This study assessed factors associated with emergency care outcomes and out-of-pocket treatment costs in traumatic brain injury (TBI) patients in Pakistan.Data on TBI patients were extracted from a four-month surveillance study conducted in the emergency departments (ED) of seven large teaching hospitals. Emergency care access to physicians and imaging facilities were compared with respect to ED outcomes . Out-of-pocket treatment costs (in United States dollars [USD]) were compared among different patient strata.ED outcomes were available for 1,787 TBI patients. Of them, most were males (79%), aged <25 years (46%) and arrived by ambulances (32%). Nurses or paramedical staff saw almost all patients (95%). Physicians with practice privileges  saw about half (55%) of them. Computerized tomography (CT) scans were performed in two of five patients (40%). Of all, 26% (n = 460) were admitted and 3% died (n = 52). Emergency care factors significantly associated with being admitted or died were arriving by ambulance  [95%CI] = 1.78-3.16); seen by medical officer/residents ; and had CT scan . Out-of-pocket treatment costs at the ED were reported in 803 patients. Average costs were USD 8, (standard deviation [SD] = 23). Costs were twice as high in those arriving in ambulances  or who underwent CT scans .TBI patients' access to ambulance transport, experienced physicians, and imaging facilities during emergency care needs to be improved in Pakistan. Emergency care plays a pivotal role in any healthcare system . EffectiTraumatic brain injuries (TBIs) - defined as a disruption in brain functioning resulting from sudden, unexpected, intolerable application of mechanical force - are relatively common and often require specialized emergency care ,7. The nAn early identification of TBIs and appropriate emergency care can prevent long-term disabilities . While ePakistan is low-income country with over 180 million population, with a high rate of TBIs . A largeWe studied TBI patients as part of a multicenter pilot surveillance study - the Pakistan National Emergency Departments Surveillance Study (hereafter referred as Pak-NEDS). More details on the aims and design of Pak-NEDS are available elsewhere . In brieAll selected hospitals had 24-hour EDs with nurses, physicians and support staff. As all were teaching hospitals, there were three levels of physicians, junior in-training doctors (or house physicians), medical officer or specialty residents (experienced), and consultants. Junior physicians had limited privileges for practice, whereas medical officers, residents and consultants had complete privileges. All patients were usually required to be seen by a physician with full privileges, which was not always possible when there was a high patient volume. Except for Benazir Bhutto Hospital in Rawalpindi, all hospitals had an in-house neurosurgery department with specialized in-patient service. AKU and Shifa International Hospital were private sector hospitals requiring all expenses to be paid by patients or their insurance agencies. The remaining hospitals had no physician charges, but patients could be required to pay up-front and out-of-pocket for medications or examinations, including imaging that was not covered by the government.AKU was the main coordinating center for the study. Ethical approval was obtained from all participating sites. Pak-NEDS was conducted for a four month period per selected site from Nov 2010 to Mar 2011. All patients  presenting to the ED during the above period were eligible for recruitment in Pak-NEDS.A one-page standardized tool was developed based on the National Hospital Ambulatory Medical Care Survey (NHAMCS) tool of the Centers for Disease Control and Prevention, USA , which wStudy-specific staff with previous medical care experience worked in three shifts to collect data on the designated tool. Twenty-four hour data collection was conducted on all sites except one; there the staff worked in two eight-hour shifts every day. At this site, the shifts were rotated every week to have a sample of patients presenting during the 24 hours. Either the patient or their next of kin or guardian was interviewed in the ED, along with a review of the ED records in order to collect the required information. Hard copies of the data collection tool were sent to the coordinating center at AKU on a weekly basis. Data were entered at AKU using EpiInfo version 3.3.2. A research coordinator supervised the data entry procedures.For this study, patients were selected when presenting complaints that were described as "head injury" and the nature of injury was one of the TBI-specified above (see introduction). Only new patients were included .P≤0.10) in the univariate analysis were kept in the final model. In the second analysis, we included only those patients where out-of-pocket treatment costs were available (n = 803). The association of patient factors with out-of-pocket costs was assessed using one-way ANOVA test. The P<0.05 indicated that at least one patient strata had significantly higher or lower costs than others. All costs were in United States dollars (USD) with the conversion rate of 100 Pakistani rupees ~ 1 USD. All analyses were performed on SPSS, version 19.Two analyses were conducted. In the first one, patients with complete data on their ED outcomes were included . Emergency care factors associated with worse ED outcomes, i.e., either admission or death, were assessed using the chi-square test. We also constructed a multivariate logistic regression model in which only variables which had a strong association with some ED outcomes  as high in those who were admitted (82.6%) than those who were discharged from ED (49.4%). The proportion of those who had a CT scan was significantly higher (P < 0.001) in those who were admitted (63.0%) than those who were discharged from the ED (31.0%). Similarly, the proportion of x-rays performed was significantly higher (P < 0.001) in those who were admitted (58.9%) than those who were discharged from the ED (41.2%). Logistic regression analysis showed that TBI-related hospital admissions or deaths were associated with intentional TBIs (adjusted odds ratio [aOR] = 1.89), ambulance use (aOR = 2.37), examination by medical officers/residents (aOR = 2.11), and CT scan (aOR = 2.93)Table P<0.001) were noted for those who were later admitted  or who died  in the ED than those who were discharged . Similarly, those arriving in ambulances paid a significantly higher cost  than those who used other means . Those who had a CT scan spent significantly more  than those who did not have a CT scan.Out-of-pocket-treatment costs were reported for 803 patients (44.9%) Table . On averTo the best of our knowledge, Pak-NEDS is the largest multicenter study of emergency patients in Pakistan. Some findings of this study were consistent with previous ones from neurosurgery centers showing that young men, traffic crashes, and falls were associated with TBIs in Pakistan ,21. ThisThis study observed a higher intensity of ambulance use with more severe TBIs. For example, TBI injury severity increased ambulance use: 66% of severe TBI and 56% of moderate TBI (as determined by the GCS) arrived by ambulances (results not shown because of <10% documentation) . CompareThe findings pointed out that the availability and costs of imaging might also be important constraints for medical care of TBIs in Pakistan. CT scan machines have considerable maintenance costs, and these are often transferred to patients as fees-for-use. As about two-thirds of the Pakistani population earn less than US$2 a day per head, most TBI patients might not be able to afford imaging unless they use their savings or borrow funds . These cThis study may have several limitations. A large number of patients had to be excluded from analysis because information about the nature of their TBI was not available. The data collectors were dependent on physicians to document this information. Still, this study had a considerable sample of TBI patients to assess factors associated with TBI care. Similarly, information about several factors, including the TBI mechanism and severity was not documented. For example, the Glasgow Coma Scale was reported in only one in ten patients. Relatedly, this study might also underestimate minor TBIs or concussions, most of which usually go unrecognized . FurtherThese findings suggest several areas of improving TBI care in Pakistan. The potential interventions might include increased access to ambulance services, better reporting of TBI details, increased examination by experienced physicians in the ED, and the availability of imaging in the ED of tertiary care centers. These steps need to be taken in conjunction with other general measures for emergency TBI care, such as improving public awareness about TBI care and capacity building within the healthcare system.The authors declare that they have no competing interests.JAB the data analysis and the initial draft. AAH and JAR conceptualized Pak-NEDS, supervised data collection, contributed in the analyses and manuscript writing. NS, KS and MUM contributed in the data cleaning, analysis, and interpretation. All authors critically read and approved the final draft before submission.


Physical activity (PA) and cardiorespiratory fitness (CRF) are associated with better cognitive function in late life, but the neural correlates for these relationships are unclear. To study these correlates, we examined the association of both PA and CRF with measures of white matter (WM) integrity in 88 healthy low-fit adults (age 60–78). Using accelerometry, we objectively measured sedentary behavior, light PA, and moderate to vigorous PA (MV-PA) over a week. We showed that greater MV-PA was related to lower volume of WM lesions. The association between PA and WM microstructural integrity (measured with diffusion tensor imaging) was region-specific: light PA was related to temporal WM, while sedentary behavior was associated with lower integrity in the parahippocampal WM. Our findings highlight that engaging in PA of various intensity in parallel with avoiding sedentariness are important in maintaining WM health in older age, supporting public health recommendations that emphasize the importance of active lifestyle. Participation in physical activity and high levels of cardiorespiratory fitness (CRF) have protective effects on brain structure and function and are associated with later onset or lower degree of age-related cognitive decline Much of the research examining PA and brain health has relied on subjective assessments of PA. Such self-reports, in contrast to quantitative measures such as accelerometry, fail to provide objective and accurate estimates of non-exercise lifestyle activities such as moderate PA (climbing stairs), light PA  and sedentary behavior  on T2-weighted images Our study goes beyond the above studies by combining objective measures of PA and CRF with two MRI measures of WM health (FA and WMH volume) in a large group of typically low–fit healthy adults . PA was objectively measured with an accelerometer worn on the hip for at least 10 waking hours for 7 days and was classified into sedentary behavior, light PA, and MV-PA Our study had two main aims. First, we aimed to test whether in healthy low-active and low-fit older adults CRF conjointly with and PA is related to WM health, measured by combining FA with WMH volume. We predicted that, in general, greater CRF and PA would be related to higher WM integrity. The second aim, given that our first hypothesis is true, was to investigate in more detail the multiple interacting pathways linking PA to WM health. Here, our main goal was to identify in post-hoc exploratory analyses the relationships between different levels of PA intensity and WM health in older adults, and to test the role of CRF in these relationships. We predicted that greater PA would be related to lower WMH volume Our findings confirmed our expectations that better physical health was related to WM health. In particular, greater PA and lower sedentariness were associated with lower WMH volume and higher FA, especially in the temporal WM regions, but our data did not support a significant relationship between CRF and WM health in the frontal regions.We recruited 103 community-dwelling healthy, older adults . The sample contained more females because less older males met the inclusion criteria or showed willingness to participate in the study. Eligible participants met the following criteria: (1) were between the ages of 60 and 79 years old, (2) were free from psychiatric and neurological illness and had no history of stroke or transient ischemic attack, (3) scored ≥23 on the Mini-Mental State Exam (MMSE) and >21 on a Telephone Interview of Cognitive Status (TICS-M) questionnaire, (4) scored <10 on the geriatric depression scale (GDS-15), (5) scored ≥75% right-handedness on the Edinburgh Handedness Questionnaire, (6) demonstrated normal or corrected-to-normal vision of at least 20/40 and no color blindness, (7) cleared for suitability in the MRI environment; that is, no metallic implants that could interfere with the magnetic field or cause injury, no claustrophobia, and no history of head trauma. The participants were a pre-intervention cross-sectional subsample from an on-going randomized controlled exercise trial , from whom good quality DTI and T2 data (as described in the following sections), as well as CRF and PA data were available. We furthermore excluded participants who had MMSE score <27, in order to limit the analyses to cognitively healthy older adults and exclude those with possible mild cognitive impairment. Seventy-two participants (83%) of the sample reported no participation in regular PA (maximum of two moderate bouts of PA/week) in the past six months. The remaining 17% reported engaging in some exercise upon recruitment; however, the subsequent accelerometer data analysis revealed that as many as 40% of them did not met the minimum recommendations for PA (>150 min of moderate PA per week). Similarly, fourteen (19%) of the self-reported “low-active” adults met the criteria of >150 min of moderate PA per week. This highlights the necessity of objective assessment of PA for accurate sample description, in addition to self-reports. In total, based on the accelerometer data, only 26%  of the 88 participants met the minimum criteria for PA for older adults and only 3 of them met the recommended criteria based on vigorous activity  were normotensive, while 18 (22%) were hypertensive, defined as either systolic BP >140 mmHg or diastolic BP >90 mm Hg. Twenty participants (23%) had normal BMI, while 68 (77%) were overweight (BMI >25). If stratified based on BMI or BP, the groups did not differ on any of the WM or fitness variables of interest, and therefore BMI and BP were not included as in the following analyses.The 88 participants had mean body mass index (BMI) MParticipants were instructed to wear the GT3× ActiGraph accelerometer  for seven consecutive days on an elastic belt on the left hip during all waking hours, except for when bathing or swimming. The participants completed a daily log to record the time that the accelerometer was worn, and this log was used to verify the accelerometer data for processing with the ActiLife v5.6.0 software. For the purposes of this study, a valid day of data consisted of at least 10 hours of valid wear-time, with a valid hour defined as no more than 30 consecutive minutes of zero counts with one minute sampling epochs . Only daEach valid measurement epoch was classified into sedentary, light, moderate, and vigorous physical activity based on displacement magnitude and frequency. We used activity intensity cut-off ranges appropriate for older adults 2) was calculated from expired air sampled at 30-s intervals until peak VO2 was reached or the test was terminated due to volitional exhaustion and/or symptom limitation. CRF was defined as the highest recorded VO2 value (VO2max) after two of three criteria were met: (1) a plateau in VO2 after increase in workload; (2) a respiratory exchange ratio >1.10, and (3) a maximal heart rate within 10 bpm of their age-predicted maximum. Our subjects represented a broad range of CRF values, with extremely high values for 2 female participants (>±2.5 SD and beyond the 90% peak VO2max percentile (superiorly/excellent fit) according to gender- and age-specific norms; ACSM's Guidelines for Exercise Testing and Prescription, www.acsm.org. Accessed 2014 June 12). They were therefore considered outliers in our largely low-fit sample and their values were removed from further analyses. As one female participant did not complete the treadmill test, the final sample for CRF assessment was 83 .All participants obtained physician's approval to engage in cardiorespiratory fitness (CRF) testing. CRF was defined as peak oxygen consumption [ml/kg/min], measured with indirect calorimetry during a modified Balke graded maximal exercise test on a motor-driven treadmill test. Oxygen consumption .Diffusion-weighted and high in-plane resolution T2-weighted images (for WMH volume estimation) were acquired on a 3T Siemens Trio Tim system with 45 mT/m gradients and 200 T/m/sec slew rates . All images were obtained parallel to the anterior-posterior commissure plane with no interslice gap. T2-weighted images consisted of 35 4-mm-thick slices with an in-plane resolution of 0.86×0.86 . DTI images were acquired with a twice-refocused spin echo single-shot Echo Planar Imaging sequence 3. The WMH volume was positively skewed (Kolmogorov-Smirnov test D(60)  = 0.28, p<0.05) and we performed a natural log-transformation of this variable for further analyses.We estimated WMH volume on T2-weighted images using a semi-automated procedure based on FMRIB's Automated Segmentation Tool  space via the FMRIB58_FA template using the FMRIB's Nonlinear Registration Tool  calTo verify how the tracts of interest were related to CRF and PA, we extracted FA values from five regions: anterior corpus callosum  inference , with the threshold-free cluster enhancement option, and controlling for age and gender.To test the first study hypothesis, we performed a dimensionality reduction by running two separate principal component analyses (PCA) with varimax rotation. The first model included the four variables: CRF, sedentary time, light PA, and MV-PA. The second model included the WM health indices: five FA values and WMH volume. Both analyses yielded a one-component model and therefore represented “CRF and PA” and “WM health”, respectively. Importantly, a PCA analysis replacing the five FA values with global FA measure (mean FA over the entire WM skeleton) yielded the same outcome, confirming that the FA in the five WM regions are representative for the overall WM health.All statistical analyses were performed using SPSS . We used partial 2-tailed correlations  and multiple step-wise linear regressions to investigate the relationships among CRF, PA, WMH volume, and FA. The p values in these post-hoc analyses were not corrected for multiple comparisons.The raw CRF, PA, WMH volume, and FA values is made available in A University of Illinois Institutional Review Board approved the study, and written informed consent was obtained from all participants and the study was performed in accordance with the 1964 Declaration of Helsinki. Participants received financial reimbursement.We summarized the descriptive statistics of main variables in our study and their correlations with chronological age in CRF was positively related to light and MV-PA, and negatively related to sedentary behavior . This confirmatory analysis showed that in the five regions, WMH and DTI are not redundant measures of WM health.Dimensionality reduction using PCA separately on WM and CRF and PA measures yielded single factors for “CRF and PA” and “FA and WMH volume”. In other words, participants with greater “CRF and PA” factor scores had higher CRF, showed more light and MV-PA, and less sedentary behavior. Participants with higher WM health factor score had higher FA in all five regions and lower WMH volume. As predicted, we found a positive association between “CRF and PA” and “FA and WMH volume” , which was a prerequisite for the following post-hoc analyses -C.MV-PA , but not sedentary or light daily PA was related to WMH volume  was associated with higher FA in the temporal lobe WM -C. A mulSedentary behavior was inversely related to FA in the parahippocampal WM. That is, participants who spent more time on sedentary behavior had lower FA adjacent to the hippocampus .We studied the relationships among CRF, PA, and WM health in a sample of 88 healthy low-active older adults. We found that “CRF and PA”, measured as a factor combining CRF and three levels of PA, was positively associated with WM health, represented by a factor “FA and WMH volume”. Post hoc analyses showed that this general result was driven by several WM-PA relationships. Specifically, higher MV-PA was associated with lower WMH volume, independent of age, gender, and CRF. Additionally, less time spent in sedentariness was linked with higher FA in the parahippocampal WM, and this association was independent of age, gender, and MV-PA. Our findings suggest that different levels of PA, although related, are associated with different aspects of WM integrity in a region-specific way. Here we focus on the specific post-hoc results and discuss how different mechanisms related to physical activity and sedentariness, such as cerebrovascular health, neurotrophic factors, or glucose and lipid metabolism, could underlie the observed relationships in specific brain regions.We found that higher MV-PA was related to lower volume of WMH. We propose that the mechanism underlying this association is the beneficial effect of the MV-PA on the cerebrovascular system.Aging is associated with stiffening and dilation of aorta and proximal elastic arteries due to accumulating “wear and tear” of their elastic and muscular components. This results in hypertension and impaired cushioning function of the arterial system, i.e. the ability to change the pulsatile flow in arteries to steady flow in the capillaries. This impaired cushioning increases vascular wall tension in arterioles and capillaries, particularly those of the brain 2max reflects not only cardiovascular health, but also reflects body composition, genetic factors, and muscle metabolic rate. An ongoing exercise intervention study will shed more light on the discrepancy between CRF and MV-PA measures in relation to WM health.These age-related vascular changes are said to be counteracted by mainly moderate PA, captured as MV-PA by accelerometry. The effects of MV-PA include reduction in arterial stiffness and blood pressure Light PA was positively related to FA in the temporal lobe WM. Our results are novel in showing that not only exercise aimed to increase CRF, but also light PA may be beneficial for the temporal lobe during aging. It is worth noting, however, that in our low-fit sample, greater daily light PA (and not only MV-PA) was also associated with greater CRF, and light PA no longer significantly predicted temporal FA after accounting for CRF. Therefore, we speculate that the effect of PA on temporal WM may be related to mechanisms related to CRF.The beneficial effects of CRF and exercise on temporal lobe structures are well known in both animals and humans Aerobic exercise upregulates the expression and release of important neuronal growth factors such as brain-derived neurotrophic factor (BDNF) 66Met polymorphism (increased levels of activity-dependent release) had decreased FA compared to Met-allele carriers BDNF supports survival and growth of many neuronal subtypes and is a mediator of synaptic efficacy and use-dependent plasticity It is also possible that the positive effects of light PA on temporal lobe WM integrity are mediated by changes in cerebrovascular supply factors related to CRF, reducing the oxygenative stress in the tissue An alternative, although not mutually exclusive, explanation for the observed association between PA and WM integrity (both FA and WMH) is that individuals with higher WMH burden or decreases in FA are at more risk of impaired mobility In sum, our results suggest that not only structured exercise, but also light PA may be associated with greater WM microstructural integrity in temporal regions, known to be prone to age-related changes and sensitive to CRF-related benefits. Future analyses linking temporal WM FA to cognitive measures, local structure, and neural activity will allow assessing the functional relevance of the reported associations.We found that older adults who spent more time in sedentary behavior had lower FA in the parahippocampal WM. Importantly, more sedentary behavior was related not only to less light PA, but also to less MV-PA, and lower CRF. Therefore, more sedentary older individuals were less exposed to beneficial effects of light and MV-PA, but also more prone to deleterious effects of sedentariness, such as increased metabolic risk Physiological differences between sedentary behavior and lack of MV-PA 2max >42.7 for men in 7th decade of life), 53% participants in 2max  = 38, while half of Finally, we observed no relationships between CRF with WMH volume or FA in the corpus callosum, the cingulum bundle, or superior longitudinal fasciculi, as reported previously by We explored the associations of objective measures of CRF and PA with measures of WM health in older low-fit and low-active adults. We showed that higher levels of MV-PA were linked to lower WMH volume. We propose that MV-PA allows keeping WMHs in check via cerebrovascular mechanisms, such as preserving higher blood vessel elasticity and wall integrity. We found an association between light PA and WM integrity in the temporal lobe while sedentary behavior was related to lower FA in the parahippocampal WM. We speculate that these associations are related to neurotrophic, cerebrovascular, lipid and insulin metabolic mechanisms related to PA or lack thereof. Together, our findings suggest that PA is associated with WM health in aging in an intensity- and region-specific manner. Our results are optimistic in showing that modifiable lifestyle factors such as increasing PA and reducing sedentariness may be beneficial for brain health. We are currently assessing in a randomized exercise intervention trial whether increases in CRF and changes in PA behavior may induce changes in WM health over shorter periods of time.We conclude that PA and CRF are related but not equivalent in their relationships with WM health in aging. Specifically, the effects are WM measure- and region-specific, showing the importance of using multiple, objective, and independent measures to assess fitness, physical activity and sedentariness, and brain integrity. Our findings pave the way for testing more targeted hypotheses linking bodily fitness and WM integrity in longitudinal designs, with improved public health recommendations on PA being the longer-term outcome of such studies.Data S1The file contains the raw demographic, PA, CRF, DTI, and WMH data of the 103 participants.(XLSX)Click here for additional data file.


We have previously demonstrated an association between increased sFRP3 expression and adverse outcome in a population of HF irrespective of cause and left ventricular ejection fraction. In this study we evaluated the prognostic value of sFRP3 in older patients with chronic systolic HF of ischemic origin.We evaluated sFRP3, by tertiles, as a risk factor for the primary endpoint , all-cause mortality, CV mortality, death from worsening HF (WHF), any coronary event, including sudden death, as well as hospitalizations for CV causes and WHF in 1444 patients from the CORONA population, randomly assigned to 10 mg rosuvastatin or placebo.st and 3rd tertile. In multivariable Cox-regression, after full adjustment including high-sensitive CRP and NT-proBNP, a lower event rate for the primary end point, all cause and CV mortality was observed for patients with tertile 2 sFRP3 levels , as well as for the number of coronary events  and sudden death . Applying sFRP3 values to the fully adjusted regression model resulted in highly significant continuous net reclassification improvements for the primary endpoint, all cause and CV mortality, coronary events and sudden death .Kaplan-Meier curves for the primary endpoint, as well as all-cause- and CV mortality revealed a markedly better survival for patients with sFRP3 levels in the middle tertile of compared to the 1Intermediate serum sFRP3 levels are associated with better survival and fewer CV events than low or high sFRP3 levels, independently of conventional risk factors, in older patients with chronic systolic HF of ischemic origin. Our study suggests that balanced Wnt activity might confer protective effects in a clinical HF setting.http://www.clinicaltrials.govNCT00206310 The wingless (Wnt) signaling pathway regulates a multitude of essential cellular processes during embryonic development  and wellSecreted Wnt modulators (e.g. sFRP3) are measurable in the systemic circulation and elevated serum and plasma levels have been associated with disease progression and response to therapy in both atherosclerosis and malignant disease ,17,18. IClinical trials identifier: NCT00206310. The trial complied with the Declaration of Helsinki and was approved by the Ethics Committees of the participating hospitals. All patients provided written informed consent. Ethics committee/institutional review board: Regional Etiksprövningskommitten I Göteborg, Sahlgrenska Akademin, Mediniargatan 3, Plan 5. Diary number: Ö284-03.The name of the ethics committees from any of the participating hospitals (378) can be provided on request. Name of study locations are added at the bottom. The design and principal findings of CORONA have been reported in detail . BrieflyThe primary predefined outcome was the composite of death from CV causes, non-fatal MI, and non-fatal stroke, analyzed as time to the first event. The secondary predefined outcomes were a) all-cause mortality, b) CV mortality (including cause-specific CV death), c) any coronary event , d) the number of hospitalizations for CV causes, and e) hospitalization for worsening HF (WHF). The definition and adjudication of all outcomes have been described in detail previously, as have data on C-reactive protein (CRP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) ,21–23.sFRP3 was measured from blood samples taken after an overnight fast. All other blood samples were non-fasting and analyzed on fresh samples at a central laboratory . NT-proBNP was analyzed using commercially available assay . An immunonephelometric high-sensitivity method was used to measure CRP . Serum sFRP3 was measured by enzyme immunoassay  as validated previously .For all baseline variables, differences between middle-tertile sFRP3 values and the combination of the highest- and lowest tertile were tested with Student’s t-test for normally distributed variables, Fisher’s exact test for categorical data, and Wilcoxon rank-sum test for non-normally distributed variables. Trends over sFRP3 tertiles were tested with the Cuzick extension of the Wilcoxon rank-sum test, and all baseline variables with a p-value for trend <0.05 were included in a multivariable analysis to identify degree of association with sFRP3. All survival analyses were conducted using the Cox proportional hazard regression model. A restricted cubic spline (RCS) analysis with three knots was undertaken on the outcome all-cause mortality to assess linearity of risk. The RCS analysis revealed a U-shaped curve with lower risk for patients in the middle tertile of sFRP3 concentration corresponding approximately to the pattern seen in Kaplan-Meier plots for all-cause and CV mortality. Therefore, in multivariate analyses, sFRP3 was included as a categorical (by tertiles) variable to a version of the three stage model described elsewhere , which iSerum concentrations of sFRP3 were measured at baseline in 1444 patients. Patient characteristics according to tertile values of sFRP3 are shown in During a median follow-up of 955 (inter-quartile range 817–1103) days, 421 patients died. Kaplan-Meier plots for the primary end point, as well as for all-cause and CV mortality revealed a markedly poorer outcome for patients in the highest and lowest tertile of sFRP3 concentration compared to the middle tertile . A restrWhen adjusting for demographic variables (step 1) in a three step multivariable analysis, sFRP3 was still associated with the primary endpoint, all-cause mortality, death due to CV cause, sudden death and coronary events . These aThese finding are in contrast to a recent study from our group demonstrating a linear increase in risk for outcome in 1202 HF patients with mixed etiology from the GISSI-HF-HF trial . When evSerum sFRP3 concentrations were similar at baseline and three month follow up (continuous variable) both in patients assigned to placebo (n = 717) or rosuvastatin (n = 727). An interaction of sFRP3 and treatment group was not observed for any endpoints.In this post-hoc analysis from CORONA we found serum concentrations of sFRP3 to be associated with fatal outcomes in a large population of elderly patients with chronic systolic HF of ischemic origin, with a significantly worse prognosis for patients in the first and third tertiles as opposed to those in the second tertile. Hazard ratios attributed to mid-tertile sFRP3 values remained significant and stable for the primary endpoint, all-cause- and CV mortality, sudden death and coronary events also after adjusting for established risk factors, including NT-proBNP and CRP, in a step-wise fashion. These data suggest a biphasic association between sFRP3 and outcome in the CORONA population with high and low levels associated with a poorer prognosis.vs. 69 mL/min/1.73m2). The CORONA population consisted of older patients (71.8±6.9 vs. 66.3±10.8 years in GISSI-HF-HF) with HF of ischemic etiology, whereas the GISSI-HF-HF patients had HF of both ischemic and non-ischemic etiology. Indeed, when evaluating mortality in the GISSI-HF-HF trial stratified by etiology and age we found that in contrast to patients with ischemic HF <70 years who demonstrated a more linear association between sFRP3 and outcome, this association was not present in older patients (i.e. >70 years) with ischemic HF. Furthermore, although caution is needed when comparing circulating sFRP3 from different populations analyzed on separate occasions, sFRP3 levels were approximately 50% higher in GISSI-HF-HF compared to CORONA. Thus, the first tertile of GISSI-HF and the second tertile in CORONA had comparable levels and were associated with the best outcome, while tertile 3 in CORONA and tertile 2 and 3 in GISSI-HF represent a further increase in adverse events. Indeed, applying the tertile limits derived from the GISSI-HF population [We have previously shown elevated sFRP3 levels in the GISSI-HF-HF population of both ischemic and non-ischemic etiologies , with unpulation  on the CThe non-linear associations between sFRP3 levels and outcomes in this study might also be explained by inherent properties of Wnt signaling and the sFRP family of Wnt-modulators. A recent report from our group has indicated that secretion of sFRP3 might be a compensatory mechanism whereby the myocardium seeks to limit increased LV wall stress . Thus, lIn the current study sFRP3 remained strongly associated with outcomes even after extensive multivariable adjustment, including NT-proBNP, with stable HRs and relatively high Wald scores. Adding sFRP3 to fully adjusted multivariable models produced highly significant NRIs for all fatal outcomes, except for death from WHF, as well as for the coronary endpoint. Although analyses of sFRP3 in the current cohort suggests a significant association with adverse prognosis, the use of the mid-tertile as a biomarker is, at least at present, not suitable for clinical use. Nonetheless, our findings indicate involvement of soluble Wnt modulators in the progression of clinical HF, with a potential complex interaction within the different members of the Wnt family. It is conceivable that a greater understanding of Wnt signaling in HF might provide us with new tools in the therapeutic armamentarium as both over-expression and exogenous administration of sFRPs reduces morbidity and mortality in murine MI models ,14.The present study examined multiple end points in a large HF population with a considerable number of events. However, for some subgroup analyses, including analyses of the endpoint Death from WHF and the interaction of sFRP3 with rosuvastatin, there were relatively few events and, therefore, these data should be interpreted cautiously. Our study was performed in trial patients of ≥60 years of age, with LV systolic dysfunction and ischemic heart disease. Thus, the results may not apply to all patients with HF. There are a number of other sFRP’s and other Wnt antagonists that future studies should evaluate as predictors of adverse outcome in HF patients. The relatively poor association with established CV determinants, and current medications in our study, may imply that Wnt signaling is relatively unaffected by state of the art treatment regimens. Thus, the Wnt signaling pathway might represent an untapped therapeutic potential for HF modulation.In conclusion, mid-tertile serum concentrations of sFRP3 were associated with reduced fatality in a large population of elderly patients with chronic systolic HF of ischemic origin. Hazard ratios attributed to mid-tertile sFRP3 values remained significant and stable also when accounting for established risk factors, including NT-proBNP and CRP. Although the use of sFRP3 as a biomarker in clinical practice is premature, our findings support the involvement of Wnt signaling in HF progression and suggest that this novel pathway might represent an as yet unmodified mechanism in HF development.


To compare one-year all-cause and uterine fibroid (UF)-related direct costs in patients treated with one of the following three uterine-sparing procedures: magnetic resonance-guided focused ultrasound (MRgFUS), uterine artery embolization (UAE) and myomectomy.MarketScan Database for the period 2003–2010. UF patients aged 25–54 on their first UF procedure (index) date with 366-day baseline experience, 366-day follow-up period, continuous health plan enrollment during baseline and follow-up, and absence of any baseline UF procedures were included in the final sample. Cost outcomes were measured by allowed charges (sum of insurer-paid and patient-paid amounts). UF-related cost was defined as difference in mean cost between study cohorts and propensity-score-matched control cohorts without UF. Multivariate adjustment of cost outcomes was conducted using generalized linear models.This retrospective observational cohort study used healthcare claims for several million individuals with healthcare coverage from employers in the P < 0.001). Adjusted all-cause mean cost was lowest for MRgFUS  followed by myomectomy  and UAE  but without statistical significance. Adjusted UF-related costs were also not significantly different between the three procedures.The study sample comprised 14,426 patients  with a higher percent of older patients in MRgFUS cohort (71% vs. 50% vs. 12% in age-group 45–54, Adjusted all-cause and UF-related costs at one year were not significantly different between patients undergoing MRgFUS, myomectomy and UAE. Uterine fibroids (UF) are benign clonal tumors affecting more than one-fifth of all women of reproductive age in the U.S ,2. AlthoUF-related morbidity has significant economic implications with direct costs ranging from $5,395 to $9,610 (in adjusted 2010 U.S. Dollars) . In addiAmong the available alternatives to hysterectomy for UF are endoscopic and abdominal myomectomy, uterine artery embolization (UAE) and magnetic resonance-guided focused ultrasound (MRgFUS). Several studies have assessed the clinical and patient-related outcomes between these three procedures -14. HoweMarketScan Commercial Claims and Encounters database, providing enrollment data and paid medical claims for patients insured primarily through large self-insured employers. MarketScan database contains inpatient and outpatient healthcare utilization, and outpatient prescription drug experience of several million employees and their dependents , covered under a variety of fee-for-service and capitated health plans, including exclusive provider organizations, preferred provider organizations (PPOs), point of service (POS) plans, indemnity plans, and health maintenance organizations (HMOs). MarketScan database also provides detailed cost and outcomes data associated with healthcare service and drug utilization described above. This is facilitated by linking medical claims for each patient to person-level enrollment data and to outpatient prescription drug claims through the use of unique enrollee identifiers.The study was a retrospective cohort analysis of healthcare costs using claims from index date) between 2003 and 2010 were used in the study. Since MRgFUS was approved by FDA in 2004 and UAE and myomectomy were approved much earlier than that, we considered all patients who had a UF procedure between 2004 and 2009. Since we required each patient to have 1-year baseline and 1-year follow-up, the possible date range for included claims was 2003 through 2010. Similar to Carls et al [pre-operative (14 days prior to the index date), peri-operative (from the index date until discharge) and post-operative (from the discharge date until 1 year after the start of the pre-operative period). The three study cohorts were defined based on the index UF procedure: MRgFUS, UAE and myomectomy , geographic region of residence of the primary enrollee (e.g. employee), whether the patient was the primary enrollee or the spouse or other dependent, year of the index date, and type of health plan. Baseline health status was measured using the Charlson Comorbidity Index (CCI) , a countThe primary study outcome was all-cause direct healthcare cost in 2010 U.S. dollars (inflation adjusted using the GDP Implicit Price Deflator), which included both insurer-paid amounts and patient-paid amounts (including copayments and deductibles) for all the claims generated through the 1-year follow-up period as has been done in previous studies . All-cauAnother outcome assessed was UF-related direct cost defined as the difference in mean costs between a study cohort and its control cohort that included similar patients from MarketScan database but without a UF diagnosis. At a minimum, patients in the control cohorts must satisfy following criteria: at least 12 months enrollment before and after the index date (randomly assigned date to match the distribution of index dates among patients with UF), be of age 25–54 on their index date, and did not have any UF diagnoses in their claims history. One-to-one propensity score matching ,22 was uDescriptive statistics for baseline characteristics, including mean and standard deviation (SD) for continuous covariates, and frequency and percent for categorical variables, are provided for each of the three study cohorts.Selection of women into each treatment cohort is likely to be the main source of bias. MRgFUS is not accessible to many patients since this treatment is considered investigational by most U.S. insurers. We address potential selection bias in two ways. First, we describe the characteristics of women in each sample, including comorbidities and cost prior to surgery, since comorbidities may influence treatment choices. Second, we adjust costs to control for observed differences between patients in each treatment group through multivariate regression.Costs were regression-adjusted to control for baseline characteristics of women in each treatment group. This was implemented using generalized linear modeling (GLM) framework with a gamma distribution and logarithmic link ,24. SepaMayo Clinic Institutional Review Board considered this study as exempt from full review given that study used already existing deidentified data. The analytic dataset was created using SAS (version 9.2), while the analyses were conducted in Stata (version 11).MarketScan database met all our criteria for length of enrollment, we provided a flowchart in Figure For the primary analysis, 14,426 patients with uterine-sparing procedures  met study criteria. For the secondary analysis of fibroid-related costs, a matched group of 14,482 patients without UF were selected . Given that only 14 of the 48 MRgFUS patients found in the Table The three cohorts were different with regard to the their ZIP code-level income distribution, with a higher percentage of women in the MRgFUS cohort (79%) coming from areas with income greater than $39,204 compared to 67% and 65% of the patients in the UAE and myomectomy cohorts, respectively. The distribution of proportion of black residents in ZIP code-level regions from which the study patients came from differed between the three study cohorts, as did the surgical setting (outpatient versus inpatient) for the patients in the three cohorts.Baseline health status, as captured by whether CCI > 0, differed significantly between cohorts . However, other data appeared to suggest that women in the MRgFUS cohort may have more active or severe UF disease. For example, the three study cohorts were different with respect to their baseline NSAID use , hormone therapy use , baseline inpatient (IP) visits , and baseline emergency room (ER) use . Compared to women in UAE and myomectomy cohorts, women undergoing MRgFUS were also more likely to have menstrual disorders and pelvic pain but less anemia . Table Table Costs increased from baseline to the operative year the least for the MRgFUS group , compared to the other treatments  although this was not a statistically significant difference.Regression adjustment did not significantly alter the conclusions from the unadjusted analyses described above. Average adjusted operative year all-cause costs for MRgFUS, UAE and myomectomy were $19,763, $25,019 and $20,407, respectively and were not statistically different. Peri-operative costs were significantly lower for MRgFUS  compared to UAE  cohort; adjusted peri-operative cost for MRgFUS cohort was also lower than that for myomectomy , but without statistical significance. The post-operative average cost was higher for MRgFUS  than UAE  and myomectomy , although this difference was not statistically significant.Table We found that one-year all-cause costs for MRgFUS , myomectomy  and UAE  were not statistically different. Concerns have been raised about the costs of an image-guided procedure such as MRgFUS due to the costs of advanced imaging. Based on the data from this study, this concern does not appear to be justified.This study significantly extends the literature on the comparability of MRgFUS costs compared to other fibroid treatments. The prior U.S. study that assessed cost-effectiveness of MRgFUS compared to other treatment options utilized expert opinions and clinical trial data yet found MRgFUS second only to hysterectomy in terms of cost-effectiveness . AnotherThe significantly higher post-operative costs for MRgFUS seen in this study was initially puzzling given that MRgFUS is an outpatient procedure. Increased costs for both outpatient office visits and inpatient costs contribute to these higher MRgFUS costs. Given that MRgFUS is a relatively novel procedure, especially during the years of this study, it is possible that patients in this cohort were seen more frequently by their providers to monitor UF symptom relief. In addition, the small number of patients in the MRgFUS cohort magnifies the effect of two subjects going on to additional UF treatment on post-operative inpatient costs. Thus, the post-operative costs for MRgFUS cohort appear to be strongly skewed only by 2 of the MRgFUS patients, thereby rendering these costs less representative.In addition to comparative cost estimates, the three study cohorts also exhibited some other notable trends. For example, a higher proportion of older women appeared to have opted for MRgFUS than the other two alternatives. More specifically, 71% of the patients aged between 45 and 54 opted for MRgFUS as opposed to 50% and 12% for UAE and myomectomy in this age group ; Abbott, GlaxoSmithKline, Gynesonics, Bayer Health Care – Consulting. Other authors do not report any conflict of interests.BB conceived of the study, contributed to study design, statistical analysis, interpretation of data, and drafted the manuscript. GC contributed in study design, data acquisition and interpretation of data. BM contributed to study design, data acquisition and interpretation of data. TG contributed to study design, data acquisition and interpretation of data. JM contributed to statistical analysis and interpretation of data. ES contributed to study design and interpretation of data. All authors read and approved the final manuscript.


Anticipating and controlling drug-drug interactions (DDIs) in older patients with painful diabetic peripheral neuropaty (pDPN) presents a significant challenge to providers. The purpose of this study was to examine the impact of newly initiated pregabalin or duloxetine treatment on Medicare Advantage Prescription Drug (MAPD) plan pDPN patients’ encounters with potential drug-drug interactions, the healthcare cost and utilization consequences of those interactions, and opioid utilization.Study subjects required a pregabalin or duloxetine pharmacy claim between 07/01/2008-06/30/2012 (index event), ≥1 inpatient or ≥2 outpatient medical claims with pDPN diagnosis between 01/01/2008-12/31/2012, and ≥12 months pre- and ≥6 post-index enrollment. Propensity score matching was used to balance the pregabalin and duloxetine cohorts on pre-index demographics and comorbidities. Potential DDIs were defined by Micromedex 2.0 and identified by prescription claims. Six-month post-index healthcare utilization (HCU) and costs were calculated using pharmacy and medical claims.No significant differences in pre-index demographics or comorbidities were found between pregabalin subjects (n = 446) and duloxetine subjects (n = 446). Potential DDI prevalence was significantly greater (p < 0.0001) among duoxetine subjects (56.7%) than among pregabalin subjects (2.9%). There were no significant differences in HCU or costs between pregablin subjects with and without a potential DDI. By contrast, duloxetine subjects with a potential DDI had higher mean all-cause costs , more subjects with ≥1 inpatient visits , and more subjects with ≥1 emergency room visits  in comparison to duloxetine subjects without a potential DDI. There was a trend toward a difference between pregabalin and duloxetine subjects in their respective pre-versus-post differences in milligrams (mg) of morphine equivalents/30 days used .The significantly higher prevalence of potential DDIs and potential cost impact found in pDPN duloxetine users, relative to pregabalin users, underscore the importance of considering DDIs when selecting a treatment. Challenging to patients, as well as providers, diabetes has the potential to cause a specific group of nerve disorders categorized as autonomic, peripheral proximal, focal, and peripheral neuropathies ,2. A comWhile the advancement of pDPN has been shown to be decreased through glycemic control , a varieAs the occurrence of pDPN increases with the degree of hyperglycemia and age of the patient, the total number of prescriptions a patient may be taking has the potential to rise dramatically due to the need to manage the effects of advancing diabetes and comorbidities related to the disease. As such, anticipating and controlling DDIs in patients with pDPN presents a significant challenge to providers, particularly in an older population. The consequences of these drug interactions have the potential to impact the quality of life of the patient, as well as increase the cost of the disease ,34.While some studies have examined aspects of treatment outcomes such as healthcare utilization and economic comparisons between pregabalin and duloxetine (where the costs were found to be comparable between the two drugs), few studies have documented the costs incurred from DDIs related to treatment of patients with pDPN ,34-36. RThe present study continues and builds on previous research by examining the impact of newly initiated pregabalin or duloxetine treatment on Medicare Advantage Prescription Drug plan (MAPD) pDPN members’ encounters with potential drug-drug interactions, the healthcare cost and utilization consequences of those interactions, and opioid utilization.This study is a retrospective, matched cohort study using medical and pharmacy claims collected from a large MAPD health plan. Medical and pharmacy claims data were extracted for the period of time between January 1, 2007 and December 31, 2012, and these data were used to identify potential subjects, measure patient characteristics, and examine study outcomes. MAPD members diagnosed with DPN were identified as potential subjects for the analysis based on International Classification of Disease, 9th revision, Clinical Modification (ICD-9-CM) diagnosis data reported on medical claims.Members receiving pregabalin (Lyrica®) or duloxetine  between January 1, 2008 and June 30, 2012 were identified based on pharmacy claims, and the first observed prescription claim during this period was assigned as the study index date. Tapentadol was not included as a comparator as the study period did not allow for sufficient sample size to analyze members prescribed that agent. Identified members were further required to have 12 months of continuous pre-index enrollment during which no prescription claim for duloxetine or pregabalin was observed.In order to enhance the likelihood that the medication of interest was being used to treat pDPN, it was further required that a diagnosis of DPN be observed within 90 days of the index date. Subjects meeting any of the following criteria were excluded from the study: Age <18 or >89 years; continuous enrollment <6 months post-index; diagnosis of fibromyalgia (FM) at any time after the index date; diagnosis and/or procedure code indicative of transplant surgery, cancer, or pregnancy during study period; long-term care facility residence of ≥90 days during the study period; or, one or more prescription claims for the non-index comparator drug  12 months prior to or on the index date. The research protocol was reviewed and approved by Shulman Associates IRB, an independent Institutional Review Board, prior to study initiation. A waiver of informed consent and a waiver of authorization to use protected health information (PHI) were granted.The subject’s assignment to either the pregabalin cohort or the duloxetine cohort was determined by the medication filled on the subject’s index date. Age, gender, race/ethnicity, geographic region of residence, low income subsidy (LIS) status, and Medicare dual eligibility (DE) status were measured based on member enrollment data. The Deyo implementation of the Charlson comorbidity index score was calculated based on medical claims adjudicated (insurer payment determined) during the pre-index observation period ,38. In aPre-index and post-index medication utilization were measured based on pharmacy claims adjudicated during their respective observation periods. Pain-related medication use patterns were measured for the following medication classes: opioids, non-opioid analgesics, antidepressants, anticonvulsants, anesthetics, muscle relaxants, and anxiolytics. Individual subjects were identified as medication users if they had one or more prescription claims for the specific medication during the observation period. Opioid use was further examined and categorized as long-acting, short-acting low potency, and short-acting high potency . In addiMedications with high potential for drug-drug interactions (DDI) with duloxetine or pregabalin Table  were ideSubjects were flagged with a DDI if they met either of the following criteria: 1) a prescription claim for an interacting medication during the pre-index period and a corresponding days’ supply indicative of coverage that overlapped the index date; or, 2) an adjudicated prescription claim for an interacting medication filled within 30 days after the index date.All-cause medical service utilization and costs were measured using medical claims data. Medical claim place of service was used to assign inpatient, emergency room, and outpatient utilization and costs. Physical therapy (PT) utilization was identified using medical claims where the Current Procedural Terminology (CPT) code billed indicated a physical therapy service was performed. Total pharmacy costs were defined as the sum of costs (plan-paid and member-paid) associated with adjudicated pharmacy claims. Total all-cause healthcare costs were defined as the sum of the respective total medical cost and total pharmacy cost components. All cost calculations included both member and plan paid components, and were adjusted to 2012 United States (US) dollars based on the medical care component of the Consumer Price Index. Post-index opioid utilization was determined both categorically and as MEq per 30 days, as previously described for the pre-index period.Propensity score (PS) matching was utilized to address potential bias in this non-randomized, observational study ,41. In tDiagnostic evaluation was considered to examine balance in pre-index covariates (from the propensity score model) between matched treatment groups. In order to account for the non-normal data distribution, continuous pre-index measures were compared between-groups using non-parametric Wilcoxon rank-sum tests. Chi-square tests were used to compare categorical pre-index data. Wilcoxon rank-sum test and chi-square tests were also performed for post-index outcomes .Multivariable statistical models were applied to examine the relationship between DDI status and healthcare costs . SpecifiDifferences in all-cause total healthcare costs were compared between the cohorts  via Difference-in-Differences (DID) analyses, using the model-based LS Means estimates and corresponding standard errors:DID = mean of values in  minus mean of values in (DDI present minus DDI absent in the duloxetine cohort).T-tests were performed to formally test the DID values for statistical significance.Differences in pre-index and post-index opioid utilization and MEq were compared between pregabalin and duloxetine cohorts via DID analysis. The t-statistic for the opioid utilization DID analysis was derived from a GLMM with a logit link and binary distribution, controlling for baseline demographics, Deyo-Charlson comorbidity index, and pre- and post-index non-opioid pain medication utilization. The t-statistic for the MEq DID analysis was derived from a GLMM with an identity link and a Gaussian distribution, controlling for baseline demographics, Deyo-Charlson comorbidity index, and pre- and post-index non-opioid pain medication utilization. The MEq DID analysis covered opioid prescription claims from 6-months pre-index to 6-months post-index.a priori alpha level for all inferential analyses was set at 0.05; all statistical tests were two-tailed.All data analyses were conducted using SAS version 9.3/SAS Enterprise Guide 5.1. The A total of 1,320 subjects met the study inclusion and exclusion criteria . After conducting the propensity score matching procedure, the analytic cohort consisted of 446 matched pairs . The lack of statistically significant differences between the matched cohorts on baseline demographics , between pregabalin subjects with and without a potential DDI  or the duloxetine cohort   is likely driven by factors inherent to the medication itself and by the population in which it was studied. Duloxetine undergoes hepatic metabolism by cytochrome P-450 (CYP450) isoenzymes 2D6 and 1A2. Further, it inhibits isoenzymes 2D6 and 1A2 and is highly plasma protein bound resulting in many potential DDIs with other medications . AlternaA recent study by Johnston et al. found the frequency of potential contraindicated, major, and moderate DDIs in DPN patients newly initiated on duloxetine to be 3.9%, 36.9%, and 33.8%, respectively . ConversPrevious research reported no statistically significant differences in post-initiation all-cause healthcare costs for pDPN patients newly initiated on pregabalin or duloxetine ,36. The The non-significant findings of the within-pregabalin cohort comparisons and in the difference-in-difference analysis must be tempered by the small number of pregabalin subjects with a potential DDI (n = 13). The increase in costs associated with potential DDIs within the duloxetine cohort, however, cannot be overlooked. Prior studies of chronic pain conditions have found that CYP450 interactions between specific opioids  and concomitant medications that serve as substrates or inhibitors of CYP450 isoenzymes 3A4 and 2D6, including duloxetine, result in higher costs and greater healthcare utilization .A retrospective analysis of 170,086 patients using claims data from 2004 to 2008 found significantly higher mean total 6-month costs in chronic pain subjects with an exposure to a potential DDI compared to matched subjects without an exposure  . This saChanges in opioid utilization after initiation of pregabalin or duloxetine, regardless of potential DDI occurrence, were also assessed in the present study. No changes in pre- to post-initiation of long-acting opioid, short-acting opioid, strong opioid, weak opioid, or “any” opioid use were found for pregabalin or duloxetine, as defined by the percentage of patients with one or more pharmacy claims, in the lone head-to-head retrospective analysis of these drugs in a pDPN population . HoweverGiven that opioids within the same category, such as “long-acting,” vary in terms of potency, the present study expanded on the aforementioned research  by assesSeveral limitations must be noted for studies involving administrative claims data. Causal effect cannot be assigned given the observational nature of this study. The use of secondary data is limited by the threat of validity posed by inaccurate data within healthcare information technology systems as well as by differences in coding and documentation practices at the provider, region, or site-specific level. Actual patient behaviors regarding medication consumption cannot be assessed through paid pharmacy claims. Further, reliance on paid pharmacy claims for medication utilization does not capture the use of over-the-counter medications or remedies impactful to the disease state in question. Indirect costs were not considered as part of this study. A reduction in confounding was attempted through the use of propensity score matching and multivariate modeling. These approaches are limited by only the covariates included in the statistical models. Even with this attempt at bias reduction, residual confounding from included covariates can still occur and confounding from unknown or unmeasured covariates remains a possibility. The use of “potential” DDIs does not imply the actual occurrence of clinically-impactful DDIs, and therefore limits the interpretation and applicability of the findings. Lastly, given the focus on pDPN patients, the results of this study should not be considered generalizable to other FDA-approved indications or off-label uses.The results of this retrospective analysis suggest that the real-world prevalence of potential duloxetine DDIs in a MAPD pDPN population is substantially greater than that of potential pregabalin DDIs. While it is desirable to find infrequent DDIs, the low prevalence of potential pregabalin DDIs places limits on both the performance and sensitivity of within or between drug comparisons. From a clinical perspective, the importance of considering DDIs during treatment selection should be considered due to the significantly higher prevalence of potential DDIs found in pDPN duloxetine users.


Historically, emergency department (ED) patients with pulmonary embolism (PE) have been admitted for several days of inpatient care. Growing evidence suggests that selected ED patients with PE can be safely discharged home after a short length of stay. However, the optimal timing of follow up is unknown. We hypothesized that higher-risk patients with short length of stay (<24 hours from ED registration) would more commonly receive expedited follow up (≤3 days).This retrospective cohort study included adults treated for acute PE in six community EDs. We ascertained the PE Severity Index risk class , facility length of stay, the first follow-up clinician encounter, unscheduled return ED visits ≤3 days, 5-day PE-related readmissions, and 30-day all-cause mortality. Stratifying by risk class, we used multivariable analysis to examine age- and sex-adjusted associations between length of stay and expedited follow up.The mean age of our 175 patients was 63.2 (±16.8) years. Overall, 93.1% (n=163) of our cohort received follow up within one week of discharge. Fifty-six patients (32.0%) were sent home within 24 hours and 100 (57.1%) received expedited follow up, often by telephone (67/100). The short and longer length-of-stay groups were comparable in age and sex, but differed in rates of low-risk status  and expedited follow up . After adjustment, we found that short length of stay was independently associated with expedited follow up in higher-risk patients , but not in low-risk patients . Adverse outcomes were uncommon (<2%) and were not significantly different between the two length-of-stay groups.Higher-risk patients with acute PE and short length of stay more commonly received expedited follow up in our community setting than other groups of patients. These practice patterns are associated with low rates of 30-day adverse events. Historically, emergency department (ED) patients with acute pulmonary embolism (PE) in the United States have been admitted for at least several days of inpatient care.Growing evidence suggests that carefully selected low-risk patients with PE can be safely discharged home either directly from the ED or after a short hospital stay (<24 hours).Prospective studies of the outpatient management of PE vary widely in their timing and frequency of scheduled follow up. The reports range, on the one hand, from daily phone contact for seven consecutive days following dischargeWe hypothesized that higher-risk outpatients with acute PE being discharged home after a short hospital length of stay (<24 hours from ED registration) would more commonly receive expedited follow up (≤3 days) than their lower-risk or longer-stay counterparts. We undertook this study to describe the practice patterns of PE management in community hospitals and to evaluate the influence of length of stay, risk class, and site-of-discharge on the timing of post-discharge outpatient follow up and short-term outcomes.This retrospective cohort study included adult ED patients who were diagnosed with acute PE between January 1, 2013 and May 31, 2013 in six community EDs within Kaiser Permanente (KP) Northern California, a large integrated healthcare delivery system that provides comprehensive care for more than 3.4 million members. KP health plan members represent approximately 25–30% of the population in areas served and are similar to the general population with respect to race/ethnicity, socioeconomic status, and education.The EDs had an annual census in 2013 from 26,000 to 85,000 and were staffed by residency-trained, board-certified emergency physicians. The medical centers had inpatient bed capacities ranging from 50 to 325. Inpatient care is provided by board-certified internists, all of whom are hospitalists. Three medical centers were satellite sites for residency training programs and had residents rotate to various degrees through their emergency and hospitalist departments.During 2013, all facilities had 24/7 access to on-site computed tomography pulmonary angiography with around-the-clock interpretation by board-certified radiologists. Formal compression ultrasonography and ventilation perfusion imaging were not available during late night hours. Two facilities had a designated clinical decision area, functioning akin to a short-stay (<24 hours) observation unit, managed by hospitalists. Initial site-of-care decisions and total length of stay were in the hands of the treating physicians; no clinical care pathways for PE were in effect.All facilities provided pre-discharge patient education regarding the disease and its treatment and had pharmacy available around-the-clock for discharge medications and supplemental patient education. Treating physicians commonly employed the standard KP Northern California discharge orderset for thromboembolism, which recommends warfarin with concomitant bridging therapy using enoxaparin. Alternative oral anticoagulants approved for the treatment of PE were not often prescribed, as the formulary restricts their use to patients who have failed or are unable to adhere to warfarin. Outpatient warfarin dosing was managed by each facility’s pharmacy-led anticoagulation service. The percent time in therapeutic international normalized ratio range at these facilities in 2013 was a respectable 72% to 74% .19Throughout the study period no follow-up policy was in effect at any of the medical centers for patients with acute PE who were discharged home. The timing and nature (telephone vs clinic) of the follow-up appointment with the patient’s primary care provider was arranged at the discretion of the discharging clinician, who either directly provided the follow-up appointment or recommended the patient arrange it themselves within a certain time frame. These patient-driven access appointments were secured either via a 24/7 telephone appointment call center, an email directly to the patient’s primary provider, or by electronically booked appointment times available through the patient portal of kp.org.22Non-gravid ED patients aged 18 years or older were included if they had an acute PE that was objectively confirmed by radiographic imaging, performed either in the ED or within the 12 hours prior to ED arrival, and no recent diagnosis of acute venous thromboembolism in the prior 30 days. Objective diagnostic confirmation was based on the final interpretation by a board-certified radiologist . We also included patients with a compression ultrasound positive for deep vein thrombosis in conjunction with respiratory complaints consistent with acute PE, as other outpatient PE research studies have done.24Patients with the following conditions were excluded from further analysis because follow up within the integrated care system was not possible or customary: discharge to a skilled nursing facility, non-members, as they received follow-up care outside our delivery system, and those who died in the ED or during hospitalization.Investigators used a standard computerized data collection tool that combined extracted administrative data with manual chart review of the comprehensive integrated electronic health record.27An outpatient appointment qualified as a clinician follow up if the provider (physician or nurse practitioner) who evaluated the patient was a generalist or a specialist in pulmonary medicine or hematology/oncology. Timing was measured in days since discharge and included both in-person and telephone visits. We excluded Internet-based secure messages between patients and their providers.30Our primary outcome measure was an expedited post-discharge follow up ≤3 days of discharge. A three-day endpoint defined expedited follow up since it represents the conservative end of the range in the outpatient PE literature32Unscheduled return ED visits ≤3 days included ED visits for any reason that were not initially arranged at the index visit. Five-day readmissions were counted as PE-related if any of the following were noted: complaints of dyspnea, chest pain, syncope, leg pain, or bleeding; findings of pleural effusion, elevated liver enzymes, new anemia or hemorrhage, new or worsening deep vein thrombosis or PE; or one of the following interventions: respiratory support , parenteral vasopressors, inferior vena cava filter placement or removal, or cardiopulmonary resuscitation.Multiple processes were instituted to enhance the accuracy and reliability of the data abstraction process. All abstractors received training on the content and coding of each data element, data handling and data transmission procedures, as well as protocols to respond to questions or problems during the study. The principal investigator (DRV) monitored day-to-day data collection activities and answered coding questions. All complications were reviewed by two investigators for confirmation. Ambiguities in classification or diagnosis were arbitrated by a third investigator. Additionally, 15% of cases were randomly selected for independent review by a second investigator to assess for inter-rater reliability, reported as percent agreement, on the following variables: PE Severity Index score, risk class, site of discharge, expedited follow up, nature of the follow up, 3-day, 5-day, and 30-day outcomes.Continuous variables are presented as means with standard deviation and categorical data are presented as the percentage of frequency of occurrence, with 95% CIs. We performed bivariate analysis to compare patients with expedited follow up (≤3 days) and those with non-expedited follow up (>3 days). P-values are shown for t-test or chi-squared test. A two-tailed p-value of less than 0.05 indicated statistical significance. In analyses stratified by PE Severity Index risk status, adjusted odds ratios (aORs) were calculated using multivariate logistic regression to determine whether length of stay <24 hours was associated with expedited follow-up after adjusting for age and sex. Tested covariates included age, sex, discharge from the ED or clinical decision area, and length of stay <24 hours from ED registration. Pairwise correlation for covariates was tested with a threshold r-value of less than 0.7 for inclusion in the model. The variance inflation factor was also determined for all variables in the regression model with an upper threshold of 10 for inclusion. We performed analyses using STATA v13.1 .We identified 203 cases of PE, 28 of which were excluded because of hospital discharge to a skilled nursing facility (n=15), non-member status (n=8), and inpatient death (n=5). The mean age of the remaining 175 patients was 63.2 (±16.8) years, and 87 (49.7%) were female. Overall, 56 patients (32.0%) were discharged within 24 hours.The short and longer length-of-stay groups were comparable in age, sex, and rate of timely engagement with anticoagulation services, but differed significantly in their PE Severity Index risk classification and their site of discharge . OverallWe report the timing of initial post-discharge follow up stratified by risk class and length of stay in Given the interaction between length of stay and risk class, we stratified the cohort by PE Severity Index class (higher risk vs. low risk) for the multivariate analysis. The association we found in bivariate analysis held up after controlling for age and sex. We found that short length of stay was independently associated with expedited follow up in the higher-risk patients , but not the low-risk patients . Site of discharge  was collinear with short length of stay (r=0.8) and accordingly was not included in the regression models.Of the 43 patients sent home from the ED or clinical decision area after a short stay, 23 were discharged from the ED and 20 from the clinical decision area. The rates of expedited follow up between these two sites-of-discharge groups were not statistically significant: ED (21/23) and clinical decision area (15/20).Unscheduled return ED visits ≤3 days were uncommon , as were PE-related readmissions to the hospital ≤5 days , neither of which were significantly different between the short-stay and the longer-stay groups . Rates oThe two patients who died were both Class V on the PE Severity Index, and hence at higher risk for 30-day all-cause mortality.The inter-rater reliability results for the following eight variables ranged between 96% to 100% agreement: PE Severity Index score, risk class, site of discharge, expedited follow up, nature of follow up, 3-day, 5-day, and 30-day outcomes.This retrospective cohort study found that higher-risk patients with acute PE sent home within 24 hours of ED registration more commonly received expedited follow up within three days than low-risk patients and those of any risk category with longer lengths of stay. Given the relative novelty in the U.S. of home management of ED patients with acute PE, we suspected that physicians might feel the need to be more vigilant when sending higher risk patients home who had received only a short period of medical observation. Our results support this hypothesis.The optimal timing of follow-up appointments for patients with acute PE who are discharged home is unknown, though this transition of care can be critical to patient safety, especially in the elderly.The nature of the initial post-discharge follow up also varies: some see their patients in person and others contact them by phone.35Follow-up appointments, either in person or over the telephone, allow for continuing patient education, encouragement of treatment compliance, management of symptoms, and the answering of questions. It is difficult to unravel the contribution made by timely follow up to the favorable outcomes associated with outpatient management of select patients with acute PE. Studies of home management all include careful post-discharge follow up one or more times within the first week as well as frequent telephone contact with anticoagulation services.This study is subject to the limitations inherent in its retrospective design. Some of those shortcomings, however, are mitigated by our comprehensive electronic health record, our excellent capture of outcomes among KP health plan members, who seek care almost exclusively within the health plan, and the study’s high inter-rater reliability. Our limited sample size means the rates of adverse outcomes we measured are estimates with wide confidence intervals. The majority of our patients were discharged on warfarin and therefore also received close and careful monitoring by the pharmacy-led anticoagulation service. It is uncertain how clinic-based follow-up arrangements will change (or should change) for patients taking newer oral anticoagulants that don’t require efficacy monitoring.36Our results may not be readily generalizable, as they reflect the practices of physicians who work within an integrated healthcare delivery system, where prompt outpatient follow up can be reliably arranged2In sum, we found that outpatients with acute PE nearly always received post-discharge follow up within the first week and over half received expedited follow up within three days. Higher-risk patients who were sent home within 24 hours of ED registration were more likely to receive expedited follow up. For all patients, the rate of adverse outcomes at both five days and 30 days was very low, though our study was not adequately powered to ensure the safety of this management approach. Short length of stay combined with expedited post-discharge follow up, however, appears to be a safe practice for selected patients in this integrated healthcare system. The effects of expedited follow up on patient satisfaction and clinical outcomes warrant further investigation.