Using prostate-specific membrane antigen positron-emission tomography to guide prostate biopsies and stage men at high-risk of prostate cancer.

OBJECTIVE: To assess whether a diagnostic pathway in which prostate-specific membrane antigen (PSMA) positron-emission tomography (PET)/computed tomography (CT) is used as a single imaging modality is feasible to guide targeted biopsy and to detect clinically significant prostate cancer (csPCa) in biopsy-naïve men at high-risk of disease. PATIENTS AND METHODS: A total of 60 men with a prostate-specific antigen (PSA) level of 20-50 ng/mL underwent 18 F-PSMA(DCFPyL)-PET/CT prior to prostate biopsies in this prospective, non-randomised cohort study. Magnetic resonance imaging (MRI) was not performed. Using a 12-segment mapping model of the prostate, PSMA-guided targeted biopsy was performed along with systematic biopsies. The detection rate of PCa and csPCa was assessed for combined systematic and targeted biopsy, and for targeted biopsy only. csPCa was defined as a prostate biopsy with an International Society of Uropathology (ISUP) Grade Group ≥2. RESULTS: Lesions suspicious for PCa in the prostate gland were observed on all PSMA-PET/CTs. A total of 27/60 men (45%) already had metastatic disease on staging 18 F-PSMA(DCFPyL)-PET/CT. Combined PSMA-guided targeted and systematic biopsies detected PCa in 56/60 (93.3%) patients, with 52 of them (92.9%) having csPCa. PSMA-guided targeted biopsy, if performed as a single biopsy modality, identified PCa in 52/60 men (86.7%) and in 27/27 men (100%) men with metastases. CONCLUSIONS: Using the PSMA-driven single imaging modality pathway in biopsy-naïve men at high-risk of PCa, a substantial number of diagnostic MRI scans could be avoided while at the same time obtaining adequate targeting, staging, and detection of csPCa.

Cancer detection and complications of transperineal prostate biopsy with antibiotics when indicated.

OBJECTIVES: To describe the prostate cancer (PCa) detection rate, including clinically significant prostate cancer (csPCa), in a large cohort of patients who underwent transperineal ultrasonography-guided systematic prostate biopsy (TPB-US) using a probe-mounted transperineal access system, with magnetic resonance imaging (MRI) cognitive fusion in case of a Prostate Imaging-Reporting and Data System grade 3-5 lesion, under local anaesthesia in an outpatient setting. Additionally, to compare the incidence of procedure-related complications with a cohort of patients undergoing transrectal ultrasonography-guided (TRB-US) and transrectal MRI-guided biopsies (TRB-MRI). PATIENTS AND METHODS: This was an observational cohort study in men who underwent TPB-US prostate biopsy in a large teaching hospital. For each participant, prostate-specific antigen level, clinical tumour stage, prostate volume, MRI parameters, number of (targeted) prostate biopsies, biopsy International Society of Uropathology (ISUP) grade and procedure-related complications were assessed. csPCa was defined as ISUP grade ≥2. Antibiotic prophylaxis was only given in those with an increased risk of urinary tract infection. RESULTS: A total of 1288 TPB-US procedures were evaluated. The overall detection rate for PCa in biopsy-naive patients was 73%, and for csPCa it was 63%. The incidence of hospitalization was 1% in TPB-US (13/1288), compared to 4% in TRB-US (8/214) and 3% in TRB-MRI (7/219; P = 0.002). CONCLUSIONS: Contemporary combined systematic and target TPB-US with MRI cognitive fusion is easy to perform in an outpatient setting, with a high detection rate of csPCa and a low incidence of procedure-related complications.

Evaluating machine learning algorithms to Predict 30-day Unplanned REadmission (PURE) in Urology patients.

BACKGROUND: Unplanned hospital readmissions are serious medical adverse events, stressful to patients, and expensive for hospitals. This study aims to develop a probability calculator to predict unplanned readmissions (PURE) within 30-days after discharge from the department of Urology, and evaluate the respective diagnostic performance characteristics of the PURE probability calculator developed with machine learning (ML) algorithms comparing regression versus classification algorithms. METHODS: Eight ML models (i.e. logistic regression, LASSO regression, RIDGE regression, decision tree, bagged trees, boosted trees, XGBoost trees, RandomForest) were trained on 5.323 unique patients with 52 different features, and evaluated on diagnostic performance of PURE within 30 days of discharge from the department of Urology. RESULTS: Our main findings were that performances from classification to regression algorithms had good AUC scores (0.62-0.82), and classification algorithms showed a stronger overall performance as compared to models trained with regression algorithms. Tuning the best model, XGBoost, resulted in an accuracy of 0.83, sensitivity of 0.86, specificity of 0.57, AUC of 0.81, PPV of 0.95, and a NPV of 0.31. CONCLUSIONS: Classification models showed stronger performance than regression models with reliable prediction for patients with high probability of readmission, and should be considered as first choice. The tuned XGBoost model shows performance that indicates safe clinical appliance for discharge management in order to prevent an unplanned readmission at the department of Urology.

STUDY NEED AND IMPORTANCE: Unplanned readmissions form a consistent problem for many hospitals. Unplanned readmission rates can go up as high as to 35%, and may differ significantly between respective hospital departments. In addition, in the field of Urology readmission rates can be greatly influenced by type of surgery performed and unplanned readmissions in patients can go up as high as 26%. Although predicting unplanned readmissions for individual patients is often complex, due to multiple factors that need to be taken into account (e.g. functional disability, poor overall condition), there is evidence that these can be prevented when discharge management is evaluated with an objective measuring tool that facilitate such risk stratification between high and low risk patients. However, to the best of our knowledge, the latter risk stratification using ML driven probability calculators in the field of Urology have not been evaluated to date. Using ML, calculated risk scores based on analysing complex data patterns on patient level can support safe discharge and inform concerning the risk of having an unplanned readmission. WHAT WE FOUND: Eight ML models were trained on 5.323 unique patients with 52 different features, and evaluated on diagnostic performance. Classification models showed stronger performance than regression models with reliable prediction for patients with high probability of readmission, and should be considered as first choice. The tuned XGBoost model shows performance that indicates safe clinical appliance for discharge management in order to prevent an unplanned readmission at the department of Urology. Limitations of our study were the quality and presence of patient data on features, and how to implement these findings in clinical setting to transition from predicting to preventing unplanned readmissions. INTERPRETATION FOR CLINICIANS: ML models based on classification should be first choice to predict unplanned readmissions, and the XGBoost model showed the strongest results.

Lung cancer care trajectory at a Canadian centre: an evaluation of how wait times affect clinical outcomes.

BACKGROUND: Lung cancer continues to be one of the most common cancers in Canada, with approximately 28,400 new cases diagnosed each year. Although timely care can contribute substantially to quality of life for patients, it remains unclear whether it also improves patient outcomes. In this work, we used a set of quality indicators that aim to describe the quality of care in lung cancer patients. We assessed adherence with existing guidelines for timeliness of lung cancer care and concordance with existing standards of treatment, and we examined the association between timeliness of care and lung cancer survival. METHODS: Patients with lung cancer diagnosed between 2010 and 2015 were identified from the Pulmonary Division Lung Cancer Registry at our centre. RESULTS: We demonstrated that the interdisciplinary pulmonary oncology service successfully treated most of its patients within the recommended wait times. However, there is still work to be done to decrease variation in wait time. Our results demonstrate a significant association between wait time and survival, supporting the need for clinicians to optimize the patient care trajectory. INTERPRETATION: It would be helpful for Canadian clinicians treating patients with lung cancer to have wait time guidelines for all treatment modalities, together with standard definitions for all time intervals. Any reductions in wait times should be balanced against the need for thorough investigation before initiating treatment. We believe that our unique model of care leads to an acceleration of diagnostic steps. Avoiding any delay associated with referral to a medical oncologist for treatment could be an acceptable strategy with respect to reducing wait time.

Dipeptidyl peptidase-4 inhibitors and the risk of community-acquired pneumonia in patients with type 2 diabetes.

AIMS: To determine whether the use of dipeptidyl peptidase-4 (DPP-4) inhibitors is associated with an increased risk of community-acquired pneumonia. METHODS: The UK Clinical Practice Research Datalink and the Hospital Episodes Statistics database were used to conduct a nested case-control analysis within a cohort of new users of antidiabetic drugs between 2007 and 2012. Incident cases of hospitalization for community-acquired pneumonia were matched with up to 20 controls on age, duration of treated diabetes, calendar year and duration of follow-up. Conditional logistic regression models were used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for hospitalization for community-acquired pneumonia associated with current use of DPP-4 inhibitors compared with current use of two or more oral antidiabetic drugs. RESULTS: The cohort included 49,653 patients, of whom 562 were hospitalized for community-acquired pneumonia during follow-up (incidence rate 5.2/1000 person-years). Compared with current use of two or more oral antidiabetic drugs, current use of DPP-4 inhibitors was not associated with an increased risk of hospitalized community-acquired pneumonia overall (adjusted OR 0.80, 95% CI 0.50-1.29) or according to duration of use (p for trend = 0.57). CONCLUSIONS: The use of DPP-4 inhibitors was not associated with an increased risk of hospitalization for community-acquired pneumonia. Additional research is needed to assess the association between these drugs and other serious infections.

The optimal duration of frequency-volume charts related to compliance and reliability.

AIMS: To assess Frequency-volume charts (FVCs) for the yield of additional recorded days and the ideal duration of recording related to compliance and reliability. METHODS: Of 500 consecutive urologic outpatients willing to complete a 7-day FVC, 378 FVCs were evaluable. During seven consecutive days every voiding time and volume were recorded. Missed entries were indicated with a coded letter, thereby assessing the true frequency and compliance. Reliability is the agreement of the day-to-day FVC parameters with the 7-day FVC pattern. Single-day reliability was assessed and used in the Spearman-Brown formula. RESULTS: FVCs of 228 male and 150 females were evaluated. Mean age was 55.2 years (standard deviation [SD]: 16.2 years), and mean 24-hr urine production was 1,856 ml (SD: 828 ml). The percentage of patients with complete FVCs decreased from 78% on day 2 to 58% on day 7, and dropped below 70% after 4 days. Single-day reliability was r = 0.63 for nocturnal urine production, r = 0.72 for 24-hr urine production, and r = 0.80 for mean voided volume. At 5 days, reliability of 90% was achieved for all parameters. CONCLUSIONS: With each additional day, FVCs showed a decrease in compliance and an increase in reliability. At day 3, reliability of 80% was achieved for all FVC parameters, but compliance dropped to 73%. Beyond 5 days, the yield of additional recorded days was limited. We advocate an FVC duration of 3 days, but the duration may be shortened or extended depending on the goal of the FVC.

Implications of resampling data to address the class imbalance problem (IRCIP): an evaluation of impact on performance between classification algorithms in medical data.

Objective: When correcting for the "class imbalance" problem in medical data, the effects of resampling applied on classifier algorithms remain unclear. We examined the effect on performance over several combinations of classifiers and resampling ratios. Materials and Methods: Multiple classification algorithms were trained on 7 resampled datasets: no correction, random undersampling, 4 ratios of Synthetic Minority Oversampling Technique (SMOTE), and random oversampling with the Adaptive Synthetic algorithm (ADASYN). Performance was evaluated in Area Under the Curve (AUC), precision, recall, Brier score, and calibration metrics. A case study on prediction modeling for 30-day unplanned readmissions in previously admitted Urology patients was presented. Results: For most algorithms, using resampled data showed a significant increase in AUC and precision, ranging from 0.74 (CI: 0.69-0.79) to 0.93 (CI: 0.92-0.94), and 0.35 (CI: 0.12-0.58) to 0.86 (CI: 0.81-0.92) respectively. All classification algorithms showed significant increases in recall, and significant decreases in Brier score with distorted calibration overestimating positives. Discussion: Imbalance correction resulted in an overall improved performance, yet poorly calibrated models. There can still be clinical utility due to a strong discriminating performance, specifically when predicting only low and high risk cases is clinically more relevant. Conclusion: Resampling data resulted in increased performances in classification algorithms, yet produced an overestimation of positive predictions. Based on the findings from our case study, a thoughtful predefinition of the clinical prediction task may guide the use of resampling techniques in future studies aiming to improve clinical decision support tools.

Spontaneous autoimmune gastritis and hypochlorhydria are manifest in the ileitis-prone SAMP1/YitFcs mice.

SAMP1/YitFcs mice serve as a model of Crohn's disease, and we have used them to assess gastritis. Gastritis was compared in SAMP1/YitFcs, AKR, and C57BL/6 mice by histology, immunohistochemistry, and flow cytometry. Gastric acid secretion was measured in ligated stomachs, while anti-parietal cell antibodies were assayed by immunofluorescence and enzyme-linked immunosorbent spot assay. SAMP1/YitFcs mice display a corpus-dominant, chronic gastritis with multifocal aggregates of mononuclear cells consisting of T and B lymphocytes. Relatively few aggregates were observed elsewhere in the stomach. The infiltrates in the oxyntic mucosa were associated with the loss of parietal cell mass. AKR mice, the founder strain of the SAMP1/YitFcs, also have gastritis, although they do not develop ileitis. Genetic studies using SAMP1/YitFcs-C57BL/6 congenic mice showed that the genetic regions regulating ileitis had comparable effects on gastritis. The majority of the cells in the aggregates expressed the T cell marker CD3 or the B cell marker B220. Adoptive transfer of SAMP1/YitFcs CD4(+) T helper cells, with or without B cells, into immunodeficient recipients induced a pangastritis and duodenitis. SAMP1/YitFcs and AKR mice manifest hypochlorhydria and anti-parietal cell antibodies. These data suggest that common genetic factors controlling gastroenteric disease in SAMP1/YitFcs mice regulate distinct pathogenic mechanisms causing inflammation in separate sites within the digestive tract.

A cutoff value based on analysis of a reference population decreases overestimation of the prevalence of nocturnal polyuria.

PURPOSE: We sought criteria for nocturnal polyuria in asymptomatic, nonurological adults of all ages by reporting reference values of the ratio of daytime and nighttime urine volumes, and finding nocturia predictors. MATERIALS AND METHODS: Data from a database of frequency-volume charts from a reference population of 894 nonurological, asymptomatic volunteers of all age groups were analyzed. The nocturnal polyuria index and the nocturia index were calculated and factors influencing these values were determined by multivariate analysis. RESULTS: The nocturnal polyuria index had wide variation but a normal distribution with a mean ± SD of 30% ± 12%. The 95th percentile of the values was 53%. Above this cutoff a patient had nocturnal polyuria. This value contrasts with the International Continence Society definition of 33% but agrees with several other reports. On multivariate regression analysis with the nocturnal polyuria index as the dependent variable sleeping time, maximum voided volume and age were the covariates. However, the increase in the nocturnal polyuria index by age was small. Excluding polyuria and nocturia from analysis did not alter the results in a relevant way. The nocturnal voiding frequency depended on sleeping time and maximum voided volume but most of all on the nocturia index. CONCLUSIONS: The prevalence of nocturnal polyuria is overestimated. We suggest a new cutoff value for the nocturnal polyuria index, that is nocturnal polyuria exists when the nocturnal polyuria index exceeds 53%. The nocturia index is the best predictor of nocturia.

The international prostate symptom score overestimates nocturia assessed by frequency-volume charts.

PURPOSE: We analyzed differences in nocturia, as estimated by the International Prostate Symptom Score and 7-day frequency-volume charts. MATERIALS AND METHODS: A total of 398 forms were collected from 500 consecutive urological outpatients willing to record a 7-day frequency-volume chart. All patients completed a general questionnaire, an International Prostate Symptom Score, and a bladder symptom and bother score. Missed recordings were indicated by a coded letter. Patients who lacked essential data, bedtimes or an International Prostate Symptom Score, or who recorded the frequency-volume chart for less than 5 days were excluded from study. RESULTS: A total of 186 men and 115 women with a mean age of 56 years were evaluable. In 10.6% of patients no nocturia occurred. Of those with nocturia 70% and 34% experienced nocturia a mean of 1 or more and 2 or more times, respectively. In 43% of patients the International Prostate Symptom Score equaled calculated categorized nocturia while 50% had a higher International Prostate Symptom Score nocturia score than calculated nocturia. On univariate analysis the correlation of International Prostate Symptom Score question 7 with mean nocturia increased with frequency-volume chart duration (day 1 r = 0.52 to day 3 r = 0.63). On longer duration frequency-volume charts the correlation showed no further increase. Multivariate regression analysis revealed that the nocturia score was determined by mean nocturia in the frequency-volume chart, the nocturia bother score and patient age. CONCLUSIONS: The International Prostate Symptom Score nocturia score overestimated nocturia in most patients, as derived from a 7-day frequency-volume chart. When scoring International Prostate Symptom Score nocturia question 7, patients included a degree of bother. The correlation of question 7 with mean nocturia increased with frequency-volume chart duration until day 3.

Time-of-flight mass spectrometry of particle emission during irradiation with slow, highly charged ions.

We describe a setup for the analysis of secondary ions and neutrals emitted from solid surfaces and two-dimensional materials during irradiation with highly charged ions. The ultrahigh vacuum setup consists of an electron beam ion source to produce bunches of ions with various charge states q (e.g., Xe1+-Xe46+) and thus potential energies, a deceleration/acceleration section to tune the kinetic energy of the ions in the range of 5 keV to 20 × q keV, a sample stage for laser-cleaning and positioning of freestanding as well as supported samples, a pulsed excimer laser for post-ionization of sputtered neutrals, and a reflectron type time-of-flight mass spectrometer, enabling us to analyze mass and velocity distributions of the emitted particles. With our setup, contributions from potential and kinetic energy deposition can be studied independently of each other. Charge dependent experiments conducted at a constant kinetic energy show a clear threshold for the emission of secondary ions from SrTiO3. Data taken with the same projectile charge state, but at a different kinetic energy, reveal a difference in the ratio of emitted particles from MoS2. In addition, first results are presented, demonstrating how velocity distributions can be measured with the new setup.

Highly Efficient Semi-Continuous Extraction and In-Line Purification of High ß-O-4 Butanosolv Lignin.

Innovative biomass fractionation is of major importance for economically competitive biorefineries. Lignin is currently severely underutilized due to the use of high severity fractionation methodologies that yield complex condensed lignin that limits high-value applicability. Mild lignin fractionation conditions can lead to lignin with a more regular C-O bonded structure that has increased potential for higher value applications. Nevertheless, such extraction methodologies typically suffer from inadequate lignin extraction efficiencies and yield. (Semi)-continuous flow extractions are a promising method to achieve improved extraction efficiency of such C-O linked lignin. Here we show that optimized organosolv extraction in a flow-through setup resulted in 93-96% delignification of 40 g walnut shells (40 wt% lignin content) by applying mild organosolv extraction conditions with a 2 g/min flowrate of a 9:1 n-butanol/water mixture with 0.18 M H2SO4 at 120°C in 2.5 h. 85 wt% of the lignin (corrected for alcohol incorporation, moisture content and carbohydrate impurities) was isolated as a powder with a high retention of the ß-aryl ether (ß-O-4) content of 63 linking motifs per 100 C9 units. Close examination of the isolated lignin showed that the main carbohydrate contamination in the recovered lignin was butyl-xyloside and other butoxylate carbohydrates. The work-up and purification procedure were investigated and improved by the implementation of a caustic soda treatment step and phase separation with a continuous integrated mixer/separator (CINC). This led to a combined 75 wt% yield of the lignin in 3 separate fractions with 3% carbohydrate impurities and a very high ß-O-4 content of 67 linking motifs per 100 C9 units. Analysis of all the mass flows showed that 98% of the carbohydrate content was removed with the inline purification step, which is a significant improvement to the 88% carbohydrate removal for the traditional lignin precipitation work-up procedure. Overall we show a convenient method for inline extraction and purification to obtain high ß-O-4 butanosolv lignin in excellent yields.

Computer-aided discovery, validation, and mechanistic characterization of novel neolignan activators of peroxisome proliferator-activated receptor gamma.

Peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists are used for the treatment of type 2 diabetes and metabolic syndrome. However, the currently used PPAR gamma agonists display serious side effects, which has led to a great interest in the discovery of novel ligands with favorable properties. The aim of our study was to identify new PPARgamma agonists by a PPAR gamma pharmacophore-based virtual screening of 3D natural product libraries. This in silico approach led to the identification of several neolignans predicted to bind the receptor ligand binding domain (LBD). To confirm this prediction, the neolignans dieugenol, tetrahydrodieugenol, and magnolol were isolated from the respective natural source or synthesized and subsequently tested for PPAR gamma receptor binding. The neolignans bound to the PPAR gamma LBD with EC(50) values in the nanomolar range, exhibiting a binding pattern highly similar to the clinically used agonist pioglitazone. In intact cells, dieugenol and tetrahydrodieugenol selectively activated human PPAR gamma-mediated, but not human PPAR alpha- or -beta/delta-mediated luciferase reporter expression, with a pattern suggesting partial PPAR gamma agonism. The coactivator recruitment study also demonstrated partial agonism of the tested neolignans. Dieugenol, tetrahydrodieugenol, and magnolol but not the structurally related eugenol induced 3T3-L1 preadipocyte differentiation, confirming effectiveness in a cell model with endogenous PPAR gamma expression. In conclusion, we identified neolignans as novel ligands for PPAR gamma, which exhibited interesting activation profiles, recommending them as potential pharmaceutical leads or dietary supplements.

A role for stem cell factor and c-kit in the murine intestinal tract secretory response to cholera toxin.

The role of stem cell factor (SCF) and its receptor (c-kit) in the intestinal secretory response to cholera toxin (CT) was investigated using a ligated intestinal loop model in mice having mutations in the dominant white spotting (W) locus and the steel (Sl) locus. W/Wv mice, which express an aberrant form of the c-kit protein, failed to give an intestinal secretory response after luminal CT challenge. In contrast, W/Wv mice and their control littermates had equivalent intestinal secretory responses to Escherichia coli heat-stable enterotoxin (STa). Sl/Sld mice, which express only a soluble truncated form of SCF, also gave a significantly reduced intestinal secretory response to CT when compared to the secretory response of their littermate controls. The unresponsiveness of W/Wv mice to CT was restricted to the intestinal tract since these mice had foot pad swelling responses to CT challenge that were equivalent to their littermate controls. Restoration of mast cells in W/Wv mice by bone marrow transplantation of control littermate bone marrow did not reverse the CT-unresponsiveness of the intestinal tract. Histological evaluation of the gastrointestinal tract from W/Wv mice showed a normal distribution of enterochromaffin cells (ECC). CT challenge of either ligated intestinal loops from C57B1/6 mice or a mouse intestinal epithelial cell line (MODE-K) resulted in elevated levels of mRNA for SCF. MODE-K cells exposed to CT also had enhanced expression of c-kit. Finally, fluid obtained from CT-challenged ligated intestinal loops from C57B1/6 mice contained significant levels of SCF. Taken together, the above results suggest that CT-induced intestinal secretory responses are dependent upon SCF-c-kit interactions. These interactions appear to be induced as a consequence of CT stimulation of the intestinal tract and may also play a role in the development or functionality of the enteric nervous system.

The effect of class II major histocompatibility complex expression on adherence of Helicobacter pylori and induction of apoptosis in gastric epithelial cells: a mechanism for T helper cell type 1-mediated damage.

Helicobacter pylori infection is associated with gastric epithelial damage, including apoptosis, ulceration, and cancer. Although bacterial factors and the host response are believed to contribute to gastric disease, no receptor has been identified that explains how the bacteria attach and signal the host cell to undergo apoptosis. Using H. pylori as "bait" to capture receptor proteins in solubilized membranes of gastric epithelial cells, class II major histocompatibility complex (MHC) molecules were identified as a possible receptor. Signaling through class II MHC molecules leading to the induction of apoptosis was confirmed using cross-linking IgM antibodies to surface class II MHC molecules. Moreover, binding of H. pylori and the induction of apoptosis were inhibited by antibodies recognizing class II MHC. Since type 1 T helper cells are present during infection and produce interferon (IFN)-gamma, which increases class II MHC expression, gastric epithelial cell lines were exposed to H. pylori in the presence or absence of IFN-gamma. IFN-gamma increased the attachment of the bacteria as well as the induction of apoptosis in gastric epithelial cells. In contrast to MHC II-negative cell lines, H. pylori induced apoptosis in cells expressing class II MHC molecules constitutively or after gene transfection. These data describe a novel receptor for H. pylori and provide a mechanism by which bacteria and the host response interact in the pathogenesis of gastric epithelial cell damage.

Geographical variations in the prevalence of atopic sensitization in six study sites across Canada.

BACKGROUND: Geographical variations in atopic sensitization in Canada have not been described previously. This study used the standardized protocol of the European Community Respiratory Health Survey-1 (ECRHS-1) to investigate the distribution and predictors of atopic sensitization in six sites across Canada and to compare the results with some ECRHS-1 centers. METHODS: Adults aged 20-44 years in six study sites across Canada underwent allergy skin testing using 14 allergens (Dermatophagoides pteronyssinus, Dermatophagoides farinae) cat, cockroach, grasses (Timothy grass, Kentucky grass), molds (Cladosporium herbarium, Alternaria alternata, Aspergillus fumigatus, Penicillium), trees (tree mix, birch, Olea europea), and common ragweed. RESULTS: The overall prevalence of atopy (skin test over 0 mm to any allergen) was 62.7%. There was significant geographical variation in the prevalence of atopy in the six study sites (lowest 55.6% [95% C.I.51.3-59.9] in Prince Edward Island, highest 66.0 [61.7-70.3] in Montreal) and of sensitization to each of the allergens tested even after adjustment for confounders. When the first eight of the nine allergens in the ECRHS were used to estimate the prevalence of atopic sensitization, the prevalence of atopy in Canada was 57% compared with 35.2% overall for centers in the ECRHS. The prevalence of atopy in Vancouver (57% [52.3-61.8]) was close to that of Portland, Oregon (52.1% [46.2-58.0]). CONCLUSION: There was a significant variation in atopic sensitization among different study sites across Canada. The prevalence of atopic sensitization is relatively high in Canada compared with sites in the ECRHS and this may, in part, account for the high prevalence of asthma and asthma symptoms in Canada.

Cotinus coggygria wood: novel flavanone dimer and development of an HPLC/UV/MS method for the simultaneous determination of fourteen phenolic constituents.

Phytochemical investigations of Cotinus coggygria Scop. wood, a medicinal and tinctorial plant used since antiquity, resulted in the isolation and structure elucidation of the novel C-3/C-3'' dimer of butin (3',4',7-trihydroxyflavanone) and other known compounds: gallic acid and its methyl ester; catechin; profisetinidins: fisetinidol-(4α→8)-(+)-catechin and epifisetinidol-(4ß→8)-(+)-catechin; flavanonols: fustin and dihydroquercetagetin; flavanones: butin and eriodictyol; flavonols: fisetin and quercetin; the chalcone butein and the aurone sulfuretin. The isolated compounds were used for the development and validation of a HPLC-method which enables the determination of these bioactive substances in C. coggygria extracts. Separation was possible on an ether-linked phenyl column material, using as mobile phase mixtures of water, methanol, and acetonitrile with 0.02% trifluoroacetic acid. Sensitivity, selectivity, linearity, precision, accuracy, and repeatability of the method were verified and assured suitability for its intended use. LC-MS experiments performed in positive and negative electrospray ionization mode confirmed the identity of analytes and allowed unambiguous assignment of all peaks of interest. The analysis of different C. coggygria samples revealed that sulfuretin (0.38-0.69%) and fustin (0.33-0.59%) dominated, followed by dihydroquercetagetin (0.12-0.35%), a rare flavanonol derivative with a 5,6,7-trihydroxysubstituted A-ring. The new natural compound C-3/C-3'' flavanone dimer occurred in concentrations of 0.03-0.06%; the two latter compounds could represent valuable markers for the identification and quality control of C. coggygria wood.

Fluoroquinolone use for uncomplicated urinary tract infections in women: a retrospective cohort study.

OBJECTIVES: The United States Food & Drug Administration released an advisory in 2016 that fluoroquinolones be relegated to second-line agents for uncomplicated urinary tract infections (UTIs) given reports of rare but serious side effects; similar warnings have followed from Health Canada and the European Medicines Agency. The objective was to determine whether alternative non-fluoroquinolone agents are as effective as fluoroquinolones in the treatment of UTIs. METHODS: We conducted a retrospective population-based cohort study using administrative health data from six Canadian provinces. We identified women (n = 1 585 997) receiving antibiotic treatment for episodes of uncomplicated UTIs (n = 2 857 243) between January 1 2005 and December 31 2015. Clinical outcomes within 30 days from the initial antibiotic dispensation were compared among patients treated with a fluoroquinolone versus non-fluoroquinolone agents. High-dimensional propensity score adjustments were used to ensure comparable treatment groups and to minimize residual confounding. RESULTS: Fluoroquinolone use for UTI declined over the study period in five of six Canadian provinces and accounted for 22.3-48.5% of treatments overall. The pooled effect across the provinces indicated that fluoroquinolones were associated with fewer return outpatient visits (OR 0.89, 95%CI 0.87-0.92), emergency department visits (OR 0.74, 95%CI 0.61-0.89), hospitalizations (OR 0.83, 95%CI 0.77-0.88), and repeat antibiotic dispensations (OR 0.77, 95%CI 0.75-0.80) within 30 days. CONCLUSIONS: Fluoroquinolones are associated with improved clinical outcomes among women with uncomplicated UTIs. This benefit must be weighed against the risk of fluoroquinolone resistance and rare but serious fluoroquinolone side effects when selecting first-line treatment for these patients.

Inter- and Intraobserver Agreement in Measuring Urolithiasis Density on Nonenhanced Computed Tomography.

Introduction: Treatment choice for urolithiasis is partially based on measuring stone density in HU on nonenhanced computed tomography (NECT). Interobserver variability in these measurements could have treatment consequences. This study aims to assess the observer agreement of measuring HU and whether the use of a protocol leads to a better agreement. Materials and Methods: We retrospectively included 155 consecutive NECTs of patients with stones ≥4 mm. Five observers (two radiologists, one urologist, one urology resident, and one radiology resident) assessed all anonymized NECTs four times in randomized order. HU was measured without instruction (rounds 1 and 2) and subsequently using two protocols (A and B, rounds 3 and 4). Protocols comprised using bone setting, zoom, and measuring HU without the penumbra, in either three (A) or one (B) axial plane. The inter- and intraobserver agreement was evaluated using the intraclass correlation coefficient (ICC). Results: Interobserver agreement on HU measurement without protocol was as follows: ICC = 0.84 (confidence interval [CI]: 0.79-0.87). Agreement diminished with protocol A, ICC = 0.62 (CI: 0.37-0.76), and improved with protocol B, ICC = 0.90 (CI: 0.86-0.92). Intraobserver agreement without protocol was ICC = 0.87, with protocol A, ICC = 0.87, and with protocol B, ICC = 0.93. The biggest improvement was seen for urologists' agreement from no protocol to protocol B, where ICC improved from 0.81 (CI: 0.70-0.87) to 0.91 (CI: 0.84-0.94). Conclusions: Observer agreement of HU measurement of urolithiasis without protocol is already good but using zoom, bone setting, and measuring in a representative plane is recommended. This protocol results in higher agreement, especially among urologists. Measuring in three axial planes does not increase agreement.

Iridoid glycosides from the leaves of Sambucus ebulus.

Six new iridoid glycosides (1-6) of the "Valeriana type" were isolated from leaves of Sambucus ebulus. The structures were elucidated by 1D- and 2D-NMR spectroscopy, mass spectrometry, and chemical degradation methods as 10-O-acetylpatrinoside-aglycone-11-O-[4''-O-acetyl-alpha-L-rhamnopyranosyl-(1-->2)-beta-D-ribohexo-3-ulopyranoside] (1), 7-O-acetylpatrinoside-aglycone-11-O-[4''-O-acetyl-alpha-L-rhamnopyranosyl-(1-->2)-beta-D-ribohexo-3-ulopyranoside] (2), 10-O-acetylpatrinoside-aglycone-11-O-[alpha-L-rhamnopyranosyl-(1-->2)-beta-D-ribohexo-3-ulopyranoside] (3), patrinoside-aglycone-11-O-[4''-O-acetyl-alpha-L-rhamnopyranosyl-(1-->2)-beta-D-ribohexo-3-ulopyranoside] (4), 10-O-acetylpatrinoside-aglycone-11-O-[4''-O-acetyl-alpha-L-rhamnopyranosyl-(1-->2)-beta-D-glucopyranoside] (5), and patrinoside-aglycone-11-O-2'-deoxy-beta-D-glucopyranoside (6). Compounds 1-4 represent the first examples of acylated iridoid diglycosides bearing the uncommon D-ribohexo-3-ulopyranosyl sugar moiety. Compound 6 is the first iridoid glycoside with a 2-deoxy-D-glucopyranosyl sugar moiety.