Progranulin, lysosomal regulation and neurodegenerative disease.

The discovery that heterozygous and homozygous mutations in the gene encoding progranulin are causally linked to frontotemporal dementia and lysosomal storage disease, respectively, reveals previously unrecognized roles of the progranulin protein in regulating lysosome biogenesis and function. Given the importance of lysosomes in cellular homeostasis, it is not surprising that progranulin deficiency has pleiotropic effects on neural circuit development and maintenance, stress response, innate immunity and ageing. This Progress article reviews recent advances in progranulin biology emphasizing its roles in lysosomal function and brain innate immunity, and outlines future avenues of investigation that may lead to new therapeutic approaches for neurodegeneration.

Adalimumab plus Methotrexate for Uveitis in Juvenile Idiopathic Arthritis.

BACKGROUND: Adalimumab, a fully human anti-tumor necrosis factor α monoclonal antibody, is effective in the treatment of juvenile idiopathic arthritis (JIA). We tested the efficacy of adalimumab in the treatment of JIA-associated uveitis. METHODS: In this multicenter, double-blind, randomized, placebo-controlled trial, we assessed the efficacy and safety of adalimumab in children and adolescents 2 years of age or older who had active JIA-associated uveitis. Patients who were taking a stable dose of methotrexate were randomly assigned in a 2:1 ratio to receive either adalimumab (at a dose of 20 mg or 40 mg, according to body weight) or placebo, administered subcutaneously every 2 weeks. Patients continued the trial regimen until treatment failure or until 18 months had elapsed. They were followed for up to 2 years after randomization. The primary end point was the time to treatment failure, defined according to a multicomponent intraocular inflammation score that was based on the Standardization of Uveitis Nomenclature criteria. RESULTS: The prespecified stopping criteria were met after the enrollment of 90 of 114 patients. We observed 16 treatment failures in 60 patients (27%) in the adalimumab group versus 18 treatment failures in 30 patients (60%) in the placebo group (hazard ratio, 0.25; 95% confidence interval [CI], 0.12 to 0.49; P<0.0001 [the prespecified stopping boundary]). Adverse events were reported more frequently in patients receiving adalimumab than in those receiving placebo (10.07 events per patient-year [95% CI, 9.26 to 10.89] vs. 6.51 events per patient-year [95% CI, 5.26 to 7.77]), as were serious adverse events (0.29 events per patient-year [95% CI, 0.15 to 0.43] vs. 0.19 events per patient-year [95% CI, 0.00 to 0.40]). CONCLUSIONS: Adalimumab therapy controlled inflammation and was associated with a lower rate of treatment failure than placebo among children and adolescents with active JIA-associated uveitis who were taking a stable dose of methotrexate. Patients who received adalimumab had a much higher incidence of adverse events and serious adverse events than those who received placebo. (Funded by the NIHR Health Technology Assessment Programme and Arthritis Research UK; SYCAMORE EudraCT number, 2010-021141-41 .).

Cell-Type-Specific Metabolic Profiling Achieved by Combining Desorption Electrospray Ionization Mass Spectrometry Imaging and Immunofluorescence Staining.

Cell-type-specific metabolic profiling in tissue with heterogeneous composition has been of great interest across all mass spectrometry imaging (MSI) technologies. We report here a powerful new chemical imaging capability in desorption electrospray ionization (DESI) MSI, which enables cell-type-specific and in situ metabolic profiling in complex tissue samples. We accomplish this by combining DESI-MSI with immunofluorescence staining using specific cell-type markers. We take advantage of the variable frequency of each distinct cell type in the lateral septal nucleus (LSN) region of mouse forebrain. This allows computational deconvolution of the cell-type-specific metabolic profile in neurons and astrocytes by convex optimization-a machine learning method. Based on our approach, we observed 107 metabolites that show different distributions and intensities between astrocytes and neurons. We subsequently identified 23 metabolites using high-resolution mass spectrometry (MS) and tandem MS, which include small metabolites such as adenosine and N-acetylaspartate previously associated with astrocytes and neurons, respectively, as well as accumulation of several phospholipid species in neurons which have not been studied before. Overall, this method overcomes the relatively low spatial resolution of DESI-MSI and provides a new platform for in situ metabolic investigation at the cell-type level in complex tissue samples with heterogeneous cell-type composition.

The Association Between Wait Times for Colorectal Cancer Treatment and Health Care Costs: A Population-Based Analysis.

BACKGROUND: Health care costs and wait times for colorectal cancer treatment are increasing in Canada, but the association between the 2 remains unclear. OBJECTIVE: This study aimed to determine the association between wait times and health care costs and utilization. DESIGN: This is a population-based retrospective cohort study. SETTING: This study was conducted in Manitoba, Canada. PATIENTS: Patients diagnosed with colorectal cancer between 2004 and 2014 were sorted and ranked into quintiles based on the time from index contact for a colorectal cancer-related symptom to first treatment. MAIN OUTCOME MEASURES: The primary outcome is risk-adjusted health care costs, and the secondary outcomes include health care utilization and overall mortality. RESULTS: We included a total of 6936 patients. Total wait times ranged between 0 and 762 days. In comparison with very short wait times, longer wait times were associated with significantly increased costs (short: mean cost ratio 1.21; 95% CI, 1.10-1.32; moderate: mean cost ratio 1.30; 95% CI, 1.19-1.43; long: mean cost ratio 1.48; 95% CI, 1.33-1.64; and very long: mean cost ratio 1.39; 95% CI, 1.26-1.54). Compared with very short wait times, longer wait times were associated with significantly lower risk of mortality (short: HR, 0.78; 95% CI, 0.71-0.86; moderate: HR, 0.72; 95% CI, 0.65-0.80; long: HR, 0.73; 95% CI, 0.66-0.82; very long: HR, 0.76; 95% CI, 0.68-0.85). The median number of pretreatment radiological and endoscopic investigations and surgeon clinic visits increased over the study period across all wait time categories. LIMITATIONS: This is a nonrandomized, retrospective cohort study with potentially limited generalizability. CONCLUSION: Patients with very short and short wait times are likely those diagnosed with life-threatening complications of colorectal cancer. Outside this window, patients with longer wait times experience increased health care costs and utilization with similar overall mortality. Improved care coordination and patient navigation may help contain the increasing wait times and associated increasing health care costs and utilization. See Video Abstract at http://links.lww.com/DCR/B81. ASOCIACIÓN ENTRE LOS TIEMPOS DE ESPERA PARA EL TRATAMIENTO DE UN CÁNCER COLORRECTAL Y LOS COSTOS DE ATENCIÓN MÉDICA: UN ANÁLISIS DE POBLACIÓN: los costos de atención médica y los tiempos de espera para el tratamiento del cáncer colorrectal están aumentando en Canadá, pero la asociación entre los dos sigue sin estar clara.determinar la asociación entre los tiempos de espera y los costos y la utilización de la atención médicaun estudio de cohorte retrospectivo basado en la población.Manitoba, Canadálos pacientes diagnosticados con cáncer colorrectal entre 2004-2014 se clasificaron y sub-clasificaron en quintiles según el tiempo desde el primer contacto índice de síntomas relacionados con cáncer colorrectal hasta el primer tratamiento.El resultado primario son los costos de atención médica ajustados al riesgo, y los resultados secundarios incluyen la utilización de la atención médica y la mortalidad general.Incluimos un total de 6,936 pacientes. Los tiempos de espera totales oscilaron entre 0-762 días. En comparación con los tiempos de espera muy cortos, los tiempos de espera más largos se asociaron con costos significativamente mayores (Corto: relación de costo promedio 1.21, intervalo de confianza del 95% 1.10-1.32; Moderado: relación de costo promedio 1.30, intervalo de confianza del 95% 1.19-1.43; Largo: media relación de costo 1.48, intervalo de confianza del 95% 1.33-1.64; Muy largo: relación de costo promedio 1.39, intervalo de confianza del 95% 1.26-1.54). En comparación con tiempos de espera muy cortos, los tiempos de espera más largos se asociaron con un riesgo de mortalidad significativamente menor (Corto: razón de riesgo 0.78, intervalo de confianza del 95% 0.71-0.86; Moderado: razón de riesgo 0.72, intervalo de confianza del 95% 0.65-0.80; Largo: peligro cociente 0.73, intervalo de confianza del 95% 0.66-0.82; Muy largo: cociente de riesgos 0.76, intervalo de confianza del 95% 0.68-0.85). La mediana del número de investigaciones radiológicas y endoscópicas previas al tratamiento y las visitas al cirujano aumentaron durante el período de estudio en todas las categorías de tiempo de espera.estudio de cohortes retrospectivo, no aleatorio con generalización potencialmente limitadalos pacientes con tiempos de espera « muy cortos ¼ y « cortos ¼ son probablemente aquellos diagnosticados con complicaciones potencialmente mortales del cáncer colorrectal. Fuera de esta ventana, los pacientes con tiempos de espera más largos experimentan mayores costos de atención médica y utilización con una mortalidad general similar. La coordinación mejorada de la atención y la navegación del paciente pueden ayudar a contener el aumento de los tiempos de espera y el aumento de los costos y la utilización de la atención médica. Consulte Video Resumen en http://links.lww.com/DCR/B81. (Traducción-Dr. Edgar Xavier Delgadillo).

Cost-Effectiveness Analysis of Adalimumab for the Treatment of Uveitis Associated with Juvenile Idiopathic Arthritis.

PURPOSE: To investigate the cost effectiveness of adalimumab in combination with methotrexate, compared with methotrexate alone, for the management of uveitis associated with juvenile idiopathic arthritis (JIA). DESIGN: A cost-utility analysis based on a clinical trial and decision analytic model. PARTICIPANTS: Children and adolescents 2 to 18 years of age with persistently active uveitis associated with JIA, despite optimized methotrexate treatment for at least 12 weeks. METHODS: The SYCAMORE (Randomised controlled trial of the clinical effectiveness, SafetY and Cost effectiveness of Adalimumab in combination with MethOtRExate for the treatment of juvenile idiopathic arthritis associated uveitis) trial (identifier, ISRCTN10065623) of methotrexate (up to 25 mg weekly) with or without fortnightly administered adalimumab (20 or 40 mg, according to body weight) provided data on resource use (based on patient self-report and electronic records) and health utilities (from the Health Utilities Index questionnaire). Surgical event rates and long-term outcomes were based on data from a 10-year longitudinal cohort. A Markov model was used to extrapolate the effects of treatment based on visual impairment. MAIN OUTCOME MEASURES: Medical costs to the National Health Service in the United Kingdom, utility of defined health states, quality-adjusted life-years (QALYs), and incremental cost per QALY. RESULTS: Adalimumab in combination with methotrexate resulted in additional costs of £39 316, with a 0.30 QALY gain compared with methotrexate alone, resulting in an incremental cost-effectiveness ratio of £129 025 per QALY gained. The probability of cost effectiveness at a threshold of £30 000 per QALY was less than 1%. Based on a threshold analysis, a price reduction of 84% would be necessary for adalimumab to be cost effective. CONCLUSIONS: Adalimumab is clinically effective in uveitis associated with JIA; however, its cost effectiveness is not demonstrated compared with methotrexate alone in the United Kingdom setting.

Timing of Palliative Care in Colorectal Cancer Patients: Does It Matter?

BACKGROUND: Palliative care can improve end-of-life care and reduce health care expenditures, but the optimal timing for initiation remains unclear. We sought to characterize the association between timing of palliative care, in-hospital deaths, and health care costs. METHODS: This is a retrospective cohort study including all patients who were diagnosed and died of colorectal cancer between 2004 and 2012 in Manitoba, Canada. The primary exposure was timing of palliative care, defined as no involvement, late involvement (less than 14 d before death), early involvement (14 to 60 d before death), and very early involvement (>60 d before death). The primary outcome was in-hospital deaths and end-of-life health care costs. RESULTS: A total of 1607 patients were included; 315 (20%) received palliative care and 162 (10%) died in hospital. Compared to those who did not receive palliative care, patients with early and very early involvement experienced significantly decreased odds of dying in hospital (OR 0.21 95% CI 0.06-0.69 P = 0.01 and OR 0.11 95% CI 0.01-0.78 P = 0.03, respectively) and significantly lower health care costs. There were no significant differences in in-hospital deaths and health care costs between patients without palliative care and those who received late palliative care. CONCLUSIONS: Early palliative care involvement is associated with decreased odds of dying in hospital and lower health care utilization and costs in patients with colorectal cancer. These findings provide real-world evidence supporting early integration of palliative care, although the optimal timing (early versus very early) remains a matter of debate.

The sinus venosus contributes to coronary vasculature through VEGFC-stimulated angiogenesis.

Identifying coronary artery progenitors and their developmental pathways could inspire novel regenerative treatments for heart disease. Multiple sources of coronary vessels have been proposed, including the sinus venosus (SV), endocardium and proepicardium, but their relative contributions to the coronary circulation and the molecular mechanisms regulating their development are poorly understood. We created an ApjCreER mouse line as a lineage-tracing tool to map SV-derived vessels onto the heart and compared the resulting lineage pattern with endocardial and proepicardial contributions to the coronary circulation. The data showed a striking compartmentalization to coronary development. ApjCreER-traced vessels contributed to a large number of arteries, capillaries and veins on the dorsal and lateral sides of the heart. By contrast, untraced vessels predominated in the midline of the ventral aspect and ventricular septum, which are vessel populations primarily derived from the endocardium. The proepicardium gave rise to a smaller fraction of vessels spaced relatively uniformly throughout the ventricular walls. Dorsal (SV-derived) and ventral (endocardial-derived) coronary vessels developed in response to different growth signals. The absence of VEGFC, which is expressed in the epicardium, dramatically inhibited dorsal and lateral coronary growth but left vessels on the ventral side unaffected. We propose that complementary SV-derived and endocardial-derived migratory routes unite to form the coronary vasculature and that the former requires VEGFC, revealing its role as a tissue-specific mediator of blood endothelial development.

Cancer Stem Cells are Depolarized Relative to Normal Stem Cells Derived from Human Livers.

INTRODUCTION AND AIM: The inability to distinguish cancer (CSCs) from normal stem cells (NSCs) has hindered attempts to identify safer, more effective therapies for hepatocellular carcinoma (HCC). The aim of this study was to document and compare cell membrane potential differences (PDs) of CSCs and NSCs derived from human HCC and healthy livers respectively and determine whether altered GABAergic innervation could explain the differences. MATERIAL AND METHODS: Epithelial cell adhesion molecule (EpCAM) positive stem cells were isolated from human liver tissues by magnetic bead separations. Cellular PDs were recorded by microelectrode impalement of freshly isolated cells. GABAA receptor subunit expression was documented by reverse transcriptase polymerase chain reaction (RT-PCR) and immunofluorescence. RESULTS: CSCs were significantly depolarized (-7.0 ± 1.3 mV) relative to NSCs (-23.0 ± 1.4 mV, p &lt; 0.01). The depolarized state was associated with different GABAA receptor subunit expression profiles wherein phasic transmission, represented by GAGAA α3 subunit expression, was prevalent in CSCs while tonic transmission, represented by GABAA α6 subunit expression, prevailed in NSCs. In addition, GABAA subunits α3, ß3, ϒ3 and δ were strongly expressed in CSCs while GABAA π expression was dominant in NSCs. CSCs and NSCs responded similarly to GABAA receptor agonists (ΔPD: 12.5 ± 1.2 mV and 11.0 ± 3.5 mV respectively). CONCLUSION: The results of this study indicate that CSCs are significantly depolarized relative to NSCs and these differences are associated with differences in GABAA receptor subunit expression. Together they provide new insights into the pathogenesis and possible treatment of human HCC.

Effect of N-acetylcysteine on liver recovery after resection: A randomized clinical trial.

BACKGROUND AND OBJECTIVES: Liver failure following hepatic resection is a multifactorial complication. In experimental studies, infusion of N-acetylcysteine (NAC) can minimize hepatic parenchymal injury. METHODS: Patients undergoing liver resection were randomized to postoperative care with or without NAC. No blinding was performed. Overall complication rate was the primary outcome; liver failure, length of stay, and mortality were secondary outcomes. Due to safety concerns, a premature multivariate analysis was performed and included within the model randomization to NAC, preoperative ASA, extent of resection, and intraoperative vascular occlusion as factors. RESULTS: Two hundred and six patients were randomized (110 to conventional therapy; 96 to NAC). No significant differences were noted in overall complications (32.7% and 45.7%, P = 0.06) or hepatic failure (3.6% and 5.4%, P = 0.537) between treatment groups. There was significantly more delirium within the NAC group (2.7% and 9.8%, P < 0.05) that caused early trial termination. In multivariate analysis, only randomization to NAC (OR = 2.21, 95%CI = 1.16-4.19) and extensive resections (OR = 2.28, 95%CI = 1.22-4.29) were predictive of postoperative complications. CONCLUSIONS: Patients randomized to postoperative NAC received no benefit. There was a trend toward a higher rate of overall complications and a significantly higher rate of delirium in the NAC group. J. Surg. Oncol. 2016;114:446-450. © 2016 Wiley Periodicals, Inc.

Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child.

BACKGROUND: There is evidence that certain antiepileptic drugs (AEDs) are teratogenic and are associated with an increased risk of congenital malformation. The majority of women with epilepsy continue taking AEDs throughout pregnancy; therefore it is important that comprehensive information on the potential risks associated with AED treatment is available. OBJECTIVES: To assess the effects of prenatal exposure to AEDs on the prevalence of congenital malformations in the child. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register (September 2015), Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 11), MEDLINE (via Ovid) (1946 to September 2015), EMBASE (1974 to September 2015), Pharmline (1978 to September 2015), Reprotox (1983 to September 2015) and conference abstracts (2010-2015) without language restriction. SELECTION CRITERIA: We included prospective cohort controlled studies, cohort studies set within pregnancy registries and randomised controlled trials. Participants were women with epilepsy taking AEDs; the two control groups were women without epilepsy and women with epilepsy who were not taking AEDs during pregnancy. DATA COLLECTION AND ANALYSIS: Three authors independently selected studies for inclusion. Five authors completed data extraction and risk of bias assessments. The primary outcome was the presence of a major congenital malformation. Secondary outcomes included specific types of major congenital malformations. Where meta-analysis was not possible, we reviewed included studies narratively. MAIN RESULTS: We included 50 studies, with 31 contributing to meta-analysis. Study quality varied, and given the observational design, all were at high risk of certain biases. However, biases were balanced across the AEDs investigated and we believe that the results are not explained by these biases.Children exposed to carbamazepine (CBZ) were at a higher risk of malformation than children born to women without epilepsy (N = 1367 vs 2146, risk ratio (RR) 2.01, 95% confidence interval (CI) 1.20 to 3.36) and women with untreated epilepsy (N = 3058 vs 1287, RR 1.50, 95% CI 1.03 to 2.19). Children exposed to phenobarbital (PB) were at a higher risk of malformation than children born to women without epilepsy (N = 345 vs 1591, RR 2.84, 95% CI 1.57 to 5.13). Children exposed to phenytoin (PHT) were at an increased risk of malformation compared with children born to women without epilepsy (N = 477 vs 987, RR 2.38, 95% CI 1.12 to 5.03) and to women with untreated epilepsy (N = 640 vs 1256, RR 2.40, 95% CI 1.42 to 4.08). Children exposed to topiramate (TPM) were at an increased risk of malformation compared with children born to women without epilepsy (N = 359 vs 442, RR 3.69, 95% CI 1.36 to 10.07). The children exposed to valproate (VPA) were at a higher risk of malformation compared with children born to women without epilepsy (N = 467 vs 1936, RR 5.69, 95% CI 3.33 to 9.73) and to women with untreated epilepsy (N = 1923 vs 1259, RR 3.13, 95% CI 2.16 to 4.54). There was no increased risk for major malformation for lamotrigine (LTG). Gabapentin (GBP), levetiracetam (LEV), oxcarbazepine (OXC), primidone (PRM) or zonisamide (ZNS) were not associated with an increased risk, however, there were substantially fewer data for these medications.For AED comparisons, children exposed to VPA had the greatest risk of malformation (10.93%, 95% CI 8.91 to 13.13). Children exposed to VPA were at an increased risk of malformation compared with children exposed to CBZ (N = 2529 vs 4549, RR 2.44, 95% CI 2.00 to 2.94), GBP (N = 1814 vs 190, RR 6.21, 95% CI 1.91 to 20.23), LEV (N = 1814 vs 817, RR 5.82, 95% CI 3.13 to 10.81), LTG (N = 2021 vs 4164, RR 3.56, 95% CI 2.77 to 4.58), TPM (N = 1814 vs 473, RR 2.35, 95% CI 1.40 to 3.95), OXC (N = 676 vs 238, RR 3.71, 95% CI 1.65 to 8.33), PB (N = 1137 vs 626, RR 1.59, 95% CI 1.11 to 2.29, PHT (N = 2319 vs 1137, RR 2.00, 95% CI 1.48 to 2.71) or ZNS (N = 323 vs 90, RR 17.13, 95% CI 1.06 to 277.48). Children exposed to CBZ were at a higher risk of malformation than those exposed to LEV (N = 3051 vs 817, RR 1.84, 95% CI 1.03 to 3.29) and children exposed to LTG (N = 3385 vs 4164, RR 1.34, 95% CI 1.01 to 1.76). Children exposed to PB were at a higher risk of malformation compared with children exposed to GBP (N = 204 vs 159, RR 8.33, 95% CI 1.04 to 50.00), LEV (N = 204 vs 513, RR 2.33, 95% CI 1.04 to 5.00) or LTG (N = 282 vs 1959, RR 3.13, 95% CI 1.64 to 5.88). Children exposed to PHT had a higher risk of malformation than children exposed to LTG (N = 624 vs 4082, RR 1.89, 95% CI 1.19 to 2.94) or to LEV (N = 566 vs 817, RR 2.04, 95% CI 1.09 to 3.85); however, the comparison to LEV was not significant in the random-effects model. Children exposed to TPM were at a higher risk of malformation than children exposed to LEV (N = 473 vs 817, RR 2.00, 95% CI 1.03 to 3.85) or LTG (N = 473 vs 3975, RR 1.79, 95% CI 1.06 to 2.94). There were no other significant differences, or comparisons were limited to a single study.We found significantly higher rates of specific malformations associating PB exposure with cardiac malformations and VPA exposure with neural tube, cardiac, oro-facial/craniofacial, and skeletal and limb malformations in comparison to other AEDs. Dose of exposure mediated the risk of malformation following VPA exposure; a potential dose-response association for the other AEDs remained less clear. AUTHORS' CONCLUSIONS: Exposure in the womb to certain AEDs carried an increased risk of malformation in the foetus and may be associated with specific patterns of malformation. Based on current evidence, LEV and LTG exposure carried the lowest risk of overall malformation; however, data pertaining to specific malformations are lacking. Physicians should discuss both the risks and treatment efficacy with the patient prior to commencing treatment.

Determining the natural history of pancreatic cystic neoplasms: a Manitoban cohort study.

BACKGROUND: Most pancreatic cystic neoplasms (PCN) are thought to harbor a low malignant potential. This historical cohort study attempts to describe the natural history of these lesions in a provincial cohort, to assess the safety of non-surgical management. Pathological diagnosis of malignancy was the primary outcome measure of interest. METHODS: All adult patients (age 18+) with PCN seen between 2000 and 2012 by the two main institutions in Manitoba were included in this study. PCN were graded as high and low risk, which dictated initial treatment plan (surgery or observation). Predictors of initial surgical treatment, delayed surgery in the observation group and the clinical/radiological predictors of malignancy were determined. RESULTS: 497 patients were included in this study. 43 (8.7%) high-risk lesions underwent initial surgery, with 13 (30.2%) cases of malignancy discovered. 450 (90.5%) low-risk cysts were observed for a median of 17.3 months (range: 0.00-142.3). 29 (6.4%) cases of delayed surgery occurred, with malignancy discovered in five (17.2%). CONCLUSIONS: This study supports current selection criteria for management of PCNs. Due to the low incidence of malignancy in low-risk PCN, it appears that long-term observation is safe and should be the treatment modality of choice in the absence of high-risk features.

Synoptic operative reports enhance documentation of best practices for rectal cancer.

BACKGROUND: Implementation of best practices surgical checklists improves patient safety and outcomes. However, documenting performance of these practices can be challenging. The American Society of Colon and Rectal Surgeons developed a Best Practices for Rectal Cancer Checklist (RCC) to standardize and improve the quality of rectal cancer surgery. This study compared the degree to which synoptic (SR) and narrative (NR) operative reports document RCC items. METHODS: Two reviewers independently reviewed a cohort of prospectively collected SR for rectal cancer surgery and a case-matched historical cohort of NR. Reports were reviewed for documentation of performance of operative items on the RCC. Abstraction time and inter-rater agreement were also measured. RESULTS: SR scored significantly higher than NR on the overall checklist score (mean adjusted score ± standard deviation 12.4 ± 0.9 vs. 5.7 ± 1.9, maximum possible score 18, P < 0.001). Reviewers abstracted data significantly faster from SR. Inter-rater agreement between reviewers was high for both types of reports. CONCLUSIONS: SR were associated with reliable and more complete and reliable documentation of items on the RCC. Use of an SR system standardizes operative reporting, providing the opportunity to enhance checklist compliance, and enable timely feedback to improve surgical outcomes for rectal cancer patients.

Are there reliable constitutive laws for dynamic friction?

Structural vibration controlled by interfacial friction is widespread, ranging from friction dampers in gas turbines to the motion of violin strings. To predict, control or prevent such vibration, a constitutive description of frictional interactions is inevitably required. A variety of friction models are discussed to assess their scope and validity, in the light of constraints provided by different experimental observations. Three contrasting case studies are used to illustrate how predicted behaviour can be extremely sensitive to the choice of frictional constitutive model, and to explore possible experimental paths to discriminate between and calibrate dynamic friction models over the full parameter range needed for real applications.

Lacosamide add-on therapy for partial epilepsy.

BACKGROUND: Around half of people with epilepsy will not achieve seizure freedom on their first antiepileptic drug; many will require add-on treatment with another drug. Sometimes multiple treatment combinations are tried to achieve maximum seizure control, although around a third of people do not achieve complete seizure control. Lacosamide is an antiepileptic drug that has been licensed as an add-on treatment for partial epilepsy. OBJECTIVES: To evaluate the efficacy and tolerability of lacosamide when used as an add-on treatment for patients with drug-resistant partial epilepsy. SEARCH METHODS: We searched the Cochrane Epilepsy Group's Specialized Register (21 May 2015), the Cochrane Central Register of Controlled Trials (CENTRAL , The Cochrane Library Issue 4, April 2015), MEDLINE (Ovid, 1946 to 21 May 2015), Scopus (1823 to 13 November 2014), ClinicalTrials.gov (21 May 2015) and the WHO International Clinical Trials Registry Platform (ICTRP, 21 May 2015). We imposed no language restrictions. We contacted UCB (sponsors of lacosamide) and experts in the field. SELECTION CRITERIA: Randomised controlled trials of add-on lacosamide in people with drug-resistant partial epilepsy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and extracted the relevant data. We assessed the following outcomes: (1) 50% or greater reduction in seizure frequency; (2) seizure freedom; (3) treatment withdrawal for any reason; and (4) adverse events. Primary analyses were intention-to-treat. Summary risk ratios were estimated for each outcome. MAIN RESULTS: We included three trials in our review (1311 participants), which were classified as having low risk of bias. All trials were placebo-controlled and assessed doses ranging from 200 mg to 600 mg per day. Trial duration ranged from 24 to 26 weeks. All trials used adequate methods of randomisation and were double-blind. Overall the quality of the evidence was rated as moderate to high. The overall risk ratio for a 50% or greater reduction in seizure frequency for all doses of lacosamide compared with placebo was 1.70 (95% confidence interval (CI) 1.38 to 2.10); for seizure freedom for all doses of lacosamide compared with placebo was 2.50 (95% CI 0.85 to 7.34); and for treatment withdrawal for all doses of lacosamide compared with placebo was 1.88 (95% CI 1.40 to 2.52). Adverse effects significantly associated with lacosamide were abnormal co-ordination (risk ratio (RR) 6.12, 99% CI 1.35 to 27.77), diplopia (RR 5.29, 99% CI 1.97 to 14.23), dizziness (RR 3.53, 99% CI 2.20 to 5.68), nausea (RR 2.37, 99% CI 1.23 to 4.58) and vomiting (RR 3.49, 99% CI 1.43 to 8.54). Adverse effects that were not statistically significant were headache (RR 1.34, 99% CI 0.83 to 2.18), fatigue (RR 2.11, 99% CI 0.92 to 4.85), nystagmus (RR 1.47, 99% CI 0.61 to 3.52) and somnolence (RR 1.44, 99% CI 0.67 to 3.09). AUTHORS' CONCLUSIONS: This review has shown lacosamide to be effective and fairly well tolerated in the short term when used as add-on treatment for drug-resistant partial epilepsy in adults. Higher doses of lacosamide may be more associated with adverse effects and withdrawal of the drug than lower doses. Additional evidence on children is needed, and longer-term efficacy is unknown.

Diagnosis of VTE postdischarge for major abdominal and pelvic oncologic surgery: implications for a change in practice.

BACKGROUND: Extended thromboprophylaxis after hospital discharge following cancer surgery has been shown to reduce the incidence of venous thromboembolism (VTE); however, this practice has not been universally adopted. We conducted a population-based analysis to determine the proportion of patients with symptomatic VTE diagnosed within 90 days after initial discharge following major abdominopelvic cancer surgery who might have benefited from extended thromboprophylaxis. METHODS: We used the Manitoba Cancer Registry to identify patients who underwent major abdominopelvic cancer surgery between 2004 and 2009. The proportion in whom VTE was diagnosed during the initial hospital stay was determined by accessing the Hospital Separations Abstracts. The proportion in whom VTE was diagnosed after discharge was determined by examining repeat admissions within 90 days and by accessing Drug Programs Information Network records for newly prescribed anticoagulants. Detailed tumour and treatment-specific data allowed calculation of VTE predictors. RESULTS: Of 6612 patients identified, 106 (1.60%) had VTE diagnosed during the initial stay and 96 (1.45%) presented with VTE after discharge. Among patients in whom VTE developed after discharge, 33.3% had a pulmonary embolus, 24% had deep vein thrombosis, and 6.3% had both. Predictors of presenting with VTE after discharge within 90 days of surgery included advanced disease, presence of other complications, increased hospital resource utilization, primary tumours of noncolorectal gastrointestinal origin and age younger than 45 years. The development of VTE was an independent predictor of decreased 5-year overall survival. CONCLUSION: The cumulative incidence of VTE within 90 days of major abdominopelvic oncologic surgery was 3.01%, with about half (1.45%) having been diagnosed within 90 days after discharge.

CONTEXTE: La thromboprophylaxie prolongée après le congé hospitalier suite à une chirurgie pour cancer a permis de réduire l'incidence de la thrombo-embolie veineuse (TEV); or, cette pratique n'a pas été universellement adoptée. Nous avons procédé à une analyse de population afin de déterminer la proportion de patients qui ont reçu un diagnostic de TEV symptomatique dans les 90 jours suivant leur congé à la suite d'une chirurgie majeure pour cancer abdomino-pelvien et qui auraient pu bénéficier d'une thromboprophylaxie prolongée. MÉTHODES: Nous avons utilisé le registre du cancer du Manitoba pour recenser les patients ayant subi une chirurgie majeure pour cancer abdomino-pelvien entre 2004 et 2009. La proportion de patients chez qui une TEV a été diagnostiquée au cours du séjour hospitalier initial a été calculée à partir des sommaires d'hospitalisation préparés au congé du patient. La proportion de patients chez qui la TEV a été diagnostiquée après le congé provient de l'examen des dossiers de réadmission dans les 90 jours et du réseau provincial d'information sur les programmes de médicaments pour les anticoagulants nouvellement prescrits. L'analyse des données détaillées sur les tumeurs et les traitements a permis d'établir les prédicteurs de la TEV. RÉSULTANTS: Sur 6612 patients recensés, 106 (1,60 %) ont reçu un diagnostic de TEV durant leur séjour initial et 96 (1,45 %), après leur congé. Parmi les patients chez qui la TEV est survenue après le congé, 33,3 % ont souffert d'une embolie pulmonaire, 24 %, d'une thrombose veineuse profonde et 6,3 %, des deux. Les prédicteurs de la TEV consécutive au congé hospitalier dans les 90 jours suivant une chirurgie incluaient : maladie avancée, présence d'autres complications, utilisation accrue des ressources hospitalières, tumeur primitive d'origine gastro-intestinale non colorectale et âge < 45 ans. La TEV s'est révélée être un prédicteur indépendant d'une plus brève survie globale à 5 ans. CONCLUSION: L'incidence cumulative des TEV dans les 90 jours suivant une chirurgie majeure pour cancer abdomino-pelvien a été de 3,01 %, environ la moitié des cas (1,45 %) ayant été diagnostiqués dans les 90 jours suivant le congé.

Is obesity associated with advanced stage or grade of colon cancer?

Population-based studies from Europe have suggested that obesity is associated with more advanced stage colorectal cancer on presentation. Obesity is an even more prevalent issue in North America, but comparable data on associations with cancer are lacking. We reviewed the cases of 672 patients with colon cancer diagnosed between 2004 and 2008 in the province of Manitoba who underwent surgical resection at a Winnipeg Regional Health Authority­affiliated hospital. We tested if obesity was associated with more advanced cancer stage or grade. On multivariate analysis, after adjusting for age, sex,tumour location and socioeconomic status, we were unable to show any significant associations between body mass index of 30 or more and advanced stage or grade cancer on presentation. The reasons for the lack of association are likely multifactorial, including the pathophysiology of the disease and process factors, such as screening habits and colonoscopic diagnostic success rates in obese patients.

Documentation of quality of care data for colon cancer surgery: comparison of synoptic and dictated operative reports.

BACKGROUND: Operative reports are a source of clinical data that can, for quality assurance purposes, be used to document the performance of processes that affect the care of surgical patients. We assessed the degree to which synoptic reports document operative quality indicators for colon cancer surgery. METHODS: Two reviewers independently reviewed 80 prospectively collected synoptic colon cancer operative reports and a case-matched historical cohort of 80 dictated reports. Reviewers rated how well reports documented performance of quality of care indicators using two checklists of previously validated, colon cancer-specific quality measures. Interrater agreement and time to extract data were also recorded. RESULTS: Synoptic reports had significantly higher overall scores on the quality indictors in comparison to dictated reports for both checklist 1 [mean adjusted score ± standard deviation 18.6 ± 1.3 vs. 9.2 ± 3.6, p < 0.01 (maximum score 38)] and checklist 2 [2.0 ± 0.3 vs. 1.3 ± 1.1, p < 0.01 (maximum score 3)]. Interrater agreement was significantly higher between synoptic reports for both checklists (data not shown). Data were extracted significantly more quickly from synoptic reports than dictated reports [mean time (minutes:seconds) ± standard deviation 2:32 ± 0:44 vs. 4:01 ± 1:14, p < 0.01]. CONCLUSIONS: Synoptic reports were associated with more complete documentation of quality indicators for colon cancer resection compared to dictated reports. Although synoptic reports may improve the documentation of quality of care data, further refinement may help to better document performance of quality measures and improve reporting standards.