Association of in-hospital resource utilization with post-acute spending in Medicare beneficiaries hospitalized for acute myocardial infarction: a cross-sectional study.

BACKGROUND: Efforts to decrease hospitalization costs could increase post-acute care costs. This effect could undermine initiatives to reduce overall episode costs and have implications for the design of health care under alternative payment models. METHODS: Among Medicare fee-for-service beneficiaries aged ≥65 years hospitalized with acute myocardial infarction (AMI) between July 2010 and June 2013 in the Premier Healthcare Database, we studied the association of in-hospital and post-acute care resource utilization and outcomes by in-hospital cost tertiles. RESULTS: Among patients with AMI at 326 hospitals, the median (range) of each hospital's mean per-patient in-hospital risk-standardized cost (RSC) for the low, medium, and high cost tertiles were $16,257 ($13,097-$17,648), $18,544 ($17,663-$19,875), and $21,831 ($19,923-$31,296), respectively. There was no difference in the median (IQR) of risk-standardized post-acute payments across cost-tertiles: $5014 (4295-6051), $4980 (4349-5931) and $4922 (4056-5457) for the low (n = 90), medium (n = 98), and high (n = 86) in-hospital RSC tertiles (p = 0.21), respectively. In-hospital and 30-day mortality rates did not differ significantly across the in-hospital RSC tertiles; however, 30-day readmission rates were higher at hospitals with higher in-hospital RSCs: median = 17.5, 17.8, and 18.0% at low, medium, and high in-hospital RSC tertiles, respectively (p = 0.005 for test of trend across tertiles). CONCLUSIONS: In our study of patients hospitalized with AMI, greater resource utilization during the hospitalization was not associated with meaningful differences in costs or mortality during the post-acute period. These findings suggest that it may be possible for higher cost hospitals to improve efficiency in care without increasing post-acute care utilization or worsening outcomes.

Sex Differences in 1-Year All-Cause Rehospitalization in Patients After Acute Myocardial Infarction: A Prospective Observational Study.

BACKGROUND: Compared with men, women are at higher risk of rehospitalization in the first month after discharge for acute myocardial infarction (AMI). However, it is unknown whether this risk extends to the full year and varies by age. Explanatory factors potentially mediating the relationship between sex and rehospitalization remain unexplored and are needed to reduce readmissions. The aim of this study was to assess sex differences and factors associated with 1-year rehospitalization rates after AMI. METHODS: We recruited 3536 patients (33% women) ≥18 years of age hospitalized with AMI from 24 US centers into the TRIUMPH study (Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status). Data were obtained by medical record abstraction and patient interviews, and a physician panel adjudicated hospitalizations within the first year after AMI. We compared sex differences in rehospitalization using a Cox proportional hazards model, following sequential adjustment for covariates and testing for an age-sex interaction. RESULTS: One-year crude all-cause rehospitalization rates for women were significantly higher than men after AMI (hazard ratio, 1.29 for women; 95% confidence interval, 1.12-1.48). After adjustment for demographics and clinical factors, women had a persistent 26% higher risk of rehospitalization (hazard ratio, 1.26; 95% confidence interval, 1.08-1.47). However, after adjustment for health status and psychosocial factors (hazard ratio, 1.14; 95% confidence interval, 0.96-1.35), the association was attenuated. No significant age-sex interaction was found for 1-year rehospitalization, suggesting that the increased risk applied to both older and younger women. CONCLUSIONS: Regardless of age, women have a higher risk of rehospitalization compared with men over the first year after AMI. Although the increased risk persisted after adjustment for clinical factors, the poorer health and psychosocial state of women attenuated the difference.

MR-guided parenchymal delivery of adeno-associated viral vector serotype 5 in non-human primate brain.

The present study was designed to characterize transduction of non-human primate brain and spinal cord with AAV5 viral vector after parenchymal delivery. AAV5-CAG-GFP (1 × 1013 vector genomes per milliliter (vg ml-1)) was bilaterally infused either into putamen, thalamus or with the combination left putamen and right thalamus. Robust expression of GFP was seen throughout infusion sites and also in other distal nuclei. Interestingly, thalamic infusion of AAV5 resulted in the transduction of the entire corticospinal axis, indicating transport of AAV5 over long distances. Regardless of site of injection, AAV5 transduced both neurons and astrocytes equally. Our data demonstrate that AAV5 is a very powerful vector for the central nervous system and has potential for treatment of a wide range of neurological pathologies with cortical, subcortical and/or spinal cord affection.

Quality of Care in the United States Territories, 1999-2012.

BACKGROUND: Millions of Americans live in the US territories, but health outcomes and payments among Medicare beneficiaries in these territories are not well characterized. METHODS: Among Fee-for-Service Medicare beneficiaries aged 65 years and older hospitalized between 1999 and 2012 for acute myocardial infarction (AMI), heart failure (HF), and pneumonia, we compared hospitalization rates, patient outcomes, and inpatient payments in the territories and states. RESULTS: Over 14 years, there were 4,350,813 unique beneficiaries in the territories and 402,902,615 in the states. Hospitalization rates for AMI, HF, and pneumonia declined overall and did not differ significantly. However, 30-day mortality rates were higher in the territories for all 3 conditions: in the most recent time period (2008-2012), the adjusted odds of 30-day mortality were 1.34 [95% confidence interval (CI), 1.21-1.48], 1.24 (95% CI, 1.12-1.37), and 1.85 (95% CI, 1.71-2.00) for AMI, HF, and pneumonia, respectively; adjusted odds of 1-year mortality were also higher. In the most recent study period, inflation-adjusted Medicare in-patient payments, in 2012 dollars, were lower in the territories than the states, at $9234 less (61% lower than states), $4479 less (50% lower), and $4403 less (39% lower) for AMI, HF, and pneumonia hospitalizations, respectively (P<0.001 for all). CONCLUSIONS AND RELEVANCE: Among Medicare Fee-for-Service beneficiaries, in 2008-2012 mortality rates were higher, or not significantly different, and hospital reimbursements were lower for patients hospitalized with AMI, HF, and pneumonia in the territories. Improvement of health care and policies in the territories is critical to ensure health equity for all Americans.

Sex Differences in the Rate, Timing, and Principal Diagnoses of 30-Day Readmissions in Younger Patients with Acute Myocardial Infarction.

BACKGROUND: Young women (<65 years) experience a 2- to 3-fold greater mortality risk than younger men after an acute myocardial infarction. However, it is unknown whether they are at higher risk for 30-day readmission, and if this association varies by age. We examined sex differences in the rate, timing, and principal diagnoses of 30-day readmissions, including the independent effect of sex following adjustment for confounders. METHODS AND RESULTS: We included patients aged 18 to 64 years with a principal diagnosis of acute myocardial infarction. Data were used from the Healthcare Cost and Utilization Project-State Inpatient Database for California (07-09). Readmission diagnoses were categorized by using an aggregated version of the Centers for Medicare and Medicaid Services' Condition Categories, and readmission timing was determined from the day after discharge. Of 42,518 younger patients with acute myocardial infarction (26.4% female), 4775 (11.2%) had at least 1 readmission. The 30-day all-cause readmission rate was higher for women (15.5% versus 9.7%, P<0.0001). For both sexes, readmission risk was highest on days 2 to 4 after discharge and declined thereafter, and women were more likely to present with noncardiac diagnoses (44.4% versus 40.6%, P=0.01). Female sex was associated with a higher rate of 30-day readmission, which persisted after adjustment (hazard ratio, 1.22; 95% confidence interval, 1.15-1.30). There was no significant interaction between age and sex on readmission. CONCLUSIONS: In comparison with men, younger women have a higher risk for readmission, even after the adjustment for confounders. The timing of 30-day readmission was similar in women and men, and both sexes were susceptible to a wide range of causes for readmission.

Association of Admission to Veterans Affairs Hospitals vs Non-Veterans Affairs Hospitals With Mortality and Readmission Rates Among Older Men Hospitalized With Acute Myocardial Infarction, Heart Failure, or Pneumonia.

IMPORTANCE: Little contemporary information is available about comparative performance between Veterans Affairs (VA) and non-VA hospitals, particularly related to mortality and readmission rates, 2 important outcomes of care. OBJECTIVE: To assess and compare mortality and readmission rates among men in VA and non-VA hospitals. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analysis involving male Medicare fee-for-service beneficiaries aged 65 years or older hospitalized between 2010 and 2013 in VA and non-VA acute care hospitals for acute myocardial infarction (AMI), heart failure (HF), or pneumonia using the Medicare Standard Analytic Files and Enrollment Database together with VA administrative claims data. To avoid confounding geographic effects with health care system effects, we studied VA and non-VA hospitals within the same metropolitan statistical area (MSA). EXPOSURES: Hospitalization in a VA or non-VA hospital in MSAs that contained at least 1 VA and non-VA hospital. MAIN OUTCOMES AND MEASURES: For each condition, 30-day risk-standardized mortality rates and risk-standardized readmission rates for VA and non-VA hospitals. Mean aggregated within-MSA differences in mortality and readmission rates were also assessed. RESULTS: We studied 104 VA and 1513 non-VA hospitals, with each condition-outcome analysis cohort for VA and non-VA hospitals containing at least 7900 patients (men; ≥65 years), in 92 MSAs. Mortality rates were lower in VA hospitals than non-VA hospitals for AMI (13.5% vs 13.7%, P = .02; -0.2 percentage-point difference) and HF (11.4% vs 11.9%, P = .008; -0.5 percentage-point difference), but higher for pneumonia (12.6% vs 12.2%, P = .045; 0.4 percentage-point difference). In contrast, readmission rates were higher in VA hospitals for all 3 conditions (AMI, 17.8% vs 17.2%, 0.6 percentage-point difference; HF, 24.7% vs 23.5%, 1.2 percentage-point difference; pneumonia, 19.4% vs 18.7%, 0.7 percentage-point difference, all P < .001). In within-MSA comparisons, VA hospitals had lower mortality rates for AMI (percentage-point difference, -0.22; 95% CI, -0.40 to -0.04) and HF (-0.63; 95% CI, -0.95 to -0.31), and mortality rates for pneumonia were not significantly different (-0.03; 95% CI, -0.46 to 0.40); however, VA hospitals had higher readmission rates for AMI (0.62; 95% CI, 0.48 to 0.75), HF (0.97; 95% CI, 0.59 to 1.34), or pneumonia (0.66; 95% CI, 0.41 to 0.91). CONCLUSIONS AND RELEVANCE: Among older men with AMI, HF, or pneumonia, hospitalization at VA hospitals, compared with hospitalization at non-VA hospitals, was associated with lower 30-day risk-standardized all-cause mortality rates for AMI and HF, and higher 30-day risk-standardized all-cause readmission rates for all 3 conditions, both nationally and within similar geographic areas, although absolute differences between these outcomes at VA and non-VA hospitals were small.

Community Level Association between Home Health and Nursing Home Performance on Quality and Hospital 30-day Readmissions for Medicare Patients.

We evaluated whether community-level home health agencies and nursing home performance is associated with community-level hospital 30-day all-cause risk-standardized readmission rates for Medicare patients used data from the Centers for Medicare & Medicaid Service from 2010 to 2012. Our final sample included 2,855 communities that covered 4,140 hospitals with 6,751,713 patients, 13,060 nursing homes with 1,250,648 residents, and 7,613 home health agencies providing services to 35,660 zipcodes. Based on a mixed effect model, we found that increasing nursing home performance by one star for all of its 4 measures and home health performance by 10 points for all of its 6 measures is associated with decreases of 0.25% (95% CI 0.17-0.34) and 0.60% (95% CI 0.33-0.83), respectively, in community-level risk-standardized readmission rates.

Improvements in the distribution of hospital performance for the care of patients with acute myocardial infarction, heart failure, and pneumonia, 2006-2011.

BACKGROUND: Medicare hospital core process measures have improved over time, but little is known about how the distribution of performance across hospitals has changed, particularly among the lowest performing hospitals. METHODS: We studied all US hospitals reporting performance measure data on process measures for acute myocardial infarction (AMI), heart failure (HF), and pneumonia (PN) to the Centers for Medicare & Medicaid Services from 2006 to 2011. We assessed changes in performance across hospital ranks, variability in the distribution of performance rates, and linear trends in the 10th percentile (lowest) of performance over time for both individual measures and a created composite measure for each condition. RESULTS: More than 4000 hospitals submitted measure data each year. There were marked improvements in hospital performance measures (median performance for composite measures: AMI: 96%-99%, HF: 85%-98%, PN: 83%-97%). A greater number of hospitals reached the 100% performance level over time for all individual and composite measures. For the composite measures, the 10th percentile significantly improved (AMI: 90%-98%, P<0.0001 for trend; HF: 70%-92%, P=0.0002; PN: 71%-92%, P=0.0003); the variation (90th percentile rate minus 10th percentile rate) decreased from 9% in 2006 to 2% in 2011 for AMI, 25%-8% for HF, and 20%-7% for PN. CONCLUSIONS: From 2006 to 2011, not only did the median performance improve but the distribution of performance narrowed. Focus needs to shift away from processes measures to new measures of quality.

National trends in hospital length of stay for acute myocardial infarction in China.

BACKGROUND: China is experiencing increasing burden of acute myocardial infarction (AMI) in the face of limited medical resources. Hospital length of stay (LOS) is an important indicator of resource utilization. METHODS: We used data from the Retrospective AMI Study within the China Patient-centered Evaluative Assessment of Cardiac Events, a nationally representative sample of patients hospitalized for AMI during 2001, 2006, and 2011. Hospital-level variation in risk-standardized LOS (RS-LOS) for AMI, accounting for differences in case mix and year, was examined with two-level generalized linear mixed models. A generalized estimating equation model was used to evaluate hospital characteristics associated with LOS. Absolute differences in RS-LOS and 95% confidence intervals were reported. RESULTS: The weighted median and mean LOS were 13 and 14.6 days, respectively, in 2001 (n = 1,901), 11 and 12.6 days in 2006 (n = 3,553), and 11 and 11.9 days in 2011 (n = 7,252). There was substantial hospital level variation in RS-LOS across the 160 hospitals, ranging from 9.2 to 18.1 days. Hospitals in the Central regions had on average 1.6 days (p = 0.02) shorter RS-LOS than those in the Eastern regions. All other hospital characteristics relating to capacity for AMI treatment were not associated with LOS. CONCLUSIONS: Despite a marked decline over the past decade, the mean LOS for AMI in China in 2011 remained long compared with international standards. Inter-hospital variation is substantial even after adjusting for case mix. Further improvement of AMI care in Chinese hospitals is critical to further shorten LOS and reduce unnecessary hospital variation.

Mortality, Hospitalizations, and Expenditures for the Medicare Population Aged 65 Years or Older, 1999-2013.

IMPORTANCE: In a period of dynamic change in health care technology, delivery, and behaviors, tracking trends in health and health care can provide a perspective on what is being achieved. OBJECTIVE: To comprehensively describe national trends in mortality, hospitalizations, and expenditures in the Medicare fee-for-service population between 1999 and 2013. DESIGN, SETTING, AND PARTICIPANTS: Serial cross-sectional analysis of Medicare beneficiaries aged 65 years or older between 1999 and 2013 using Medicare denominator and inpatient files. MAIN OUTCOMES AND MEASURES: For all Medicare beneficiaries, trends in all-cause mortality; for fee-for-service beneficiaries, trends in all-cause hospitalization and hospitalization-associated outcomes and expenditures. Geographic variation, stratified by key demographic groups, and changes in the intensity of care for fee-for-service beneficiaries in the last 1, 3, and 6 months of life were also assessed. RESULTS: The sample consisted of 68,374,904 unique Medicare beneficiaries (fee-for-service and Medicare Advantage). All-cause mortality for all Medicare beneficiaries declined from 5.30% in 1999 to 4.45% in 2013 (difference, 0.85 percentage points; 95% CI, 0.83-0.87). Among fee-for-service beneficiaries (n = 60,056,069), the total number of hospitalizations per 100,000 person-years decreased from 35,274 to 26,930 (difference, 8344; 95% CI, 8315-8374). Mean inflation-adjusted inpatient expenditures per Medicare fee-for-service beneficiary declined from $3290 to $2801 (difference, $489; 95% CI, $487-$490). Among fee-for-service beneficiaries in the last 6 months of life, the number of hospitalizations decreased from 131.1 to 102.9 per 100 deaths (difference, 28.2; 95% CI, 27.9-28.4). The percentage of beneficiaries with 1 or more hospitalizations decreased from 70.5 to 56.8 per 100 deaths (difference, 13.7; 95% CI, 13.5-13.8), while the inflation-adjusted inpatient expenditure per death increased from $15,312 in 1999 to $17,423 in 2009 and then decreased to $13,388 in 2013. Findings were consistent across geographic and demographic groups. CONCLUSIONS AND RELEVANCE: Among Medicare fee-for-service beneficiaries aged 65 years or older, all-cause mortality rates, hospitalization rates, and expenditures per beneficiary decreased from 1999 to 2013. In the last 6 months of life, total hospitalizations and inpatient expenditures decreased in recent years.

Comparative evaluation of variations in torque expression in maxillary incisor and canine using different bracket prescriptions placed at different crown levels by finite element (FE) method: An in-vitro analysis.

OBJECTIVE: While using preadjusted brackets, the position of the bracket on the crown is one of the deciding factors that determine the tooth's final tip, torque, height, and rotation. The final tooth position is not optimal if the bracket is placed incorrectly or if the varying crown morphology does not correspond with the bracket design. The present study was conducted to evaluate and compare the variations in torque expression in maxillary incisor and canine using different bracket prescriptions placed at different crown levels by finite element method. METHODS: For the present study, three-dimensional models of maxillary right central incisor and canine were made using CREO version 4.0 software. CREO is a powerful three-dimensional (3-D) computer-based, computer-aided design (CAD) software developed by Parametric Technology Corporation (PTC) to aid in design processes. Simulation was done to replicate the clinical situation of an active palatal root torque acting on the incisor and canine. The induced palatal movement of root tips and labial movement of crowns tips, overall stress, and von Mises stress generated in the brackets and the total equivalent strains developed in the periodontal ligament (PDL) were calculated, while the values obtained were tabulated and subjected to statistical analysis. RESULTS: Based on the findings of the present study, the average maximum stress produced in the bracket was calculated as 265.069 Mpa in incisor and 166.742 Mpa in the canine. Likewise, the average of the maximum displacement of root apex observed in the present study was calculated as 0.01401 mm in the incisor and 0.00421 mm in the canine, while the average strain developed in the PDL was calculated as 0.0587 for incisor and 0.0498 for the canine. Furthermore, it was, also, observed that the magnitude of strain developed in the PDL increased with increase in the stress produced by the bracket prescription for both incisor and canine. CONCLUSIONS: Within the limitations of the present study, it was concluded that the magnitude of displacement of root apex was significantly influenced by bracket prescription and bracket position. Also, the stress developed in the bracket was influenced by bracket prescription and position, while the variation in crown morphology in the incisor and canine played a significant role in the eventual strain developed in the PDL after torque application.

Cyclolobatriene, a novel prenylated germacrene diterpene, from the soft coral Lobophytum pauciflorum.

A new 10-membered-ring diterpene, cyclolobatriene (1), along with three other known diterpenes, lobatriene (2), eunicol (3), and fuscol (4), were isolated from the Okinawan soft coral Lobophytum pauciflorum. Their structures were established by extensive NMR spectroscopic analyses. Cyclolobatriene (1) is an additional example of rare prenylated germacrenes. Although 1, due to a 10-membered-ring structure, exists as an equilibrium mixture of three conformers, the NMR measurement in CDCl(3) at 7°C enabled us to assign the NMR signals of the three, which is the first example of the complete NMR assignment of all the existing conformers of germacrene-type compounds. Cyclolobatriene (1) was thermally unstable and converted into 2 through Cope rearrangement upon heating at 70°C. Eunicol (3) also possesses the same prenylated germacrene structure as 1, showing similar physico-chemical properties to 1. All four compounds 1-4 showed cytotoxic effect with IC(50)'s of 0.64, 0.41, 0.35 and 0.52 µM, respectively, against human epidermoid carcinoma A431 cells.

Novel cytotoxic polyoxygenated steroids from an Okinawan sponge Dysidea sp.

A library of extracts established from hundreds of marine organisms was screened by a cytotoxicity test. The active organic extract of an Okinawan marine sponge of the genus Dysidea was subjected to bioassay-guided fractionation to give three new polyoxygenated steroids dysideasterols F-H (1-3), together with two known related compounds (4 and 5). Their structures were confirmed by NMR and mass spectroscopic analyses. A characteristic structural feature of 2, 4 and 5 is an allylic epoxide, whereas this epoxide undergoes ring-opening by a neighbouring hydroxyl group to give a tetrahydrofuran ring in 1 and 3. All compounds 1-5 exhibited a similar cytotoxic effect with IC50 values of 0.15-0.3 µM against human epidermoid carcinoma A431 cells, demonstrating that the allylic epoxide moiety was not responsible for this cytotoxic effect.

Management of Cepacia syndrome in an immunocompetent non-cystic fibrosis adult patient.

Burkholderia cepacia complex (BCC) is nonfermenting, Gram-negative bacteria known to cause high morbidity and mortality. They commonly affect patients with cystic fibrosis (CF) and are often missed in those without, despite being fatal if left untreated. We report a case of cepacia syndrome in a 42-year-old, immunocompetent man without CF who initially presented with sepsis secondary to pneumonia. Multiple isolates from blood, synovial fluid, and wound swabs grew BCC. Treatment options and management strategies remain poorly understood for BCC in general and in cases without CF in specific. We successfully treated the patient using a combination of intravenous and inhalational antibiotics. This case report elaborates on the disease presentation, investigations, and management strategy employed to treat this rare infection.

Evaluation of Change in Surface Enamel Microhardness in Patients Undergoing Fixed Orthodontic Appliance Therapy - A Randomized Control Trial.

AIM: This study aims at determining the amount of enamel decalcification in terms of microhardness. MATERIALS AND METHODS: Twenty patients requiring treatment by extraction method for Class I malocclusion with bimaxillary protrusion were selected for the study. Twenty patients were randomly divided into control group and experimental group. In the control group (n = 40), extraction of permanent first premolars was done on day 1 of bonding to assess the Vickers hardness number (VHN) of enamel surface, and in the experimental group (n = 40), extraction of the contralateral premolars was done on the 28th day after bonding to assess the VHN of enamel surface. The values are tabulated and analyzed by SPSS software. RESULTS: There is significant surface enamel dissolution of enamel crystals in the experimental group compared to the control group, and a statistically significant difference in VHN is evident between the control and experimental groups. The surface enamel dissolution (VHN) is not significant difference noted between mandibular and maxillary premolars of the control and experimental groups. CONCLUSION: The present study has demonstrated a higher level of surface enamel dissolution in the experimental group. There is a marked difference in the VHN between the control and experimental groups, which is statistically significant. The scanning electron microscopy study also confirms the presence of surface enamel demineralization following orthodontic bonding.

Digoxin Use and Associated Adverse Events Among Older Adults.

BACKGROUND: Over the past 2 decades, guidelines for digoxin use have changed significantly. However, little is known about the national-level trends of digoxin use, hospitalizations for toxicity, and subsequent outcomes over this time period. METHODS: To describe digoxin prescription trends, we conducted a population-level, cohort study using data from IQVIA, Inc.'s National Prescription Audit (2007-2014) for patients aged ≥65 years. Further, in a national cohort of Medicare fee-for-service beneficiaries aged ≥65 years in the United States, we assessed temporal trends of hospitalizations associated with digoxin toxicity and the outcomes of these hospitalizations between 1999 and 2013. RESULTS: From 2007 through 2014, the number of digoxin prescriptions dispensed decreased by 46.4%; from 8,099,856 to 4,343,735. From 1999 through 2013, the rate of hospitalizations with a principal or secondary diagnosis of digoxin toxicity decreased from 15 to 2 per 100,000 person-years among Medicare fee-for-service beneficiaries. In-hospital and 30-day mortality rates associated with hospitalization for digoxin toxicity decreased significantly among Medicare fee-for-service beneficiaries; from 6.0% (95% confidence interval [CI], 5.2-6.8) to 3.7% (95% CI, 2.2-5.7) and from 14.0% (95% CI, 13.0-15.2) to 10.1% (95% CI, 7.6-13.0), respectively. Rates of 30-day readmission for digoxin toxicity decreased from 23.5% (95% CI, 22.1-24.9) in 1999 to 21.7% (95% CI, 18.0-25.4) in 2013 (P < .05). CONCLUSION: While digoxin prescriptions have decreased, it is still widely prescribed. However, the rate of hospitalizations for digoxin toxicity and adverse outcomes associated with these hospitalizations have decreased. These findings reflect the changing clinical practice of digoxin use, aligned with the changes in clinical guidelines.