Effect of preoperative long-term opioid therapy on patient outcomes after total knee arthroplasty: an analysis of multicentre population-based administrative data.

Background: Up to 40% of patients are receiving opioids at the time of total knee arthroplasty (TKA) in the United States despite evidence suggesting opioids are ineffective for pain associated with arthritis and have substantial risks. Our primary objective was to determine whether preoperative opioid users had worse knee pain and physical function outcomes 12 months after TKA than patients who were opioid-naive preoperatively; our secondary objective was to determine the prevalence of opioid use before and after TKA in Alberta, Canada. Methods: In this retrospective analysis of population-based data, we identified adult patients who underwent TKA between 2013 and 2015 in Alberta. We used multivariable linear regression to examine the association between preoperative opioid use and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and physical function scores 12 months after TKA, adjusting for potentially confounding variables. Results: Of the 1907 patients, 592 (31.0%) had at least 1 opioid dispensed before TKA, and 124 (6.5%) were classified as long-term opioid users. Long-term opioid users had worse adjusted WOMAC pain and physical function scores 12 months after TKA than patients who were opioid-naive preoperatively (pain score ß = 7.7, 95% confidence interval [CI] 4.0 to 11.6; physical function score ß = 7.8, 95% CI 4.0 to 11.6; p < 0.001 for both). The majority (89 ([71.8%]) of patients who were long-term opioid users preoperatively were dispensed opioids 180-360 days after TKA, compared to 158 (12.0%) patients who were opioid-naive preoperatively. Conclusion: A substantial number of patients were dispensed opioids before and after TKA, and patients who received opioids preoperatively had worse adjusted pain and functional outcome scores 12 months after TKA than patients who were opioidnaive preoperatively. These results suggest that patients prescribed opioids preoperatively should be counselled judiciously regarding expected outcomes after TKA.

Contexte: Jusqu'à 40 % des patients se font prescrire des opioïdes lors d'une chirurgie pour prothèse totale du genou (PTG) aux États-Unis, et ce, malgré des données selon lesquelles les opioïdes sont inefficaces pour la douleur associée à l'arthrite et comportent des risques substantiels. Notre objectif principal était de déterminer si les patients qui utilisaient déjà des opioïdes en période préopératoire obtenaient des résultats plus négatifs aux plans de la douleur et du fonctionnement 12 mois après leur PTG, comparativement aux patients qui ne prenaient pas d'opioïdes avant leur intervention; notre objectif secondaire était de mesurer la prévalence du recours aux opioïdes avant et après la PTG en Alberta, au Canada. Méthodes: Dans cette analyse rétrospective menée sur des données de population, nous avons identifié les patients adultes soumis à une PTG entre 2013 et 2015 en Alberta. Nous avons utilisé un modèle de régression linéaire multivarié pour examiner le lien entre l'utilisation d'opioïdes en période préopératoire et les scores de douleur et de fonctionnement à l'échelle WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) 12 mois après la PTG, en tenant compte de potentielles variables de confusion. Résultats: Sur les 1907 patients, 592 (31,0 %) ont reçu au moins 1 opioïde avant leur PTG, et 124 (6,5 %) en étaient considérés des utilisateurs de longue date. Les utilisateurs d'opioïdes de longue date présentaient de moins bons scores WOMAC ajustés pour les domaines de douleur et de fonctionnement 12 mois après la PTG, comparativement aux patients qui n'en prenaient pas avant l'intervention (score de douleur ß = 7,7, intervalle de confiance [IC] de 95 % 4,0 à 11,6; score de fonctionnement ß = 7,8, IC de 95 % 4,0 à 11,6; p < 0,001 pour les 2 domaines). La majorité (89 [71,8 %]) des patients utilisateurs d'opioïdes de longue date avant l'intervention se sont fait servir des opioïdes 180­360 jours après la PTG, comparativement à 158 patients (12,0 %) qui n'en prenaient pas avant l'intervention. Conclusion: Un nombre substantiel de patients ont reçu des opioïdes avant et après la PTG, et ceux qui en prenaient avant l'intervention présentaient des scores de douleur et de fonctionnement ajustés plus défavorables 12 mois après la PTG, comparativement aux patients qui n'en prenaient pas avant l'intervention. Selon ces résultats, il faut adresser des conseils judicieux aux patients qui sont déjà sous opioïdes en période préopératoire et les informer des résultats possibles de la PTG.

Effect of Cognitive Reserve on Risk of Cognitive Impairment and Recovery After Stroke: The KOSCO Study.

Background and Purpose- The theory of cognitive reserve (CR) was introduced to account for individual differences in the clinical manifestation of neuropathology. This study investigated whether CR has a modulating effect on cognitive impairment and recovery after stroke. Methods- This study is an interim analysis of the Korean Stroke Cohort for Functioning and Rehabilitation. A total of 7459 patients with first-ever stroke were included for analysis. Education, occupation, and composite CR scores derived from those 2 variables were used as CR proxies. Scores from the Korean version of the Mini-Mental State Examination analyzed for 30 months after stroke onset were analyzed. Results- Lower CR increased the risk of cognitive impairment after stroke. The odds ratio was 1.89 (95% CI, 1.64-2.19) in patients with secondary education and 2.42 (95% CI, 2.03-2.90) in patients with primary education compared with patients with higher education. The odds ratio was 1.48 (95% CI, 1.23-1.98) in patients with a skilled manual occupation and 2.01 (95% CI, 1.42-2.83) in patients with a nonskilled manual occupation compared with patients with a managerial or professional occupation. In the multilevel model analysis, the Korean version of the Mini-Mental State Examination total score increased during the first 3 months (1.93 points per month) and then plateaued (0.02 point per month). The slopes were moderated by the level of education, occupation, and composite CR score: the higher the level of education, occupation, or CR score, the faster the recovery. In the older adult group, the Korean version of the Mini-Mental State Examination scores showed a long-term decline that was moderated by education level. Conclusions- Education and occupation can buffer an individual against cognitive impairment caused by stroke and promote rapid cognitive recovery early after stroke. In addition, higher education minimizes long-term cognitive decline after stroke, especially in older patients. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT03402451.

UBC12-mediated SREBP-1 neddylation worsens metastatic tumor prognosis.

Activation of sterol regulatory element-binding protein 1 (SREBP-1), a master lipogenic transcription factor, is associated with cancer metabolism and metabolic disorders. Neddylation, the process of adding NEDD8 to its substrate, contributes to diverse biological processes. Here, we identified SREBP-1 as a substrate for neddylation by UBC12 and explored its impact on tumor aggressiveness. In cell-based assays, SREBP-1 neddylation prolonged SREBP-1 stability with a decrease in ubiquitination. Consequently, NEDD8 overexpression facilitated proliferation, migration, and invasion of SK-Hep1 liver tumor cells. MLN4924 (an inhibitor of the NEDD8-activating enzyme-E1) treatment or UBC12 knockdown prevented SREBP-1 neddylation and tumor cell phenotype change. This effect was corroborated in an in vivo xenograft model. In human specimens, SREBP-1, UBC12, and NEDD8 were all upregulated in hepatocellular carcinoma (HCC) compared to nontumorous regions. Moreover, SREBP-1 levels positively correlated with UBC12. In GEO database analyses, SREBP-1 levels were greater in metastatic HCC samples accompanying UBC12 upregulation. In HCC analysis, tumoral SREBP-1 and UBC12 levels discriminated overall patient survival rates. Additionally, MLN4924 treatment destabilized SREBP-1 in MDA-MB-231 breast cancer cells and in the tumor cell xenograft. SREBP-1 and UBC12 were also highly expressed in human breast cancer tissues. Moreover, most breast cancers with lymph node metastasis displayed predominant SREBP-1 and UBC12 expressions, which compromised overall patient survival rates. In summary, SREBP-1 is neddylated by UBC12, which may contribute to HCC and breast cancer aggressiveness through SREBP-1 stabilization, and these events can be intervented by MLN4924 therapy. Our findings may also provide potential reliable prognostic markers for tumor metastasis.

Low-intensity pulsed ultrasound enhances callus consolidation in distraction osteogenesis of the tibia by the technique of lengthening over the nail procedure.

BACKGROUND: Low-intensity pulsed ultrasound (LIPUS) has been widely accepted in promoting the fracture healing process. However, there have been limited clinical trials focused on the efficacy of LIPUS during distraction osteogenesis (DO) by the technique of lengthening over the nail procedure. The purpose of the current study was to evaluate the efficacy of LIPUS during DO. METHODS: We retrospectively evaluated 30 patients (60 segments) who underwent simultaneous bilateral tibial lengthening over the nail. The patients were grouped into the LIPUS group and the control group based on LIPUS stimulation. The two patient groups were compared for demographic data (sex, age at operation, preoperative height, BMI, and smoking history), qualitative assessments of the callus (callus shape and type), external fixation index, and four cortical healing indexes. RESULTS: Fifteen patients (30 segments) were classified as the LIPUS group, and another 15 patients (30 segments) were classified as the control group. No significant differences were found in the assessed demographic data between the groups. LIPUS stimulated a more cylindrical, more homogenous, and denser type of callus formation at the end of the distraction phase. The two groups exhibited equivalent outcomes in terms of external fixation index (p = 0.579). However, significant differences were found in healing indexes of the anterior and medial cortices (p <  0.001 and p = 0.002, respectively). The healing indexes of those cortices in the LIPUS group (mean of 36.6 days/cm and 32.5 days/cm, respectively) reflected their significantly faster healing compared to the control group (mean HI of 57.5 days/cm and 44.2 days/cm, respectively). There were no LIPUS-related complications. CONCLUSIONS: LIPUS is a noninvasive and effective adjuvant therapy to enhance callus maturation during DO. It enhances callus consolidation and may have a positive effect on the appropriate callus shape and type.

Preoperative opioid use is associated with worse patient outcomes after Total joint arthroplasty: a systematic review and meta-analysis.

BACKGROUND: A significant number of patients use opioids prior to total joint arthroplasty (TJA) in North America and there is growing concern that preoperative opioid use negatively impacts postoperative patient outcomes after surgery. This systematic review and meta-analysis evaluated the current evidence investigating the influence of preoperative opioid use on postoperative patient-reported outcomes (PRO) after total joint arthroplasty. METHODS: A systematic search was performed using Ovid, Embase, Cochrane Library, Scopus, Web of Science Core Collection, CINAHL on February 15th, 2018. Studies reporting baseline and postoperative PRO among those prescribed preoperative opioids and those who were not prior to total knee and hip arthroplasty were included. Standardized mean differences (SMD) in absolute difference and relative change in PRO measures between the two groups was calculated using random effect models. RESULTS: Six studies were included (n = 7356 patients); overall 24% of patients were prescribed preoperative opioids. Patients with preoperative opioid use had worse absolute postoperative PRO scores when compared to those with no preoperative opioid use (standardized mean difference (SMD) -0.53, 95% Confidence interval (CI) -0.75, - 0.32, p < 0.0001). When relative change in PRO score was analyzed, as measured by difference between postoperative and preoperative PRO scores, there was no group differences (SMD -0.26, 95% CI -0.56, 0.05, p = 0.10). CONCLUSION: Patients prescribed preoperative opioids may attain worse overall pain and function benefits after TJA when compared to opioid-naïve patients, but do still benefit from undergoing TJA. These results suggest preoperative opioid users should be judiciously counselled regarding potential postoperative pain and function improvements after TJA.

Spontaneous Regression of Glioma-Mimicking Brainstem Lesion in a Child: A Case Report.

Differential diagnosis of focal brainstem lesions detected on MRI is challenging, especially in young children. Formerly, brainstem gliomas were classified mainly based on MRI features and location. However, since 2016, the World Health Organization's brainstem lesion classification requires tissue biopsy to reveal molecular characteristics. Although modern techniques of stereotactic or navigation-guided biopsy ensure accurate biopsy of the lesion with safety, biopsy of brainstem lesions is still generally not performed. Here, we report a focal brainstem lesion mimicking brainstem glioma in a 9-year-old girl. Initial MRI, MR spectroscopy, and 11C-methionine positron emission tomography (PET) features suggested low-grade glioma or diffuse intrinsic pontine glioma. However, repeated MR spectroscopy, perfusion MRI, and 18fluorodeoxyglucose PET findings suggested that it was more likely a non-tumorous lesion. As the patient presented not with a neurological manifestation but with precocious puberty, the attending oncologist chose to observe with regular follow-up MRI. The pontine lesion with high signal intensity on T2-weighted MRI regressed from the 6-month follow-up and became invisible on the 1.5-year follow-up MRI. We reviewed brainstem glioma-mimicking lesions in the literature and discussed the key points of differential diagnosis.

Quantitative proteomic analysis of induced pluripotent stem cells derived from a human Huntington's disease patient.

HD (Huntington's disease) is a devastating neurodegenerative genetic disorder caused by abnormal expansion of CAG repeats in the HTT (huntingtin) gene. We have recently established two iPSC (induced pluripotent stem cell) lines derived from a HD patient carrying 72 CAG repeats (HD-iPSC). In order to understand the proteomic profiles of HD-iPSCs, we have performed comparative proteomic analysis among normal hESCs (human embryonic stem cells; H9), iPSCs (551-8) and HD-iPSCs at undifferentiated stages, and identified 26 up- and down-regulated proteins. Interestingly, these differentially expressed proteins are known to be involved in different biological processes, such as oxidative stress, programmed cell death and cellular oxygen-associated proteins. Among them, we found that oxidative stress-related proteins, such as SOD1 (superoxide dismutase 1) and Prx (peroxiredoxin) families are particularly affected in HD-iPSCs, implying that HD-iPSCs are highly susceptible to oxidative stress. We also found that BTF3 (basic transcription factor 3) is up-regulated in HD-iPSCs, which leads to the induction of ATM (ataxia telangiectasia mutated), followed by activation of the p53-mediated apoptotic pathway. In addition, we observed that the expression of cytoskeleton-associated proteins was significantly reduced in HD-iPSCs, implying that neuronal differentiation was also affected. Taken together, these results demonstrate that HD-iPSCs can provide a unique cellular disease model system to understand the pathogenesis and neurodegeneration mechanisms in HD, and the identified proteins from the present study may serve as potential targets for developing future HD therapeutics.

The influence of organizational context on the use of research by nurses in Canadian pediatric hospitals.

BACKGROUND: Organizational context is recognized as an important influence on the successful implementation of research by healthcare professionals. However, there is relatively little empirical evidence to support this widely held view. METHODS: The objective of this study was to identify dimensions of organizational context and individual (nurse) characteristics that influence pediatric nurses' self-reported use of research. Data on research use, individual, and contextual variables were collected from registered nurses (N = 735) working on 32 medical, surgical and critical care units in eight Canadian pediatric hospitals using an online survey. We used Generalized Estimating Equation modeling to account for the correlated structure of the data and to identify which contextual dimensions and individual characteristics predict two kinds of self-reported research use: instrumental (direct) and conceptual (indirect). RESULTS: Significant predictors of instrumental research use included: at the individual level; belief suspension-implement, research use in the past, and at the hospital unit (context) level; culture, and the proportion on nurses possessing a baccalaureate degree or higher. Significant predictors of conceptual research use included: at the individual nurse level; belief suspension-implement, problem solving ability, use of research in the past, and at the hospital unit (context) level; leadership, culture, evaluation, formal interactions, informal interactions, organizational slack-space, and unit specialty. CONCLUSIONS: Hospitals, by focusing attention on modifiable elements of unit context may positively influence nurses' reported use of research. This influence of context may extend to the adoption of best practices in general and other innovative or quality interventions.

Assessment of variation in the Alberta Context Tool: the contribution of unit level contextual factors and specialty in Canadian pediatric acute care settings.

BACKGROUND: There are few validated measures of organizational context and none that we located are parsimonious and address modifiable characteristics of context. The Alberta Context Tool (ACT) was developed to meet this need. The instrument assesses 8 dimensions of context, which comprise 10 concepts. The purpose of this paper is to report evidence to further the validity argument for ACT. The specific objectives of this paper are to: (1) examine the extent to which the 10 ACT concepts discriminate between patient care units and (2) identify variables that significantly contribute to between-unit variation for each of the 10 concepts. METHODS: 859 professional nurses (844 valid responses) working in medical, surgical and critical care units of 8 Canadian pediatric hospitals completed the ACT. A random intercept, fixed effects hierarchical linear modeling (HLM) strategy was used to quantify and explain variance in the 10 ACT concepts to establish the ACT's ability to discriminate between units. We ran 40 models (a series of 4 models for each of the 10 concepts) in which we systematically assessed the unique contribution (i.e., error variance reduction) of different variables to between-unit variation. First, we constructed a null model in which we quantified the variance overall, in each of the concepts. Then we controlled for the contribution of individual level variables (Model 1). In Model 2, we assessed the contribution of practice specialty (medical, surgical, critical care) to variation since it was central to construction of the sampling frame for the study. Finally, we assessed the contribution of additional unit level variables (Model 3). RESULTS: The null model (unadjusted baseline HLM model) established that there was significant variation between units in each of the 10 ACT concepts (i.e., discrimination between units). When we controlled for individual characteristics, significant variation in the 10 concepts remained. Assessment of the contribution of specialty to between-unit variation enabled us to explain more variance (1.19% to 16.73%) in 6 of the 10 ACT concepts. Finally, when we assessed the unique contribution of the unit level variables available to us, we were able to explain additional variance (15.91% to 73.25%) in 7 of the 10 ACT concepts. CONCLUSION: The findings reported here represent the third published argument for validity of the ACT and adds to the evidence supporting its use to discriminate patient care units by all 10 contextual factors. We found evidence of relationships between a variety of individual and unit-level variables that explained much of this between-unit variation for each of the 10 ACT concepts. Future research will include examination of the relationships between the ACT's contextual factors and research utilization by nurses and ultimately the relationships between context, research utilization, and outcomes for patients.

Move It or Lose It? The Effect of Early Active Movement on Clinical Outcomes Following Rotator Cuff Repair: A Systematic Review With Meta-analysis.

OBJECTIVE: To assess the effect of early active shoulder movement after rotator cuff repair, compared to delayed active shoulder movement, on clinical outcomes, rotator cuff integrity, and return to work. STUDY DESIGN: Intervention systematic review. LITERATURE SEARCH: We searched 14 databases in November 2017 and updated the search in December 2018 and February 2020. STUDY SELECTION CRITERIA: We included comparative studies that assessed the effect of early active shoulder movement versus delayed active shoulder movement following rotator cuff repair. DATA SYNTHESIS: Means and SDs were used to calculate weighted mean differences and 95% confidence intervals for outcomes of interest. The sensitivity analysis included only randomized controlled trials and was performed when heterogeneity among studies was statistically significant. RESULTS: Eight studies with a total of 756 participants (early active shoulder movement, n = 379; delayed active shoulder movement, n = 377) were included. There was high-certainty evidence favoring early active movement for forward flexion (6 weeks), abduction (6 weeks), and external rotation (6 weeks and 3 and 6 months) postsurgery. There was moderate-certainty evidence of worse Western Ontario Rotator Cuff Index score (6 weeks) for the early active movement group, and no difference in rotator cuff integrity between the early and delayed active movement groups. There were no group differences for all other outcomes. CONCLUSION: Patients who commenced active shoulder movement early after rotator cuff repair had greater shoulder range of motion and worse shoulder-specific quality of life after surgery than patients who delayed active shoulder movement. However, the group differences did not appear to be clinically important, and rotator cuff integrity was similar. J Orthop Sports Phys Ther 2021;51(7):331-344. Epub 15 May 2021. doi:10.2519/jospt.2021.9634.

Factors associated with maintaining reduction following locking plate fixation of proximal humerus fractures: a population-based retrospective cohort study.

BACKGROUND: Loss of reduction (LoR) can occur after locking plate fixation of proximal humerus fractures (PHFs). This study determined biomechanical features of fracture fixation associated with preventing LoR postoperatively. One-year reoperation rates were also compared between those with/without LoR. METHODS: Population-based administrative data for 359 adults treated using a locking plate for PHF between 2010 and 2016 were examined. Two trained assessors reviewed standardized shoulder radiographs. LoR (Yes/No) was defined as any fracture displacement >0.5 cm, and/or >10° change in neck-shaft angle (NSA) alignment relative to intraoperative imaging. Multiple logistic regression assessed how the following affected maintaining reduction: (1) sex, (2) age, (3) Neer classification, (4) shaft impaction (SI), (5) shaft medialization (SM), (6) calcar reduction (CR), (7) NSA alignment, and (8) screw use. RESULTS: LoR was seen in 79 (22%) patients. LoR was significantly associated with increasing age (odds ratio [OR] = 1.06/yr, P < .001), fracture severity (4-part vs. 2-part fracture; OR = 4.63, P = .001), and varus NSA alignment (<125° vs. ≥145°: OR = 5.6, P = .02; <125° vs. 125-145°, OR = 2.2, P = .02]). Patients achieving simultaneous SI, SM, and CR were significantly less likely (OR = 0.009, P < .001) to lose reduction, after controlling for age, fracture severity, and NSA alignment. If only SI was achieved, patients were still significantly less likely to lose reduction relative to achieving none of these mechanical features (OR = 0.17, P = .006). Reoperations were higher when LoR occurred (n = 26/77 [33.4%]) compared with no LoR (n = 20/276 [7.2%]) (P < .001). CONCLUSIONS: SI was strongly associated with preventing LoR in patients treated using a locking plate for PHF. SI with concurrent SM, CR, and a neutral or valgus NSA had the lowest rates of LoR. LoR was associated with higher rates of reoperation.

Determining the cut-off score for the Modified Barthel Index and the Modified Rankin Scale for assessment of functional independence and residual disability after stroke.

Assessment of functional independence and residual disability is very important for measuring treatment outcome after stroke. The modified Rankin Scale (mRS) and the modified Barthel Index (MBI) are commonly used scales to measure disability or dependence in activities of daily living (ADL) of stroke survivors. Lack of consensus regarding MBI score categories has caused confusion in interpreting stroke outcomes. The purpose of this study was to identify the optimal corresponding MBI and modified Rankin scale (mRS) grades for categorization of MBI. The Korean versions of the MBI (K-MBI) and mRS were collected from 5,759 stroke patients at 3 months after onset of stroke. The sensitivity and specificity were calculated at K-MBI score cutoffs for each mRS grade to obtain optimally corresponding K-MBI scores and mRS grades. We also plotted receiver operating characteristic (ROC) curves of sensitivity and specificity and determined the area under the curve (AUC). The K-MBI cutoff points with the highest sum of sensitivity and specificity were 100 (sensitivity 0.940; specificity 0.612), 98 (sensitivity 0.904; specificity 0.838), 94 (sensitivity 0.885; specificity 0.937), 78 (sensitivity 0.946; specificity, 0.973), and 55 (sensitivity 937; specificity 0.986) for mRS grades 0, 1, 2, 3, and 4, respectively. From this result, the K-MBI cutoff score range for each mRS grade can be obtained. For mRS grade 0, the K-MBI cutoff score is 100, indicating no associated score range. For mRS grades 1, 2, 3, 4, and 5, the K-MBI score ranges is from 99 to 98, 97 to 94, 93 to 78, 77 to 55, and under 54, respectively.The AUC for the ROC curve was 0.791 for mRS grade 0, 0.919 for mRS grade 1, 0.970 for mRS grade 2, 0.0 for mRS grade 3, and 0.991 for mRS grade 4. The K-MBI cutoff score ranges for representing mRS grades were variable; mRS grades 0, 1, and 2 had narrow K-MBI score ranges, while mRS grades 3, 4, and 5 exhibited broad K-MBI score ranges. mRS grade seemed to sensitively differentiate mild residual disability of stroke survivors, whereas K-MBI provided more specific information of the functional status of stroke survivors with moderate to severe residual impairment.

Elevated release of inflammatory but not sensory mediators from the urothelium is maintained following epirubicin treatment.

Intravesical treatment of superficial bladder cancer with epirubicin is associated with local urological adverse effects, the causes of which are unknown. Our aim was to investigate the effects of epirubicin on the release of urothelial mediators and inflammatory cytokines. UROtsa cells were treated with epirubicin for 1 h at 37 °C. Release of urothelial transmitters and inflammatory cytokines was examined immediately, 24 h and 7 days following treatment. Release of ATP and nitric oxide were increased transiently after treatment with epirubicin (0.01 mg/ml), but this was not evident one-week after treatment. Basal prostaglandin E2 release was decreased at 24 h but not at 7 days. An increase in basal acetylcholine release and decrease in stretch-induced acetylcholine release were observed 24-h after treatment (0.01 mg/ml). One week following epirubicin treatment (0.001 mg/ml), stretch-induced, but not basal acetylcholine release, was observed. Secretion of interleukin-6 and interleukin-8 was increased 70-fold and 5-fold respectively, at 24 h (0.01 mg/ml). This was sustained and one week after epirubicin treatment (0.001 mg/ml), the increase in the secretion of both inflammatory cytokines was still evident. Epirubicin treatment induces several transient changes in urothelial function. However, the increased secretion of inflammatory cytokines (IL-6 and IL-8) is sustained and these mediators may be involved in the pathophysiology of bladder toxicity following intravesical epirubicin treatment.

The Influence of Allowable Refill Gaps on Detecting Long-Term Opioid Therapy: An Analysis of Population-Based Administrative Dispensing Data Among Patients with Knee Arthritis Awaiting Total Knee Arthroplasty.

BACKGROUND: It is challenging to detect long-term opioid therapy (LTOT) using administrative data, as refill gaps can disrupt opioid utilization episodes. Previous studies have used various methods to define LTOT and allowable refill gaps with little supporting evidence. OBJECTIVE: To describe the effect of allowable refill gaps on detecting LTOT among a cohort of patients with arthritis awaiting total knee arthroplasty (TKA) using 3 different methods. METHODS: A retrospective analysis of multicenter population-based data between January 1, 2012, and December 31, 2016, identified patients prescribed opioids before TKA in Alberta, Canada. We described 3 methods to detect LTOT based on a (1) fixed number of days between prescriptions; (2) fraction of the preceding prescription length; and (3) combination method that selected whichever refill gap was greatest. We then compared the number of patients classified as long-term opioid users by varying the number of days between prescriptions from 1-90 days (fixed method) or 0.04-3.2 times the duration (fraction method) for each method and refill gap. RESULTS: Of the 14,252 patients included in our cohort, 4,393 patients (31%) had an opioid prescription within 180 days before TKA. Detection of LTOT varied from 4.4% to 14.6% (fixed method), 4.2% to 13.2% (fraction method), and 4.5% to 15.1% (mixed method) as refill gaps varied from minimum to maximum. As refills gaps increased, the dose and duration of opioids in the utilization episode decreased for all 3 methods. CONCLUSIONS: The allowable refill gap between opioid prescriptions can influence the estimated rate of LTOT when using administrative pharmaceutical dispensing data. Definitional parameters should be carefully considered when using administrative data to define consistent opioid use. DISCLOSURES: This work was supported by the Department of Surgery's Clinical Research Grant at the University of Alberta (RES0039945). The authors have no potential conflicts of interest.

Changes in Language Function and Recovery-Related Prognostic Factors in First-Ever Left Hemispheric Ischemic Stroke.

OBJECTIVE: To investigate longitudinal changes in language function in left-hemispheric ischemic stroke patients as well as factors that influence language recovery until 1 year after stroke onset. METHODS: We analyzed data from 235 patients with first-ever left-hemispheric ischemic stroke. All patients completed the Korean version of the Frenchay Aphasia Screening Test (K-FAST) at 7 days (T1), 3 months (T2), 6 months (T3), and 1 year (T4) after stroke onset. Repeated measures analysis of variance (ANOVA) was used to investigate changes in language function between time points. Subgroup analysis was performed according to the K-FAST scores at T1. Stroke lesion volume was assessed using diffusion tensor images, and involvement of language-related brain regions was examined. Multiple regression analysis was used to analyze factors influencing improvement of K-FAST score. RESULTS: The K-FAST scores at T1, T2, T3, and T4 differed significantly (p<0.05). In the subgroup analysis, only the severe group showed continuous significant improvement by 1 year. Factors that negatively influenced improvement of language function were the age at onset, initial National Institutes of Health Stroke Scale (NIHSS) score, and initial K-FAST score, whereas education level and stroke lesion volume positively affected recovery. Involvement of language-related brain regions did not significantly influence long-term language recovery after ischemic stroke. CONCLUSION: Recovery of language function varied according to the severity of the initial language deficit. The age at stroke onset, education level, initial severity of aphasia, initial NIHSS score, and total stroke lesion volume were found to be important factors for recovery of language function.

Prevention of TNF-induced necrotic cell death by rottlerin through a Nox1 NADPH oxidase.

Previous studies have demonstrated that rottlerin, a specific PKCdelta inhibitor, potentiates death receptor- mediated apoptosis through a cytochrome c-dependent or -independent pathway. However, its ability to regulate necrotic cell death, as well as the underlying mechanism, remains unknown. We found that in murine fibrosarcoma L929 cells, treatment with rottlerin protected the cells against TNF-induced necrosis, whereas it sensitized the cells to apoptosis induced by co-treatment with Hsp90 inhibitor geldanamycin and TNF, in a manner independent of its ability to inhibit PKC-delta. TNF treatment induced rapid accumulation of mitochondrial superoxide (O2-) through the Nox1 NADPH oxidase when cells undergo necrosis. Moreover, pretreatment with rottlerin failed to induce the GTP-bound form of small GTPase Rac1 by TNF treatment, and subsequently suppressed mitochondrial O2- production and poly(ADP-ribose) polymerase activation, thus inhibiting necrotic cell death. Therefore, our study suggests that Nox1 NADPH oxidase is a new molecular target for anti-necrotic activity of rottlerin upon death-receptor ligation.

Increased inhibition of inward rectifier K+ channels by angiotensin II in small-diameter coronary artery of isoproterenol-induced hypertrophied model.

OBJECTIVE: We investigated the effects of angiotensin II (Ang II) on inward rectifier K+ (Kir) channels in small-diameter coronary arterial smooth muscle cells (SCASMCs) of control and isoproterenol (Iso)-induced hypertrophied rabbits. METHODS AND RESULTS: Kir current amplitude and Kir channel protein expression were definitely lower in the Iso-induced hypertrophied model than in the control. In a pressurized arterial experiment, 15 mmol/L K+-induced vasodilation was greater in the control arteries than in the arteries of Iso-induced hypertrophied model. Ang II reduced the Kir current in a concentration-dependent manner, and this inhibition was greater in SCASMCs from Iso-induced hypertrophied model than from control. Although, there was no difference in the expression of Ang II type 2 (AT2) receptor between SCASMCs of control and Iso-induced hypertrophied model, the expression of Ang II type 1 (AT1) receptor and phosphorylated PKC alpha were greater in SCASMCs of Iso-induced hypertrophied model than of control. CONCLUSION: Ang II inhibits Kir channels more prominently in SCASMCs of Iso-induced hypertrophied model owing to increases in the expression of AT1 receptor and the activation of PKC alpha. Our findings about the differential expression of Kir channels and different modulation of Kir channels by a vasoconstrictor (Ang II) in a hypertrophy model are important for better understanding the responsiveness of small-diameter arteries during hypertrophy.

Can energy intake alter clinical and hospital outcomes in PICU?

BACKGROUND & AIMS: Energy is essential for the treatment and recovery of children admitted to Pediatric Intensive Care Units (PICU). There are significant immediate and long-term health consequences of both under- and over-feeding in this population. Energy requirements of critically ill children vary depending on age, nutritional status, sepsis, fever, pharmacotherapy, and duration and stage of critical illness. This study aimed to determine the incidence of over- and under-feeding and to compare hospital outcomes between these feeding categories. Secondary outcomes were collected to describe the association between feeding categories and biochemistries (serum lactate, triglycerides, C-reactive protein). METHODS: An ethics approved retrospective study of children admitted to PICU was performed. All intubated patients admitted to PICU (2008-2013) were included, except those in which an IC test was not feasible. Data collection included demographics, the primary outcome variable reported as under feeding (<90%MREE), appropriate (MREE ±10%) or overfeeding (>110% MREE) determined through comparison of measured resting energy expenditure (MREE) using indirect calorimetry (IC) to actual energy intake based on predicted basal metabolic rate (PBMR) and clinical outcomes mechanical ventilation and PICU length of stay (LOS). Data were analysed with descriptive methods, ANOVA and linear regression models. RESULTS: A total of 139 patients aged 10 (range 0.03-204) months were included. Sixty (43%) were female and 77 (55%) were admitted after a surgical procedure. A total of 210 IC tests were conducted showing a statistically significant difference between MREE measurements and PBMR (p = 0.019). Of the 210 measurements, only 26 measures (12.4%) demonstrated appropriate feeding, while 72 (34.3) were underfed and 112 (53.3%) were overfed. Children who were overfed had significantly longer PICU LOS (median 45.5, IQR 47.8 days) compared to those children in the appropriately fed (median 21.0, IQR 54.5 days), and underfed groups (median 16.5, IQR 21.3 days). There was a mean difference between the over and under feeding category and ventilation days after adjusting for age and PRISM score (p = 0.026), suggesting decreased mechanical ventilation days for underfed. Children who were underfed had significantly higher CRP (median 75.5, IQR 152.8 mg/L) compared to those children in the appropriately fed (median 57.8, IQR 90.9 mg/L) and overfed groups (median 22.4, IQR 56.2 mg/L). CONCLUSIONS: This retrospective study confirms that estimations of energy expenditure in critically ill children are inaccurate leading to unintended under and overfeeding. Importantly under feeding seems to be associated with fewer mechanical ventilation days and PICU LOS. Further research is required to elucidate the role of optimal nutrition in altering clinical variables in this population.

Direct modulation of Ca(2+)-activated K(+) current by H-89 in rabbit coronary arterial smooth muscle cells.

The effects of H-89, a potent and selective inhibitor of protein kinase A (PKA) on Ca(2+)-activated K(+) (BK(Ca)) channels in coronary arterial smooth muscle cells were examined using a patch-clamp technique. In inside-out configuration, H-89 increased the NP(o) of the BK(Ca) channel, but it reduced the dwell time of BK(Ca) currents. In whole-cell configuration, H-89 markedly increased BK(Ca) currents in a concentration-dependent manner. The EC(50) was 0.470+/-0.0741 microM based on dwell time, 0.582+/-0.0691 microM based on the NP(o), and 0.519+/-0.0295 microM based on the whole-cell current, respectively. H-85, which is an inactive form of H-89, increased BK(Ca) currents, similar to the result of H-89. The other PKA inhibitors (Rp-8-CPT-cAMPs and KT 5720) and protein phosphatase inhibitor (okadaic acid, 1 microM) had little effect on BK(Ca) currents and did not significantly alter the stimulatory effects of 1 microM H-89. These findings suggest that H-89 increases the BK(Ca) current independently of PKA.

Cracked Teeth: Distribution, Characteristics, and Survival after Root Canal Treatment.

INTRODUCTION: The aims of this study were to analyze the distribution and characteristic features of cracked teeth and to evaluate the outcome of root canal treatments (RCTs) for cracked teeth. The prognostic factors for tooth survival were investigated. METHODS: Over the 5-year study period, 175 teeth were identified as having cracks. Data were collected regarding the patients' age, sex, tooth type, location and direction of cracks, probing depth, pulp vitality, type of restoration, cavity classification, opposing teeth, and previous endodontic treatment history. Cracked teeth were managed via various treatment methods, and the 2-year survival rate after RCT was analyzed using the Kaplan-Meier method in which significance was identified using the log-rank test. Possible prognostic factors were investigated using Cox multivariate proportional hazards modeling. RESULTS: One hundred seventy-five teeth were diagnosed with cracks. Most of the patients were aged 50-60 years (32.0%) or over 60 (32.6%). The lower second molar was the most frequently (25.1%) affected tooth. Intact teeth (34.3%) or teeth with class I cavity restorations (32.0%) exhibited a higher incidence of cracks. The 2-year survival rate of 88 cracked teeth after RCT was 90.0%. A probing depth of more than 6 mm was a significant prognostic factor for the survival of cracked teeth restored via RCT. The survival rate of root-filled cracked teeth with a probing depth of more than 6 mm was 74.1%, which is significantly lower than that of teeth with probing depths of less than 6 mm (96.8%) (P = .003). CONCLUSIONS: Cracks were commonly found in lower second molars and intact teeth. RCT was a reliable treatment for cracked teeth with a 2-year survival rate of 90.0%. Deep probing depths were found to be a significant clinical factor for the survival of cracked teeth treated with RCT.