Advanced practice physiotherapy care in emergency departments for patients with musculoskeletal disorders: a pragmatic cluster randomized controlled trial and cost analysis.

BACKGROUND: Advanced practice physiotherapy (APP) models of care where physiotherapists are primary contact emergency department (ED) providers are promising models of care to improve access, alleviate physicians' burden, and offer efficient centered patient care for patients with minor musculoskeletal disorders (MSKD). OBJECTIVES: To compare the effectiveness of an advanced practice physiotherapist (APPT)-led model of care with usual ED physician care for persons presenting with a minor MSKD, in terms of patient-related outcomes, health care resources utilization, and health care costs. METHODS: This trial is a multicenter stepped-wedge cluster randomized controlled trial (RCT) with a cost analysis. Six Canadian EDs (clusters) will be randomized to a treatment sequence where patients will either be managed by an ED APPT or receive usual ED physician care. Seven hundred forty-four adults with a minor MSKD will be recruited. The main outcome measure will be the Brief Pain Inventory Questionnaire. Secondary measures will include validated self-reported disability questionnaires, the EQ-5D-5L, and other health care utilization outcomes such as prescription of imaging tests and medication. Adverse events and re-visits to the ED for the same complaint will also be monitored. Health care costs will be measured from the perspective of the public health care system using time-driven activity-based costing. Outcomes will be collected at inclusion, at ED discharge, and at 4, 12, and 26 weeks following the initial ED visit. Per-protocol and intention-to-treat analyses will be performed using linear mixed models with a random effect for cluster and fixed effect for time. DISCUSSION: MSKD have a significant impact on health care systems. By providing innovative efficient pathways to access care, APP models of care could help relieve pressure in EDs while providing efficient care for adults with MSKD. TRIAL REGISTRATION: ClinicalTrials.gov NCT05545917 . Registered on September 19, 2022.

Arterial stiffness for the early prediction of pre-eclampsia compared with blood pressure, uterine artery Doppler and angiogenic biomarkers: a prospective cohort study.

OBJECTIVE: Our aim was to evaluate the ability of arterial stiffness parameters to predict pre-eclampsia early compared with peripheral blood pressure, uterine artery Doppler and established angiogenic biomarkers. DESIGN: Prospective cohort study. SETTING: Tertiary care antenatal clinics in Montreal, Canada. POPULATION: Women with singleton high-risk pregnancies. METHODS: In the first trimester, arterial stiffness was measured by applanation tonometry, along with peripheral blood pressure and serum/plasma angiogenic biomarkers; uterine artery Doppler was measured in the second trimester. The predictive ability of different metrics was assessed through multivariate logistic regression. MAIN OUTCOME MEASURES: Arterial stiffness (carotid-femoral pulse wave velocity, carotid-radial pulse wave velocity) and wave reflection (augmentation index, reflected wave start time), peripheral blood pressure, ultrasound indices of velocimetry and circulating angiogenic biomarker concentrations. RESULTS: In this prospective study, among 191 high-risk pregnant women, 14 (7.3%) developed pre-eclampsia. A first-trimester 1 m/s increase in carotid-femoral pulse wave velocity was associated with 64% increased odds (P < 0.05), and a 1-millisecond increase in time to wave reflection with 11% decreased odds for pre-eclampsia (P < 0.01). The area under the curve of arterial stiffness, blood pressure, ultrasound indices and angiogenic biomarkers was 0.83 (95% confidence interval [CI] 0.74-0.92), 0.71 (95% CI 0.57-0.86), 0.58 (95% CI 0.39-0.77), and 0.64 (95% CI 0.44-0.83), respectively. With a 5% false-positive rate, blood pressure had a sensitivity of 14% for pre-eclampsia and arterial stiffness a sensitivity of 36%. CONCLUSIONS: Arterial stiffness predicted pre-eclampsia earlier and with greater ability than blood pressure, ultrasound indices or angiogenic biomarkers.

Pulse-shape discrimination against low-energy Ar-39 beta decays in liquid argon with 4.5 tonne-years of DEAP-3600 data.

The DEAP-3600 detector searches for the scintillation signal from dark matter particles scattering on a 3.3 tonne liquid argon target. The largest background comes from 39 Ar beta decays and is suppressed using pulse-shape discrimination (PSD). We use two types of PSD estimator: the prompt-fraction, which considers the fraction of the scintillation signal in a narrow and a wide time window around the event peak, and the log-likelihood-ratio, which compares the observed photon arrival times to a signal and a background model. We furthermore use two algorithms to determine the number of photons detected at a given time: (1) simply dividing the charge of each PMT pulse by the mean single-photoelectron charge, and (2) a likelihood analysis that considers the probability to detect a certain number of photons at a given time, based on a model for the scintillation pulse shape and for afterpulsing in the light detectors. The prompt-fraction performs approximately as well as the log-likelihood-ratio PSD algorithm if the photon detection times are not biased by detector effects. We explain this result using a model for the information carried by scintillation photons as a function of the time when they are detected.

First Results from the DEAP-3600 Dark Matter Search with Argon at SNOLAB.

This Letter reports the first results of a direct dark matter search with the DEAP-3600 single-phase liquid argon (LAr) detector. The experiment was performed 2 km underground at SNOLAB (Sudbury, Canada) utilizing a large target mass, with the LAr target contained in a spherical acrylic vessel of 3600 kg capacity. The LAr is viewed by an array of PMTs, which would register scintillation light produced by rare nuclear recoil signals induced by dark matter particle scattering. An analysis of 4.44 live days (fiducial exposure of 9.87 ton day) of data taken during the initial filling phase demonstrates the best electronic recoil rejection using pulse-shape discrimination in argon, with leakage <1.2×10^{-7} (90% C.L.) between 15 and 31 keV_{ee}. No candidate signal events are observed, which results in the leading limit on weakly interacting massive particle (WIMP)-nucleon spin-independent cross section on argon, <1.2×10^{-44} cm^{2} for a 100 GeV/c^{2} WIMP mass (90% C.L.).

Integrating cytokines and angiogenic factors and tumour bulk with selected clinical criteria improves determination of prognosis in advanced renal cell carcinoma.

BACKGROUND: In two clinical trials of the vascular endothelial growth factor (VEGF) receptor inhibitor pazopanib in advanced renal cell carcinoma (mRCC), we found interleukin-6 as predictive of pazopanib benefit. We evaluated the prognostic significance of candidate cytokines and angiogenic factors (CAFs) identified in that work relative to accepted clinical parameters. METHODS: Seven preselected plasma CAFs (interleukin-6, interleukin-8, osteopontin, VEGF, hepatocyte growth factor, tissue inhibitor of metalloproteinases (TIMP-1), and E-selectin) were measured using multiplex ELISA in plasma collected pretreatment from 343 mRCC patients participating in the phase 3 registration trial of pazopanib vs placebo (NCT00334282). Tumour burden (per sum of longest diameters (SLD)) and 10 other clinical factors were also analysed for association with overall survival (OS; based on initial treatment assignment). RESULTS: Osteopontin, interleukin-6, and TIMP-1 were independently associated with OS in multivariable analysis. A model combining the three CAFs and five clinical variables (including SLD) had higher prognostic accuracy than the International Metastatic Renal Cell Carcinoma Database Consortium criteria (concordance-index 0.75 vs 0.67, respectively), and distinguished two groups of patients within the original intermediate risk category. CONCLUSIONS: A prognostic model incorporating osteopontin, interleukin-6, TIMP-1, tumour burden, and selected clinical criteria increased prognostic accuracy for OS determination in mRCC patients.

Northern innovation in rabies prevention and control: The Weeneebayko Area Health Authorities (WAHA) dog population management pilot project.

BACKGROUND: Remote northern communities in Ontario face unique challenges in rabies prevention and control. With large, free-roaming dog populations at high risk of exposure to rabies from wildlife, and a lack of regular access to veterinary services and vaccinations, these communities run a higher risk of human exposure to rabies than southern regions of the province. OBJECTIVE: To provide the baseline data on a novel approach to controlling the dog population in the Weeneebayko Area Health Authority (WAHA) in northern Ontario, implemented as part of a sustainable, humane and cost-effective pilot project to manage dog population numbers and improve public safety. INTERVENTION: In 2015, WAHA launched a large-scale two-year regional project that involved microchipping all dogs in the region to quantify and monitor population levels, vaccinating them with canine core vaccinations (including rabies) and piloting the use of an injectable ganodotropin-releasing hormone (GnRH) agonist contraceptive implant in female dogs. The Project's objectives included control of dog population numbers, reducing aggressive behaviours in community dogs, reducing the risk of rabies in communities, improving the health of community dogs and educating community members about the importance of dog population control. OUTCOMES: In 2015, 513 dogs were microchipped and vaccinated as part of the WAHA Project: 211 females and 301 males. Seventy-six intact, free-roaming females were given the contraceptive implant, 113 females were identified as previously spayed and only 22 females were either too young or too small (toy breeds) to receive an implant. CONCLUSION: While the final outcomes of the WAHA Project are still pending, preliminary findings, including dog population demographics and observed dynamics, support the feasibility of contraceptive implants in female dogs as a primary intervention to quickly and cost-effectively reduce dog population numbers in remote northern regions and reduce the risk of rabies transmission.

A metabolomic study reveals novel plasma lyso-Gb3 analogs as Fabry disease biomarkers.

Fabry disease is an X-linked, multisystemic lysosomal storage disorder due to alpha-galactosidase A deficiency. It is characterized by the accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb(3)), in biological fluids, vascular endothelium, heart, and kidneys. Treatment by enzyme replacement therapy has been shown to be beneficial in both males and females affected with the disease. In addition to Gb(3), increased concentrations of globotriaosylsphingosine (lyso-Gb(3)) have recently been reported in urine and plasma of Fabry patients. The overall objective of this metabolomic study was to identify and characterize new potential plasma biomarkers in treated and untreated males and females affected with Fabry disease which might better reflect disease severity and progression. We employed a time-of-flight mass spectrometry metabolomic approach using plasma samples of Fabry patients compared to age-matched controls. We found three new lyso-Gb(3) analogs in Fabry patients presenting m/z ratios at 802, 804, and 820. As previously detected by our group, we also found a m/z ratio of 784 corresponding to the lyso-Gb(3) molecule minus two hydrogen atoms. Using exact mass measurements and tandem mass spectrometry, we confirmed that these analogs result from modifications of the lyso-Gb(3) sphingosine moiety. We evaluated the relative plasma concentration by measuring area counts for each lyso-Gb(3) analog. None of these analogs was detected in the majority of healthy controls. The relative concentration of each analog was higher in males compared to female Fabry patients. We demonstrated that mass spectrometry combined to a metabolomic approach is a powerful tool to detect and identify new potential biomarkers.

Script concordance testing in continuing professional development: local or international reference panels?

Context The PRACTICUM Institute has developed large-scale international programs of on-line continuing professional development (CPD) based on self-testing and feedback using the Practicum Script Concordance Test© (PSCT). Aims To examine the psychometric consequences of pooling the responses of panelists from different countries (composite panels) and the effect of increasing composite panel size. Method 97 cardiologists in Mexico answered a set of 62 PSCT cases/305 questions. A local panel was recruited in Mexico (n = 7). Other panelists were recruited in Argentina (n = 10) and Brazil (n = 11). Together they constituted a composite panel of 28 experts. Random panels of reference of increasing sizes (5, 10, 15, 20, and 25) were generated. Participants' scores were computed for each panel sample. Units of analysis were means of participants' scores per case. Discrimination, ranking and reliability of the scores obtained with each panel were estimated. Descriptive statistics, Pearson correlation coefficient, generalizability analysis, computation of Cronbach's alpha were used in the analyses. Results Correlation coefficients between the local and the composite panels ranged from 0.951 to 0.981. Cronbach alpha coefficient values were above 0.85 for all panels. The value of the relative G coefficient from the generalizability analyses varied from 0.91 to 0.93, indicating very high and stable ranking of participants, though absolute value of scores increased with increasing composite panel size. Conclusions In CPD environments, and with panel members selected with the highest standards, composite panels can be used. Panels of all sizes yielded high psychometric qualities. Absolute scores should be interpreted with caution.

Increased collagen deposition in the heart of chronically hypoxic ovine fetuses.

This study determined the effect of chronic intrauterine hypoxia on collagen deposition in the fetal sheep heart. Moderate or severe hypoxia was induced by placental embolization in chronically catheterized fetal sheep for 15 days starting at gestational day 116 ± 2 (term ∼147 days). The fetal right and left ventricle were evaluated for collagen content using a Sirius red dye and for changes in signaling components of pathways involved in collagen synthesis and remodeling using quantitative polymerase chain reaction and Western blot. In severely hypoxic fetuses (n = 6), there was a two-fold increase (P < 0.05) in the percentage staining for collagen in the right ventricle, compared with control (n = 6), whereas collagen content was not altered in the moderate group (n = 4). Procollagen I and III mRNA levels were increased in the right ventricle, two-fold (P < 0.05) and three-fold (P < 0.05), respectively, in the severe group relative to control. These changes were paralleled by a two-fold increase (P < 0.05) in mRNA levels of the pro-fibrotic cytokine, transforming growth factor ß (TGF-ß1), in the right ventricle. In the right ventricle, the mRNA levels of matrix metalloproteinase 2 (MMP-2) and its activator, membrane-type MMP (MTI-MMP) were increased five-fold (P = 0.06) and three-fold (P < 0.05), respectively, relative to control. Protein levels of TGF-ß were increased in the left ventricle (P < 0.05). Thus, up-regulated collagen synthesis leading to increased collagen content occurs in the chronically hypoxic fetal heart and may contribute to the right ventricular diastolic and systolic dysfunction reported in human intrauterine growth restriction fetuses.

Feasibility of vesicoamniotic shunt insertion in an inanimate model: comparison of fetoscopic and ultrasound-guided techniques.

OBJECTIVES: To determine the feasibility of fetoscopic vesicoamniotic shunt insertion (F-VASI) in an inanimate model and to compare F-VASI to ultrasound (US)-guided VASI (US-VASI) with respect to accuracy of shunt placement and overall success rate. METHODS: An inanimate second-trimester fetus with a replaceable bladder balloon was suspended in a pressurized water tank and localized with US. Fetal position was randomized, the operator was blinded and a 5-Fr Harrison Shunt® decompressed the bladder in both groups. Thirty shunt insertions were performed per group. RESULTS: Procedure time was longer for F-VASI (15.0 vs. 2.8 min, p < 0.05), although it decreased with practice. F-VASI and US-VASI were similar for adequate depth of insertion (27/30 vs. 27/30, p = 1.0), placement within 1 cm of midline (27/30 vs. 25/30, p = 0.42), bladder puncture (28/30 vs. 28/30, p = 1.0), and overall success rate (27/30 vs. 23/30, p = 0.3). CONCLUSIONS: F-VASI is feasible in an inanimate model. Overall success rate was similar between the groups, although procedure time was longer for F-VASI. Further study is required to determine whether shunt migration is decreased with F-VASI.

Lapatinib monotherapy in patients with relapsed, advanced, or metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies.

BACKGROUND: HER2-positive metastatic breast cancer (MBC) relapsing after trastuzumab-based therapy may require continued HER2 receptor inhibition to control the disease and preserve the patients' quality-of-life. Efficacy and safety of lapatinib monotherapy was evaluated in Japanese breast cancer patients after trastuzumab-based therapies. METHODS: In studies, EGF100642 and EGF104911 evaluated the efficacy and safety of oral lapatinib given 1500 mg once daily in patients with advanced or MBC. All patients progressed on anthracyclines and taxanes; HER2-positive patients had also progressed on trastuzumab. RESULTS: For HER2-positive tumours (n=100), objective response rate was 19.0% (95% confidence interval (CI): 11.8-28.1) and clinical benefit rate (CBR) was 25.0% (95% CI: 16.9-34.7). One out of 22 HER2-negative tumour was documented as complete response (n=22). The median time-to-progression (TTP) in the HER2-positive and HER2-negative groups was 13.0 and 8.0 weeks (P=0.007); median overall survival was 58.3 and 40.0 weeks, respectively. The most frequent adverse event was diarrhoea. TTP and CBR were significantly associated with HER2 expression. Patients with tumours harbouring an H1047R PIK3CA mutation or low expression of PTEN derived clinical benefit from lapatinib. CONCLUSION: Lapatinib monotherapy had shown anti-tumour activity in Japanese patients with HER2-positive MBC that relapsed after trastuzumab-based therapy, including those with brain metastases. Patients benefiting from lapatinib may have biomarker profiles differing from that reported for trastuzumab.

Relationship between total and high molecular weight adiponectin levels and plasma nonesterified fatty acid tolerance during enhanced intravascular triacylglycerol lipolysis in men.

CONTEXT: Increased plasma nonesterified fatty acid (NEFA) appearance during enhanced intravascular triacylglycerol (TG) lipolysis is a marker of metabolic adipose tissue dysfunction and may lead to the development of insulin resistance. The relationship between total and high molecular weight (HMW) adiponectin levels, NEFA appearance, and total TG lipolytic capacity has not been previously studied in humans. OBJECTIVES: Our objective was to determine whether total and HMW adiponectin plasma levels are associated with plasma NEFA level and appearance, and with total TG lipolytic rate during enhanced intravascular TG lipolysis in men. DESIGN: This was a cross-sectional metabolic study. SETTING: The study was performed at an academic clinical research center. PARTICIPANTS: There were 15 healthy men (mean +/- sd body mass index 25.5 +/- 4.7 kg/m(2)) aged 21-50 yr (mean +/- sd 31.1 +/- 10.2) without first-degree relatives with type 2 diabetes included in the study. INTERVENTIONS: Pancreatic clamps and iv infusion of stable isotopic tracers ([1,1,2,3,3-(2)H(5)]glycerol and [U-(13)C]palmitate) were performed, whereas intravascular TG lipolysis was clamped by iv infusion of heparin plus Intralipid at low (fasting) and high insulin levels. Total and HMW adiponectin levels were measured using an ELISA. MAIN OUTCOME MEASURES: Levels of total and HMW adiponectin, palmitate appearance (plasma palmitate appearance rate), and glycerol appearance (plasma glycerol appearance rate) were calculated. RESULTS: During heparin plus Intralipid infusion, total and HMW adiponectin was inversely correlated with plasma palmitate appearance rate (r = -0.65; P = 0.01), but this association was lost when expressed per nonlean weight. Adiponectin levels were positively associated with plasma glycerol appearance rate per nonlean weight (r = 0.71 and r = 0.66, respectively; P < or = 0.01). CONCLUSIONS: Increased adipose tissue mass likely explains the association between low adiponectin and reduced NEFA tolerance. Adiponectin level is a marker of total TG lipolytic rate per adipose tissue mass in men.

Viability of Lactobacillus rhamnosus R0011 in an apple-based fruit juice under simulated storage conditions at the consumer level.

Lactobacillus rhamnosus R0011 was inoculated in an apple-pear-raspberry juice blend at 4.5 x 10(9) CFU/250 mL portion, and viability was followed during storage in conditions simulating consumer use. Study parameters were age of the juice (2 or 4 wk), sampling size (one to three 250-mL portions), incubation temperature (between 2 and 7 degrees C), and atmosphere (aerobic compared with anaerobic). Dependent variables were pH, dissolved oxygen (DO) level, and viable count. The DO level in the unopened PETE commercial bottles decreased from 10% to 3% over a 5-wk storage period at 7 degrees C. In shaken and opened bottles, DO increased to 15% during the 1st week of storage, irrespective of sampling size. However, agitation of bottles having more that 250 mL of headspace initially increased DO readings to 30% of maximum, but the DO level subsequently dropped to 15% during the 1-wk storage period between samplings. The presence of L. rhamnosus R0011 did not affect the DO data. The pH varied between 3.6 and 3.9, and was not influenced by L. rhamnosus R0011. However, the pH increased on average by 0.1 unit following multiple agitations and samplings. When the juices remained unopened in the PETE bottles, the viable population gradually dropped by 75% over 5 wk of storage at 7 degrees C, while in opened bottles reduction were only between 20% and 40%. Viability losses under anaerobic conditions were twice as high at 7 degrees C than at 4 degrees C. Data show that consumers can expect good viability of L. rhamnosus R0011 over a few weeks of storage in a refrigerator, even if the bottles have been opened and cells are exposed to oxygen.

Diabetes screening of children in a remote First Nations community on the west coast of Canada: challenges and solutions.

Type 2 diabetes (T2D) and its precursor, impaired glucose tolerance (IGT), are now reaching epidemic proportions among Aboriginal Canadians. Of particular concern is the appearance and increasing prevalence of T2D and IGT among Aboriginal youth. At the request of three communities in the Tsimshian nation on the northern coast of British Columbia (with which the Department of Pediatrics, University of British Columbia, had a pre-existing partnership) a screening program was undertaken to determine the prevalence of T2D and IGT among the children. The long-term goal was the collaborative development of intervention programs for each community. The challenges of meeting this request included the sociological and ethical issues associated with research in First Nations communities, as well as the pragmatic issues of conducting complex research in remote communities. Three separate visits were undertaken to respect the cultural dynamics and capacity of the community to accommodate a project of this magnitude. The process began with dialogue, listening and presentations to the community. Only then began the planning of logistics and application for funding. Next, the team visited the communities to ensure understanding of exactly what was involved for the community, each child and family, and to be certain that consent was fully informed. For the diabetes screening visit, special arrangements including chartering a Beaver float plane were needed for the transport of the five-member team with all the necessary equipment, including a -20(o)C freezer to safeguard the integrity of blood samples. The 100% consent rate, successful conduct of study, and retention of community support achieved by the process, indicate that population-based clinical research is possible in remote First Nations communities. This is best achieved with appropriate dialogue, care, respect and planning to overcome the sociological, ethical and practical challenges.

Province-wide population survey of acute appendicitis in Canada. New twists to an old disease.

BACKGROUND: This study, sponsored and conducted by Le Collège des Médecins du Québec, audited the management of acute appendicitis in the Province of Québec (Population 7.6 million), Canada, over a period of 1 year (April 2002-March 2003). METHODS: A questionnaire was sent to the Health Records Department of all hospitals surgically treating appendicitis in the province. Data from 85 (100%) hospitals were received and reviewed. RESULTS: During the study period, 7,599 appendectomies were performed, and 5,707 (75%) were selected for study (55% men). The rate of normal and perforated appendix was 5.4% and 15.9% respectively. Median hospital stay for simple and perforated appendicitis was 2.6 and 5.8 days, respectively. At least one imaging procedure was done in 86% of cases (23% computed tomography [CT], 55% ultrasound). Antibiotics were not given in 7% of cases and in 8% of patients with a perforation. Seventeen percent of patients did not receive preoperative or intraoperative doses, and postoperatively, 69% of patients received unnecessary doses. Laparoscopy was used in 35% of cases and was associated with a reduction in postoperative stay for simple (2.6 versus 2.9 days, p < 0.001) and perforated appendicitis (4.6 versus 5.9 days, p = 0.004). A low rate of laparoscopy (<25%) was found in 53% of teaching (University and Affiliated) and 45% of nonteaching institutions. Conversion to open surgery was necessary in 9.7% of simple appendicitis and 29.3% of perforated ones (p < 0.001). CONCLUSIONS: Although results of this survey are comparable to those of similar published series, a few concerns emerge. Many have to do with patient noncompliance with recommended antibiotic usage for acute appendicitis. Further, although laparoscopy seems to be slowly making its way into the surgical armamentarium, the low rate of laparoscopic appendectomies in teaching hospitals raises the issue of appropriate resident training.