated per visit in both the outpatient and the ED settings, and adjusted for inflation. RESULTS: After controlling for covariates like age, gender, region, insurance status, income, education level, and self-reported health status, we found substantially lower use of outpatient musculoskeletal care among patients who were Hispanic (odds ratio 0.79 [95% confidence interval 0.72 to 0.86]; p < 0.001), non-Hispanic black (OR 0.77 [95% CI 0.70 to 0.84]; p < 0.001), lesser-educated (OR 0.72 [95% CI 0.65 to 0.81]; p < 0.001), lower-income (OR 0.80 [95% CI 0.73 to 0.88]; p < 0.001), and nonprivately-insured (OR 0.85 [95% CI 0.79 to 0.91]; p < 0.001). Public insurance status (OR 1.30 [95% CI 1.17 to 1.44]; p < 0.001), lower income (OR 1.53 [95% CI 1.28 to 1.82]; p < 0.001), and lesser education status (OR 1.35 [95% CI 1.14 to 1.60]; p = 0.001) were also associated with greater use of musculoskeletal care in the ED. Healthcare expenditures associated with care for musculoskeletal conditions was substantially greater in the ED than in the office-based orthopaedic setting. CONCLUSIONS: There are substantial sociodemographic disparities in the use of office-based orthopaedic care and ED care for common, nonemergent musculoskeletal conditions. Because of the lower expenditures associated with office-based orthopaedic care, orthopaedic surgeons should make a concerted effort to improve access to outpatient care for these populations. This may be achieved through collaboration with policymakers, greater initiatives to provide care specific to minority populations, and targeted efforts to improve healthcare literacy. LEVEL OF EVIDENCE: Level III, therapeutic study.

Limitations of medical treatment among patients attended by the rapid response team.

BACKGROUND: Rapid response teams (RRTs) are called to deteriorating ward patients in order to improve their outcome. The involvement of the team also in end-of-life care issues needs to be addressed. Our objective was to evaluate the RRT with focus on limitations of medical treatment (LOMT). METHODS: Observational cohort study of RRT calls from 2005 to 2010 at a university hospital. RESULTS: There were 2189 calls in 1818 admissions. Six hundred forty-two patients (35.3%) were assigned LOMT, and in 296 cases (46.1%) it was documented on the same day as the first RRT call. In total, 152 calls were for patients where a decision was already in place. Among patients with multiple calls, 44.6% received limitations. Hospital mortality was 25.6% in total, 60.6% for patients with limitations and 6.6% for patients without. Mortality at 180 days was 43.2% for the whole cohort, and 83.6% and 21.2% with and without limitations, respectively. Cardiac arrest rate has remained at the level of 0.82/1000 admissions since the introduction of the RRT. CONCLUSION: Patients attended by the RRT have high short- and long-term mortality. Distinction of when deteriorations may be amenable to treatment or when focus should be laid on palliative care is not always made in the wards. Many decisions of limitations are taken in close conjunction to the call, although limitations do not preclude repeated visits from the team, indicating a need to support wards that care for patients at end of life.

Age-period-cohort modelling of type 1 diabetes incidence rates among children included in the EURODIAB 25-year follow-up study.

AIMS: Specific patterns in incidence may reveal environmental explanations for type 1 diabetes incidence. We aimed to study type 1 diabetes incidence in European childhood populations to assess whether an increase could be attributed to either period or cohort effects. METHODS: Nineteen EURODIAB centres provided single year incidence data for ages 0-14 in the 25-year period 1989-2013. Case counts and person years were classified by age, period and cohort (APC) in 1-year classes. APC Poisson regression models of rates were fitted using restricted cubic splines for age, period and cohort per centre and sex. Joint models were fitted for all centres and sexes, to find a parsimonious model. RESULTS: A total of 57,487 cases were included. In ten and seven of the 19 centres the APC models showed evidence of nonlinear cohort effects or period effects, respectively, in one or both sexes and indications of sex-specific age effects. Models showed a positive linear increase ranging from approximately 0.6 to 6.6%/year. Centres with low incidence rates showed the highest overall increase. A final joint model showed incidence peak at age 11.6 and 12.6 for girls and boys, respectively, and the rate-ratio was according to sex below 1 in ages 5-12. CONCLUSION: There was reasonable evidence for similar age-specific type 1 diabetes incidence rates across the EURODIAB population and peaks at a younger age for girls than boys. Cohort effects showed nonlinearity but varied between centres and the model did not contribute convincingly to identification of environmental causes of the increase.

Trends in emergency department visits due to sunburn and factors associated with severe sunburns in the United States.

Little is known regarding the burden of sunburns leading to emergency department (ED) visits in the United States (US). The objectives of this research were to characterize the burden of sunburn ED visits, investigate predictors of severe sunburns, and evaluate risk factors for increased cost of care in patients presenting to the ED for sunburn. In this nationally representative cross-sectional study of the National Emergency Department Sample (NEDS, 2013-2015), multivariable models were created to evaluate adjusted odds for sunburn ED visits, seasonal/regional variation in sunburn ED visits, adjusted odds for second and third degree sunburns, and risk factors for increased ED expenditure. 82,048 sunburn ED visits were included in this study. On average, the cost of care for a sunburn ED visit was $1132.25 (± $28.69). The prevalence and cost of ED visits due to sunburn increased during the summer months. Controlling for sociodemographic factors, comorbidities, and hospital characteristics, patients presenting to the ED for all sunburns (and for severe sunburns) were most likely to be lower income young adult men. Older, higher income patients in metropolitan hospitals had more expensive ED visits. This research provides nationally representative estimates of visits to the ED due to sunburn in the US, as well as evaluates determinants for severe sunburns and more expensive sunburn ED visits. Ultimately, characterizing the national burden of ED visits due to sunburn is critical in the development of interventions to reduce the impact of sunburn ED visits on the US healthcare system.

Impact of congenital cutaneous hemangiomas on newborn care in the United States.

Little is known regarding the characteristics of newborns with congenital cutaneous hemangioma (CH) and the burden of CH on newborn care. The objective of this study is to describe the burden of CH on newborn inpatient stays in the United States. Specific aims include characterizing newborns with CH, assessing factors predictive of CH and procedures performed during hospitalization, determining characteristics associated with increased cost of care and length of stay in newborns with CH, and investigating trends in prevalence, length of stay, and cost of care. This is a nationally representative retrospective cohort study (National Inpatient Sample, 2009-2015). Sociodemographic factors associated with CH and risk factors for increased cost of care/length of stay were evaluated using weighted multivariable regression models. Overall prevalence of CH is 17.0 per 10,000 newborns. Cost of care and length of stay for newborns with CH are increasing over time. Controlling for all covariates, white (aOR 1.69), female (aOR 1.52) newborns from higher income families (aOR 1.44) were more likely to be born with CH (p < 0.001). Newborns with CH who were premature (aOR 3.88), underwent more procedures (aOR 8.81), and born in urban teaching hospitals (aOR 2.66) had the greatest cost of care (p < 0.001). Premature (aOR 3.74) newborns with CH in urban teaching hospitals (aOR 1.31) had the longest hospital stays (p < 0.001). The burden of CH in newborns is substantial and increasing over time. Understanding contributors to costly hospital stays is critical in developing evidence-based guidelines to reduce the growing impact of CH on newborn care.

Toll-like receptor 2-deficient mice are protected from insulin resistance and beta cell dysfunction induced by a high-fat diet.

AIMS/HYPOTHESIS: Inflammation contributes to both insulin resistance and pancreatic beta cell failure in human type 2 diabetes. Toll-like receptors (TLRs) are highly conserved pattern recognition receptors that coordinate the innate inflammatory response to numerous substances, including NEFAs. Here we investigated a potential contribution of TLR2 to the metabolic dysregulation induced by high-fat diet (HFD) feeding in mice. METHODS: Male and female littermate Tlr2(+/+) and Tlr2(-/-) mice were analysed with respect to glucose tolerance, insulin sensitivity, insulin secretion and energy metabolism on chow and HFD. Adipose, liver, muscle and islet pathology and inflammation were examined using molecular approaches. Macrophages and dendritic immune cells, in addition to pancreatic islets were investigated in vitro with respect to NEFA-induced cytokine production. RESULTS: While not showing any differences in glucose homeostasis on chow diet, both male and female Tlr2(-/-) mice were protected from the adverse effects of HFD compared with Tlr2(+/+) littermate controls. Female Tlr2(-/-) mice showed pronounced improvements in glucose tolerance, insulin sensitivity, and insulin secretion following 20 weeks of HFD feeding. These effects were associated with an increased capacity of Tlr2(-/-) mice to preferentially burn fat, combined with reduced tissue inflammation. Bone-marrow-derived dendritic cells and pancreatic islets from Tlr2(-/-) mice did not increase IL-1beta expression in response to a NEFA mixture, whereas Tlr2(+/+) control tissues did. CONCLUSION/INTERPRETATION: These data suggest that TLR2 is a molecular link between increased dietary lipid intake and the regulation of glucose homeostasis, via regulation of energy substrate utilisation and tissue inflammation.

10-day hyperlipidemic clamp in cats: effects on insulin sensitivity, inflammation, and glucose metabolism-related genes.

Obesity and hyperlipidemia are associated with impaired insulin sensitivity in human type 2 diabetes mellitus, possibly due to activation of a mild inflammatory response. Because obesity-induced insulin resistance predisposes cats to diabetes and because hyperlipidemia is a frequent concurrent finding, excess lipids may also impair insulin sensitivity in cats. Healthy cats (n=6) were infused with lipids (Lipovenoes 10%) for 10 days to clamp blood triglycerides at the approximate concentration of untreated feline diabetes (3-7 mmol/l). Controls received saline (n=5). On day 10, plasma adiponectin and proinflammatory markers were measured. Whole-body insulin sensitivity was calculated following an intravenous glucose tolerance test. Tissue mRNAs of glucose metabolism-related genes were quantified in subcutaneous and visceral fat, liver, and skeletal muscles. Accumulation of lipids was assessed in liver. At the termination of infusion, whole-body insulin sensitivity did not differ between groups. Compared to saline, cats infused with lipids had 50% higher plasma adiponectin and 2-3 times higher alpha(1)-acid glycoprotein and monocyte chemoattractant protein-1. Unexpectedly, lipid-infused cats had increased glucose transporter-4 (GLUT4) mRNA in the visceral fat, and increased peroxisome proliferative activated receptor-gamma2 (PPARgamma2) in subcutaneous fat; adiponectin expression was not affected in any tissue. Lipid-infused cats developed hepatic steatosis. Although hyperlipidemia induced systemic inflammation, whole-body insulin sensitivity was not impaired after 10 day infusion. Increased circulating adiponectin may have contributed to prevent insulin resistance, possibly by increasing GLUT4 and PPARgamma2 transcripts in fat depots.

Direct incremental healthcare costs associated with mood disorders in the United States, 2007-2017.

BACKGROUND: This study provides nationally representative estimates of the direct incremental economic burden of mood disorders in the United States between 2007-2017, and examines trends in spending on mood disorders by healthcare setting over time. METHODS: The Medical Expenditure Panel Survey (MEPS) was used to analyze nationally-representative data related to healthcare expenditures between 2007-2017. A two-part regression model was used to estimate healthcare expenditures for patients with mood disorders compared to those without, adjusting for several sociodemographic and health-related factors. RESULTS: Total annual healthcare costs for patients with mood disorders were over twice as high as for those without, even after adjusting for potential confounders. A mood disorder diagnosis independently accounted for $6,591.60 in additional annual healthcare spending over this period. While healthcare spending on mood disorders increased significantly in the outpatient setting (14%), home health setting (84%), and on prescription medications (17%), it decreased in the inpatient setting and remained stable for emergency care. LIMITATIONS: Study limitations include an inability to determine specific components of cost in each setting, analyze costs for distinct depressive and bipolar disorders by four- or five-digit diagnosis code, and the potential for recall bias during data collection. CONCLUSIONS: Spending on outpatient care, prescription medications, and home health care for mood disorder patients grew significantly between 2007 and 2017, but decreased for inpatient care and remained stable in the emergency care setting. Future research should examine drivers of spending in these settings and explore ways to improve patient outcomes and stabilize growing healthcare expenditures.

Health Disparities in the Access and Cost of Health Care for Otolaryngologic Conditions.

OBJECTIVE: To demonstrate whether race, education, income, or insurance status influences where patients seek medical care and the cost of care for a broad range of otolaryngologic diseases in the United States. STUDY DESIGN: Retrospective cohort study using data from the Medical Expenditure Panel Survey, from 2007 to 2015. SETTING: Nationally representative database. SUBJECTS AND METHODS: Patients with 14 common otolaryngologic conditions were identified using self-reported data and International Classification of Diseases, 9th Revision Clinical Modification diagnosis codes. To analyze disparities in the utilization and cost of otolaryngologic care, a multivariate logistic regression model was used to compare outpatient and emergency department visit rates and costs for African American, Hispanic, and Caucasian patients, controlling for sociodemographic characteristics. RESULTS: Of 78,864 respondents with self-reported otolaryngologic conditions, African American and Hispanic patients were significantly less likely to visit outpatient otolaryngologists than Caucasians (African American: adjusted odds ratio [aOR], 0.57; 95% CI, 0.5-0.65; Hispanic: aOR, 0.64; 95% CI, 0.56-0.73) and reported lower average costs per emergency department visit than Caucasians (African American: $4013.67; Hispanic: $3906.21; Caucasian: $7606.46; P < .001). In addition, uninsured, low-income patients without higher education were significantly less likely to receive outpatient otolaryngologic care than privately insured, higher-income, and more educated individuals (uninsured: aOR, 0.38; 95% CI, 0.29-0.51; poor: aOR, 0.75; 95% CI, 0.64-0.87; no degree: aOR, 0.67; 95% CI, 0.54-0.82). CONCLUSION: In this study, significant racial and socioeconomic discrepancies exist in the utilization and cost of health care for otolaryngologic conditions in the United States.

Basal lipolysis, not the degree of insulin resistance, differentiates large from small isolated adipocytes in high-fat fed mice.

AIMS/HYPOTHESIS: Adipocytes in obesity are characterised by increased cell size and insulin resistance compared with adipocytes isolated from lean patients. However, it is not clear at present whether hypertrophy actually does drive adipocyte insulin resistance. Thus, the aim of the present study was to metabolically characterise small and large adipocytes isolated from epididymal fat pads of mice fed a high-fat diet (HFD). METHODS: C57BL/6J mice were fed normal chow or HFD for 8 weeks. Adipocytes from epididymal fat pads were isolated by collagenase digestion and, in HFD-fed mice, separated into two fractions according to their size by filtration through a nylon mesh. Viability was assessed by lactate dehydrogenase and 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium assays. Basal and insulin-stimulated D-[U-(14)C]glucose incorporation and lipolysis were measured. Protein levels and mRNA expression were determined by western blot and real-time RT-PCR, respectively. RESULTS: Insulin-stimulated D-[U-(14)C]glucose incorporation into adipocytes isolated from HFD-fed mice was reduced by 50% compared with adipocytes from chow-fed mice. However, it was similar between small (average diameter 60.9 +/- 3.1 microm) and large (average diameter 83.0 +/- 6.6 microm) adipocytes. Similarly, insulin-stimulated phosphorylation of protein kinase B and AS160 were reduced to the same extent in small and large adipocytes isolated from HFD-mice. In addition, insulin failed to inhibit lipolysis in both adipocyte fractions, whereas it decreased lipolysis by 30% in adipocytes of chow-fed mice. In contrast, large and small adipocytes differed in basal lipolysis rate, which was twofold higher in the larger cells. The latter finding was associated with higher mRNA expression levels of Atgl (also known as Pnpla2) and Hsl (also known as Lipe) in larger adipocytes. Viability was not different between small and large adipocytes. CONCLUSIONS/INTERPRETATION: Rate of basal lipolysis but not insulin responsiveness is different between small and large adipocytes isolated from epididymal fat pads of HFD-fed mice.

National Burden of Hospitalization Due to Cutaneous Melanoma in Adolescents and Young Adults.

OBJECTIVES: Although adolescents and young adults (AYA) suffer disproportionately from cutaneous melanoma (CM), little is known regarding the burden of CM leading to hospitalization in AYA. The objective of this study was to elucidate sociodemographic/hospitalization characteristics of AYA CM inpatients, determine which factors lead to the greater length of stay (LOS) and cost of care for AYA CM inpatients, and evaluate trends in the prevalence, LOS, and cost of care for AYA CM hospitalizations. MATERIALS AND METHODS: A retrospective cohort study of nationally representative data from the 2009 to 2015 National Inpatient Sample. Multivariable survey-weighted logistic regression models were used to determine sociodemographic factors associated with AYA CM hospitalization. Multivariable survey-weighted linear regression models were used to determine characteristics associated with the greater cost of care and LOS in AYA CM inpatients. RESULTS: A total of 8986 AYA CM inpatients were included in this study. The prevalence of AYA CM hospitalizations is decreasing over time while the cost of care is increasing. On average, AYA CM hospitalizations were 3.3 days long and cost $38,018.40. Controlling for all covariates, male sex, older age, non-Hispanic white race, higher income, private insurance, and elective admissions were associated with AYA hospitalization due to CM (P<0.0001). Male sex was associated with longer LOS (P=0.007) and cost of care (P=0.01) among AYA hospitalized for CM. CONCLUSIONS: Despite a decreasing prevalence of CM hospitalizations in AYA inpatients, the economic burden of these hospitalizations is increasing. Substantial sex-based differences exist in the inpatient burden of AYA CM. Further research is required to elucidate the causes of these differences and prevent AYA hospitalization due to CM.

Incremental Health Care Expenditure of Chronic Cutaneous Ulcers in the United States.

Importance: Despite the increasing incidence of chronic cutaneous ulcers (CCUs), limited information exists regarding their incremental economic burden. Objective: To provide nationally representative estimates regarding the incremental health care cost of CCUs, controlling for comorbidities and sociodemographic characteristics. Design, Setting, and Participants: This retrospective analysis used 9 years of longitudinal data from the Medical Expenditure Panel Survey (MEPS; January 1, 2007, through December 31, 2015). Patients with CCUs were identified using Agency for Healthcare Research and Quality-produced software that included several codes from the International Classification of Disease, 9th Revision Clinical Modification, for chronic ulcers of the skin. A cross-validated 2-part generalized linear model estimated the adjusted incremental expenditure for individuals with CCUs while controlling for comorbidities and sociodemographic covariates. Data were analyzed from July 1 through September 1, 2018. Main Outcomes and Measures: Incremental cost of CCUs, total cost of care, and expenditures associated with inpatient care, outpatient care, prescription medications, emergency department visits, and home health care. Results: A total of 288 698 patients (52.4% female; mean [SD] age, 38.2 [22.4] years) were included, of whom 1786 had CCUs and 286 912 did not. Patients with CCUs were more likely to be female (1078 [60.4%]), non-Hispanic (1388 [77.7%]), previously or currently married (1440 [80.6%]), and covered by Medicaid/Medicare (852 [47.7%]) and had a lower income (954 [53.4%]) when compared with patients without CCUs (P < .001 for all). The mean (SD) annual cost of care per patient with CCUs was greater than 4 times that of patients without CCUs ($17 958 [$1031.90] vs $4373.20 [$48.48]). After controlling for Charlson comorbidity index and sociodemographic factors measured in MEPS, the cost of care for patients with CCUs was 1.73 times as high as that of patients without CCUs (95% CI, 1.53-1.96; P < .001), and patients with CCUs were estimated to incur $7582.00 (95% CI, $6201.47-$8800.45) more in annual health care expenditures. When accounting for the prevalence of CCUs (0.6%), CCUs were associated with more than $16.7 billion per year in population-level US health care expenditures. Among patients with CCUs, mean annual expenditures rose from the 2010-2012 to 2013-2015 periods in association with prescription medications ($3117.26 to $6169.12), outpatient care ($3568.06 to $5920.75), and home health care ($1039.54 to $1670.56). Conclusions and Relevance: Results of this study suggest that chronic cutaneous ulcers are associated with substantial incremental increases in annual health care expenditure. Expenses for patients with CCUs are increasing, particularly with regard to outpatient cost of care and prescription medication expenditure. As health care costs rise, investigators must identify strategies to prevent and treat CCUs.

Raman Biomarkers Are Associated with Cyclic Fatigue Life of Human Allograft Cortical Bone.

BACKGROUND: Structural bone allografts are an established treatment method for long-bone structural defects resulting from such conditions as traumatic injury and sarcoma. The functional lifetime of structural allografts depends on resistance to cyclic loading (cyclic fatigue life), which can lead to fracture at stress levels well below the yield strength. Raman spectroscopy biomarkers can be used to non-destructively assess the 3 primary components of bone (collagen, mineral, and water), and may aid in optimizing allograft selection to decrease fatigue fracture risk. We studied the association of Raman biomarkers with the cyclic fatigue life of human allograft cortical bone. METHODS: Twenty-one cortical bone specimens were machined from the femoral diaphyses of 4 human donors (a 63-year old man, a 61-year-old man, a 51-year-old woman, and a 48-year-old woman) obtained from the Musculoskeletal Transplant Foundation. Six Raman biomarkers were analyzed: collagen disorganization, mineral maturation, matrix mineralization, and 3 water compartments. The specimens underwent cyclic fatigue testing under fully reversed conditions (35 and 45 MPa), during which they were tested to fracture or to 30 million cycles ("runout"), simulating 15 years of moderate activity. A tobit censored linear regression model for cyclic fatigue life was created. RESULTS: The multivariate model explained 60% of the variance in the cyclic fatigue life (R = 0.604, p < 0.001). Increases in Raman biomarkers for disordered collagen (coefficient: -2.74×10, p < 0.001) and for loosely collagen-bound water compartments (coefficient: -2.11×10, p < 0.001) were associated with a decreased cyclic fatigue life. Increases in Raman biomarkers for mineral maturation (coefficient: 3.50×10, p < 0.001), matrix mineralization (coefficient: 2.32×10, p < 0.001), tightly collagen-bound water (coefficient: 1.19×10, p < 0.001), and mineral-bound water (coefficient: 3.27×10, p < 0.001) were associated with an increased cyclic fatigue life. Collagen disorder accounted for 44% of the variance in the cyclic fatigue life, mineral maturation accounted for 6%, and all bound water compartments accounted for 3%. CONCLUSIONS: Increasing baseline collagen disorder was associated with a decreased cyclic fatigue life and had the strongest correlation with the cyclic fatigue life of human cortical donor bone. This model should be prospectively validated. CLINICAL RELEVANCE: Raman analysis is a promising tool for the non-destructive evaluation of structural bone allograft quality for load-bearing applications.

Interaction with the hERG channel and cytotoxicity of amiodarone and amiodarone analogues.

BACKGROUND AND PURPOSE: Amiodarone (2-n-butyl-3-[3,5 diiodo-4-diethylaminoethoxybenzoyl]-benzofuran, B2-O-CH(2)CH(2)-N-diethyl) is an effective class III antiarrhythmic drug demonstrating potentially life-threatening organ toxicity. The principal aim of the study was to find amiodarone analogues that retained human ether-a-go-go-related protein (hERG) channel inhibition but with reduced cytotoxicity. EXPERIMENTAL APPROACH: We synthesized amiodarone analogues with or without a positively ionizable nitrogen in the phenolic side chain. The cytotoxic properties of the compounds were evaluated using HepG2 (a hepatocyte cell line) and A549 cells (a pneumocyte line). Interactions of all compounds with the hERG channel were measured using pharmacological and in silico methods. KEY RESULTS: Compared with amiodarone, which displayed only a weak cytotoxicity, the mono- and bis-desethylated metabolites, the further degraded alcohol (B2-O-CH(2)-CH(2)-OH), the corresponding acid (B2-O-CH(2)-COOH) and, finally, the newly synthesized B2-O-CH(2)-CH(2)-N-pyrrolidine were equally or more toxic. Conversely, structural analogues such as the B2-O-CH(2)-CH(2)-N-diisopropyl and the B2-O-CH(2)-CH(2)-N-piperidine were significantly less toxic than amiodarone. Cytotoxicity was associated with a drop in the mitochondrial membrane potential, suggesting mitochondrial involvement. Pharmacological and in silico investigations concerning the interactions of these compounds with the hERG channel revealed that compounds carrying a basic nitrogen in the side chain display a much higher affinity than those lacking such a group. Specifically, B2-O-CH(2)-CH(2)-N-piperidine and B2-O-CH(2)-CH(2)-N-pyrrolidine revealed a higher affinity towards hERG channels than amiodarone. CONCLUSIONS AND IMPLICATIONS: Amiodarone analogues with better hERG channel inhibition and cytotoxicity profiles than the parent compound have been identified, demonstrating that cytotoxicity and hERG channel interaction are mechanistically distinct and separable properties of the compounds.