Moncton Hospital

BACKGROUND: Treatment with an aromatase inhibitor for 5 years as up-front monotherapy or after tamoxifen therapy is the treatment of choice for hormone-receptor-positive early breast cancer in postmenopausal women. Extending treatment with an aromatase inhibitor to 10 years may further reduce the risk of breast-cancer recurrence. METHODS: We conducted a double-blind, placebo-controlled trial to assess the effect of the extended use of letrozole for an additional 5 years. Our primary end point was disease-free survival. RESULTS: We enrolled 1918 women. After a median follow-up of 6.3 years, there were 165 events involving disease recurrence or the occurrence of contralateral breast cancer (67 with letrozole and 98 with placebo) and 200 deaths (100 in each group). The 5-year disease-free survival rate was 95% (95% confidence interval [CI], 93 to 96) with letrozole and 91% (95% CI; 89 to 93) with placebo (hazard ratio for disease recurrence or the occurrence of contralateral breast cancer, 0.66; P=0.01 by a two-sided log-rank test stratified according to nodal status, prior adjuvant chemotherapy, the interval from the last dose of aromatase-inhibitor therapy, and the duration of treatment with tamoxifen). The rate of 5-year overall survival was 93% (95% CI, 92 to 95) with letrozole and 94% (95% CI, 92 to 95) with placebo (hazard ratio, 0.97; P=0.83). The annual incidence rate of contralateral breast cancer in the letrozole group was 0.21% (95% CI, 0.10 to 0.32), and the rate in the placebo group was 0.49% (95% CI, 0.32 to 0.67) (hazard ratio, 0.42; P=0.007). Bone-related toxic effects occurred more frequently among patients receiving letrozole than among those receiving placebo, including a higher incidence of bone pain, bone fractures, and new-onset osteoporosis. No significant differences between letrozole and placebo were observed in scores on most subscales measuring quality of life. CONCLUSIONS: The extension of treatment with an adjuvant aromatase inhibitor to 10 years resulted in significantly higher rates of disease-free survival and a lower incidence of contralateral breast cancer than those with placebo, but the rate of overall survival was not higher with the aromatase inhibitor than with placebo. (Funded by the Canadian Cancer Society and others; ClinicalTrials.gov numbers, NCT00003140 and NCT00754845.).

Importance: Single-agent immune checkpoint inhibition has not shown activities in advanced refractory colorectal cancer (CRC), other than in those patients who are microsatellite-instability high (MSI-H). Objective: To evaluate whether combining programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibition improved patient survival in metastatic refractory CRC. Design, Setting, and Participants: A randomized phase 2 study was conducted in 27 cancer centers across Canada between August 2016 and June 2017, and data were analyzed on October 18, 2018. Eligible patients had histologically confirmed adenocarcinoma of the colon or rectum; received all available standard systemic therapies (fluoropyrimidines, oxaliplatin, irinotecan, and bevacizumab if appropriate; cetuximab or panitumumab if RAS wild-type tumors; regorafenib if available); were aged 18 years or older; had adequate organ function; had Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease. Interventions: We randomly assigned patients to receive either 75 mg of tremelimumab every 28 days for the first 4 cycles plus 1500 mg durvalumab every 28 days, or best supportive care alone (BSC) in a 2:1 ratio. Main Outcomes and Measures: The primary end point was overall survival (OS) and a 2-sided P<.10 was considered statistically significant. Circulating cell-free DNA from baseline plasma was used to determine microsatellite instability (MSI) and tumor mutation burden (TMB). Results: Of 180 patients enrolled (121 men [67.2%] and 59 women [32.8%]; median [range] age, 65 [36-87] years), 179 were treated. With a median follow-up of 15.2 months, the median OS was 6.6 months for durvalumab and tremelimumab and 4.1 months for BSC (hazard ratio [HR], 0.72; 90% CI, 0.54-0.97; P = .07). Progression-free survival was 1.8 months and 1.9 months respectively (HR, 1.01; 90% CI, 0.76-1.34). Grade 3 or 4 adverse events were significantly more frequent with immunotherapy (75 [64%] patients in the treatment group had at least 1 grade 3 or higher adverse event vs 12 [20%] in the BSC group). Circulating cell-free DNA analysis was successful in 168 of 169 patients with available samples. In patients who were microsatellite stable (MSS), OS was significantly improved with durvalumab and tremelimumab (HR, 0.66; 90% CI, 0.49-0.89; P = .02). Patients who were MSS with plasma TMB of 28 variants per megabase or more (21% of MSS patients) had the greatest OS benefit (HR, 0.34; 90% CI, 0.18-0.63; P = .004). Conclusions and Relevance: This phase 2 study suggests that combined immune checkpoint inhibition with durvalumab plus tremelimumab may be associated with prolonged OS in patients with advanced refractory CRC. Elevated plasma TMB may select patients most likely to benefit from durvalumab and tremelimumab. Further confirmation studies are warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT02870920.

BACKGROUND: Pain is the primary indication for both primary and revision total knee arthroplasty (TKA); however, most arthroplasty outcome measures do not take pain into account. OBJECTIVE: To document the prospective pain experience following TKA, with subjective pain-specific questionnaires to determine if comorbidities, preoperative pain or preoperative pain catastrophizing scores are predictive of long-term pain outcomes. METHODS: Fifty-five patients with a primary diagnosis of osteoarthritis of the knee, who were scheduled to undergo TKA, were asked to fill out the McGill Pain Questionnaire (MPQ) and the Pain Catastrophizing Scale (PCS) preoperatively and at three, 12 and 24 months follow-up. Comorbidities were extracted from the Queen Elizabeth II Health Sciences Centre health information system. RESULTS: The overall response rate (return of completed questionnaires) was 84%. There was a significant decrease in the MPQ scores (P<0.05) postoperatively. PCS scores did not change over time. Receiver operating characteristic curves revealed the number of comorbidities per patient predicted the presence of pain postoperatively, as documented by the numerical rating subscale of the MPQ at 24 months (P<0.05). Receiver operating characteristic curves for preoperative PCS and rumination subscale scores predicted the presence of pain, as measured by the Pain Rating Index subscale of the MPQ at 24 months (P<0.05). Preoperative PCS scores and comorbidities were significantly higher in the persistent pain group (P<0.05). CONCLUSIONS: The number of comorbidities predicted the presence of pain at 24 months follow-up and, for the first time, preoperative PCS scores were shown to predict chronic postoperative pain. This may enable the identification of knee arthroplasty patients at risk for persistent postoperative pain, thus allowing for efficient administration of preoperative interventions to improve arthroplasty outcomes.

Chronic wounds all have bacterial contamination, which will not impair healing. Wound contamination must be distinguished from wound colonization and infection. Bacterial infection in wounds depends on the number of organisms present, their virulence, and host resistance. The most important indicators of infection are both local and systemic host characteristics and a holistic assessment of the patient. Several specimen collection and culture techniques are available to measure bacterial burden in the chronic wound. Advantages and disadvantages of each one discussed along with a rational approach to systemic antibiotic therapy. The presence of foreign material such as skin grafts or skin substitutes may lower the bacterial burden that may impair healing from 1.0 x 10(6) colony-forming units to 1.0 x 10(5) or less. The benefits of wound debridement, wound irrigation, and local nonantibiotic modes of treatment have been proven but the use of topical antibiotics and antiseptics requires further assessment. More widespread use of multiple nonantibiotic modalities of treatment for infected chronic wounds and rational antibiotic prescribing should reduce the risk of future antimicrobial resistance such as MRSA.

Background: Despite the epidemic of cardiovascular disease and the benefits of cardiac rehabilitation (CR), availability is known to be insufficient, although this is not quantified. This study ascertained CR availability, volumes and its drivers, and density. Methods: A survey was administered to CR programs globally. Cardiac associations and local champions facilitated program identification. Factors associated with volumes were assessed using generalized linear mixed models, and compared by World Health Organization region. Density (i.e. annual ischemic heart disease [IHD] incidence estimate from Global Burden of Disease study divided by national CR capacity) was computed. Findings: CR was available in 111/203 (54.7%) countries; data were collected in 93 (83.8% country response; N = 1082 surveys, 32.1% program response rate). Availability by region ranged from 80.7% of countries in Europe, to 17.0% in Africa (p b .001). There were 5753 programs globally that could serve 1,655,083 patients/year, despite an estimated 20,279,651 incident IHD cases globally/year. Volume was significantly greater where patients were systematically referred (odds ratio [OR] = 1.36, 95% confidence interval [CI] = 1.35-1.38) and programs offered alternative models (OR = 1.05, 95%CI = 1.04-1.06), and significantly lower with private (OR = .92, 95%CI = .91-.93) or public (OR = .83, 95%CI = .82-84) funding compared to hybrid sources. Median capacity (i.e., number of patients a program could serve annually) was 246/program (Q25-Q75 = 150-390). The absolute density was one CR spot per 11 IHD cases in countries with CR, and 12 globally. Interpretation: CR is available in only half of countries globally. Where offered, capacity is grossly insufficient, such that most patients will not derive the benefits associated with participation.

This is an update to the 2014 Canadian Hereditary Angioedema Guideline with an expanded scope to include the management of hereditary angioedema (HAE) patients worldwide. It is a collaboration of Canadian and international HAE experts and patient groups led by the Canadian Hereditary Angioedema Network. The objective of this guideline is to provide evidence-based recommendations, using the GRADE system, for the management of patients with HAE. This includes the treatment of attacks, short-term prophylaxis, long-term prophylaxis, and recommendations for self-administration, individualized therapy, quality of life, and comprehensive care. New to the 2019 version of this guideline are sections covering the diagnosis and recommended therapies for acute treatment in HAE patients with normal C1-INH, as well as sections on pregnant and paediatric patients, patient associations and an HAE registry. Hereditary angioedema results in random and often unpredictable attacks of painful swelling typically affecting the extremities, bowel mucosa, genitals, face and upper airway. Attacks are associated with significant functional impairment, decreased health-related quality of life, and mortality in the case of laryngeal attacks. Caring for patients with HAE can be challenging due to the complexity of this disease. The care of patients with HAE in Canada, as in many countries, continues to be neither optimal nor uniform. It lags behind some other countries where there are more organized models for HAE management, and greater availability of additional licensed therapeutic options. It is anticipated that providing this guideline to caregivers, policy makers, patients, and advocates will not only optimize the management of HAE, but also promote the importance of individualized care. The primary target users of this guideline are healthcare providers who are managing patients with HAE. Other healthcare providers who may use this guideline are emergency and intensive care physicians, primary care physicians, gastroenterologists, dentists, otolaryngologists, paediatricians, and gynaecologists who will encounter patients with HAE and need to be aware of this condition. Hospital administrators, insurers and policy makers may also find this guideline helpful.

BACKGROUND: Current antibiotic therapies for Clostridium difficile-associated diarrhea have limitations, including progression to severe disease, recurrent C. difficile-associated diarrhea, and selection for nosocomial pathogens. Tolevamer, a soluble, high-molecular weight, anionic polymer that binds C. difficile toxins A and B is a unique nonantibiotic treatment option. METHODS: In this 3-arm, multicenter, randomized, double-blind, active-controlled, parallel-design phase II study, patients with mild to moderately severe C. difficile-associated diarrhea were randomized to receive 3 g of tolevamer per day (n = 97), 6 g of tolevamer per day (n = 95), or 500 mg of vancomycin per day (n = 97). The primary efficacy parameter was time to resolution of diarrhea, defined as the first day of 2 consecutive days when the patient had hard or formed stools (any number) or < or = 2 stools of loose or watery consistency. RESULTS: In the per-protocol study population, resolution of diarrhea was achieved in 48 (67%) of 72 patients receiving 3 g of tolevamer per day (median time to resolution of diarrhea, 4.0 days; 95% confidence interval, 2.0-6.0 days), in 58 (83%) of 70 patients receiving 6 g of tolevamer per day (median time to resolution of diarrhea, 2.5 days; 95% confidence interval, 2.0-3.0 days), and in 73 (91%) of 80 patients receiving vancomycin (median time to resolution of diarrhea, 2.0 days; 95% confidence interval, 1.0-3.0 days). Tolevamer administered at a dosage of 6 g per day was found to be noninferior to vancomycin administered at a dosage of 500 mg per day with regard to time to resolution of diarrhea (P = .02) and was associated with a trend toward a lower recurrence rate. Tolevamer was well tolerated but was associated with an increased risk of hypokalemia. CONCLUSIONS: Tolevamer, a novel polystyrene binder of C. difficile toxins A and B, effectively treats mild to moderate C. difficile diarrhea and merits further clinical development.

The response of psoriasis to antibodies targeting the interleukin (IL)-23/IL-17A pathway suggests a prominent role of T-helper type-17 (Th17) cells in this disease. We examined the clinical and immunological response patterns of 100 subjects with moderate-to-severe psoriasis receiving 3 different intravenous dosing regimens of the anti-IL-17A antibody secukinumab (1 × 3 mg/kg or 1 × 10 mg/kg on Day 1, or 3 × 10 mg/kg on Days 1, 15 and 29) or placebo in a phase 2 trial. Baseline biopsies revealed typical features of active psoriasis, including epidermal accumulation of neutrophils and formation of microabscesses in >60% of cases. Neutrophils were the numerically largest fraction of infiltrating cells containing IL-17 and may store the cytokine preformed, as IL-17A mRNA was not detectable in neutrophils isolated from active plaques. Significant clinical responses to secukinumab were observed 2 weeks after a single infusion, associated with extensive clearance of cutaneous neutrophils parallel to the normalization of keratinocyte abnormalities and reduction of IL-17-inducible neutrophil chemoattractants (e.g. CXCL1, CXCL8); effects on numbers of T cells and CD11c-positive dendritic cells were more delayed. Histological and immunological improvements were generally dose dependent and not observed in the placebo group. In the lowest-dose group, a recurrence of neutrophils was seen in some subjects at Week 12; these subjects relapsed faster than those without microabscesses. Our findings are indicative of a neutrophil-keratinocyte axis in psoriasis that may involve neutrophil-derived IL-17 and is an early target of IL-17A-directed therapies such as secukinumab.

Cardiovascular disease (CVD) is the leading cause of premature death for women in Canada. Although it has long been recognized that estrogen impacts vascular responses in women, there is emerging evidence that physiologic and pathophysiologic cardiovascular responses are uniquely affected across the spectrum of a woman's life. Despite a global understanding that manifestations and outcomes of CVD are known to differ between men and women, uptake of the recognition of sex and gender influences on the clinical care of women has been slow or absent.\n\nTo highlight the need for better research, diagnosis, treatment, awareness, and support of women with CVD in Canada, the Canadian Women's Heart Health Alliance (CWHHA), supported by the University of Ottawa Heart Institute, and in collaboration with the Heart and Stroke Foundation of Canada (HSFC), undertook a comprehensive review of the evidence on sex‐ and gender‐specific differences in comorbidities, risk factors, disease awareness, presentation, diagnosis, and treatment across the entire spectrum of CVD. The intent of this review was not to directly compare women and men on epidemiological and outcome measures of CVD, but to synthesize the state of the evidence for CVD in women and identify significant knowledge gaps that hinder the transformation to clinical practice and care that is truly tailored for women, a significant health challenge that has only been recognized in Canada relatively recently. This review highlights the scarcity of Canadian data on CVD in women as part of the ongoing struggle to increase awareness of and improve outcomes for women with CVD. Because of a paucity of published Canada‐specific evidence, the purpose of this review is to provide an infrastructure to summarize world‐wide published evidence, including knowledge gaps that must be understood to then make effective recommendations to alleviate the glaring “unders” of CVD for women in Canada: under‐aware, under‐diagnosed and under‐treated, under‐researched, and under‐support.

BACKGROUND: Cardiac rehabilitation (CR) is a clinically-effective but complex model of care. The purpose of this study was to characterize the nature of CR programs around the world, in relation to guideline recommendations, and compare this by World Health Organization (WHO) region. METHODS: In this cross-sectional study, a piloted survey was administered online to CR programs globally. Cardiac associations and local champions facilitated program identification. Quality (benchmark of ≥ 75% of programs in a given country meeting each of 20 indicators) was ranked. Results were compared by WHO region using generalized linear mixed models. FINDINGS: 111/203 (54.7%) countries in the world offer CR; data were collected in 93 (83.8%; N = 1082 surveys, 32.1% program response rate). The most commonly-accepted indications were: myocardial infarction (n = 832, 97.4%), percutaneous coronary intervention (n = 820, 96.1%; 0.10), and coronary artery bypass surgery (n = 817, 95.8%). Most programs were led by physicians (n = 680; 69.1%). The most common CR providers (mean = 5.9 ± 2.8/program) were: nurses (n = 816, 88.1%; low in Africa, p < 0.001), dietitians (n = 739, 80.2%), and physiotherapists (n = 733, 79.3%). The most commonly-offered core components (mean = 8.7 ± 1.9 program) were: initial assessment (n = 939, 98.8%; most commonly for hypertension, tobacco, and physical inactivity), risk factor management (n = 928, 98.2%), patient education (n = 895, 96.9%), and exercise (n = 898, 94.3%; lower in Western Pacific, p < 0.01). All regions met ≥ 16/20 quality indicators, but quality was < 75% for tobacco cessation and return-to-work counseling (lower in Americas, p = < 0.05). INTERPRETATION: This first-ever survey of CR around the globe suggests CR quality is high. However, there is significant regional variation, which could impact patient outcomes.

Immunotherapy-based monotherapy treatment in metastatic pancreatic ductal adenocarcinoma (mPDAC) has shown limited benefit outside of the mismatch repair deficiency setting, while safety and efficacy of combining dual-checkpoint inhibitor immunotherapy with chemotherapy remains uncertain. Here, we present results from the CCTG PA.7 study (NCT02879318), a randomized phase II trial comparing gemcitabine and nab-paclitaxel with and without immune checkpoint inhibitors durvalumab and tremelimumab in 180 patients with mPDAC. The primary endpoint was overall survival. Secondary endpoints included progression-free survival and objective response rate. Results of the trial were negative as combination immunotherapy did not improve survival among the unselected patient population (p = 0.72) and toxicity was limited to elevation of lymphocytes in the combination immunotherapy group (p = 0.02). Exploratory baseline circulating tumor DNA (ctDNA) sequencing revealed increased survival for patients with KRAS wildtype tumors in both the combination immunotherapy (p = 0.001) and chemotherapy (p = 0.004) groups. These data support the utility of ctDNA analysis in PDAC and the prognostic value of ctDNA-based KRAS mutation status.

OBJECTIVE: To characterize the causes of marked elevation of C-reactive protein (CRP) levels, investigate patient outcomes, and examine factors that might influence the CRP response. DESIGN: Health records were used to retrospectively determine patient characteristics, diagnoses, and outcomes over a 2-year period (2012 to 2013). SETTING: A large referral centre in Moncton, NB. PARTICIPANTS: Adult inpatients and outpatients with a CRP level above 100 mg/L. MAIN OUTCOME MEASURES: Differences among the CRP distributions of various diagnosis categories were examined using Kruskal-Wallis tests, and factors affecting outcomes were examined using Fisher exact tests. RESULTS: = .002). CONCLUSION: Most patients had infections and the proportion of patients with infections increased with the level of CRP, although many diagnoses were associated with markedly elevated CRP levels. These data could help guide health care professionals in the evaluation and management of these patients.

[See related article at [www.cmaj.ca/lookup/doi/10.1503/cmaj.170931][2]][2] KEY POINTS Chronic hepatitis C virus (HCV) is a highly burdensome public health problem in Canada, causing more years of life lost than any other infectious disease in the country. [1][2]–[3][3] A recent modelling study

CONTEXT: Permanent hearing loss affects 1 to 3 per 1000 children and interferes with typical communication development. Early detection through newborn hearing screening and hearing technology provide most children with the option of spoken language acquisition. However, no consensus exists on optimal interventions for spoken language development. OBJECTIVE: To conduct a systematic review of the effectiveness of early sign and oral language intervention compared with oral language intervention only for children with permanent hearing loss. DATA SOURCES: An a priori protocol was developed. Electronic databases (eg, Medline, Embase, CINAHL) from 1995 to June 2013 and gray literature sources were searched. Studies in English and French were included. STUDY SELECTION: Two reviewers screened potentially relevant articles. DATA EXTRACTION: Outcomes of interest were measures of auditory, vocabulary, language, and speech production skills. All data collection and risk of bias assessments were completed and then verified by a second person. Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) was used to judge the strength of evidence. RESULTS: Eleven cohort studies met inclusion criteria, of which 8 included only children with severe to profound hearing loss with cochlear implants. Language development was the most frequently reported outcome. Other reported outcomes included speech and speech perception. LIMITATIONS: Several measures and metrics were reported across studies, and descriptions of interventions were sometimes unclear. CONCLUSIONS: Very limited, and hence insufficient, high-quality evidence exists to determine whether sign language in combination with oral language is more effective than oral language therapy alone. More research is needed to supplement the evidence base.

Immune checkpoint inhibitors (icis) such as inhibitors of ctla-4, PD-1, and PD-L1, given as monotherapy or combination therapy have emerged as effective treatment options for immune-sensitive solid tumours and hematologic malignancies. The benefits of icis can be offset by immune-related adverse events (iraes) that leave all organ systems vulnerable and subsequently increase the risk for morbidity and mortality. Because of fluctuating onset and prolonged duration, the toxicities associated with iraes represent a shift from the understanding of conventional anticancer toxicities. The ctla-4 and PD-1/PD-L1 inhibitors modulate T-cell response differently, resulting in distinct toxicity patterns, toxicity kinetics, and dose-toxicity relationships. Using individualized patient education, screening, and assessment for the early identification of iraes is key to proactive management and is therefore key to improving outcomes and prolonging therapy. Management of iraes is guided by appropriate grading, which sets the stage for the treatment setting (outpatient vs. inpatient), ici treatment course (delay vs. discontinuation), supportive care, corticosteroid use, organ specialist consultation, and additional immunosuppression. Health care professionals in oncology must work collaboratively with emergency and community colleagues to facilitate an understanding of iraes in an effort to optimize seamless care.

BACKGROUND: Most patients with psoriasis have nail changes, and treating nail psoriasis is challenging. OBJECTIVES: To assess improvement in fingernail psoriasis with ustekinumab treatment in the PHOENIX 1 trial. METHODS: Patients received ustekinumab 45 mg or 90 mg, or placebo at weeks 0 and 4. Ustekinumab-randomized patients continued maintenance dosing every 12 weeks, while patients receiving placebo crossed over to receive ustekinumab 45 mg or 90 mg at weeks 12/16 followed by dosing every 12 weeks. At week 40, initial responders [those with ≥ 75% improvement from baseline in Psoriasis Area and Severity Index (PASI 75)] were rerandomized either to continue maintenance dosing or to withdraw from treatment. Nail involvement was evaluated using the Nail Psoriasis Severity Index (NAPSI) on a target fingernail, Nail Physician's Global Assessment (Nail PGA) and mean number of nails involved. RESULTS: Of 766 randomized patients, 545 (71·1%) had nail psoriasis. At week 24, the percentage improvement from baseline NAPSI score was 46·5% (ustekinumab 45 mg) and 48·7% (ustekinumab 90 mg). Percentage improvements in NAPSI ranged from 29·7% (PASI < 50) to 57·3% (PASI ≥ 90). Mean NAPSI scores improved from 4·5 at baseline to 2·4 at week 24 (45 mg) and from 4·4 to 2·2 (90 mg). Nail PGA scores and the mean number of psoriatic nails improved by week 24. Further improvement was observed for all end points among initial responders continuing maintenance treatment through week 52. CONCLUSIONS: Ustekinumab significantly improves nail psoriasis, and improvements continue over time until up to 1 year of treatment in those receiving maintenance treatment.

The efficacy and safety of twice-daily aclidinium bromide/formoterol fumarate was compared with that of salmeterol/fluticasone propionate in patients with stable, moderate-to-severe chronic obstructive pulmonary disease (COPD). AFFIRM COPD (Aclidinium and Formoterol Findings in Respiratory Medicine COPD) was a 24-week, double-blind, double-dummy, active-controlled study. Patients were randomised (1:1) to aclidinium/formoterol 400/12 µg twice-daily via Genuair/Pressair or salmeterol/fluticasone 50/500 µg twice-daily via Accuhaler. The primary end-point was peak forced expiratory volume in 1 s (FEV 1 ) at week 24. Other end-points included Transition Dyspnoea Index (TDI) focal score at week 24, TDI and St George's Respiratory Questionnaire (SGRQ) responders, COPD Assessment Test and SGRQ scores, assessment of COPD symptoms and exacerbations, use of reliever medication, and device preference. Adverse events were monitored throughout. In total, 933 patients were eligible (mean age 63.4 years, 65.1% male). Aclidinium/formoterol was superior to salmeterol/fluticasone in peak FEV 1 and noninferior in TDI. Health status and reduction in exacerbation risk were similar in both groups. While both treatments were well tolerated, pneumonia occurred less frequently with aclidinium/formoterol than salmeterol/fluticasone. In stable COPD, aclidinium/formoterol significantly improved bronchodilation versus salmeterol/fluticasone, with equivalent benefits in symptom control and reduction in exacerbation risk. Both treatments were well tolerated and treatment-related adverse events were less common with aclidinium/formoterol.

Every year, approximately 62 000 people with stroke and transient ischemic attack are treated in Canadian hospitals, and the evidence suggests one-third or more will experience vascular-cognitive impairment, and/or intractable fatigue, either alone or in combination. The 2015 update of the Canadian Stroke Best Practice Recommendations: Mood, Cognition and Fatigue Module guideline is a comprehensive summary of current evidence-based recommendations for clinicians in a range of settings, who provide care to patients following stroke. The three consequences of stroke that are the focus of the this guideline (poststroke depression, vascular cognitive impairment, and fatigue) have high incidence rates and significant impact on the lives of people who have had a stroke, impede recovery, and result in worse long-term outcomes. Significant practice variations and gaps in the research evidence have been reported for initial screening and in-depth assessment of stroke patients for these conditions. Also of concern, an increased number of family members and informal caregivers may also experience depressive symptoms in the poststroke recovery phase which further impact patient recovery. These factors emphasize the need for a system of care that ensures screening occurs as a standard and consistent component of clinical practice across settings as stroke patients transition from acute care to active rehabilitation and reintegration into their community. Additionally, building system capacity to ensure access to appropriate specialists for treatment and ongoing management of stroke survivors with these conditions is another great challenge.

We compared the effects of cimetidine, metoclopramide, and placebo in the short-term therapy of symptomatic gastroesophageal reflux in a placebo double-blind trial. Of 50 patients, 20 received cimetidine 300 mg, 20 received metoclopramide 10 mg, and 10 received placebo, all four times a day before meals and at bedtime. Patients followed other conventional therapy for gastroesophageal reflux. Before and at the end of the 8-week period, the esophagus was assessed endoscopically, its mucosal sensitivity was tested by a quantitative Bernstein test, and its mean resting lower sphincter pressure (LESP) was measured. We made frequent assessments of symptom severity, frequency of antacid usage, adverse effects, and laboratory studies. After 8 weeks, the percentage of patients with endoscopic improvement was slightly higher for metoclopramide-treated patients than for the others. LESP was not different for cimetidine, metoclopramide, or placebo patients and did not rise from low pretreatment values. Bernstein tests showed mucosai sensitivity had not altered in cimetidine or metoclopramide patients. A significant number of patients who were taking cimetidine or metoclopramide, however, had less pain than before. Although antacid usage decreased in all three groups, it was significantly lower only in patients treated with cimetidine or metoclopramide. There were no laboratory abnormalities. Six of 20 patients taking metoclopramide reported neurologic and psychotropic symptoms such as drowsiness, lethargy and hyperactivity; three withdrew after 48 hours, one had acute torticollis, and of the remaining three, two became depressed. Cimetidine or metoclopramide is therefore more effective than placebo for the relief of symptoms of gastroesophageal reflux disease, but metoclopramide is attended by significant side effects.

This study of selected plants of the Rutaceae family was carried out to investigate their phenolic content, antioxidant activity, and the in vitro inhibitory potential of extracted phenolics towards enzymes relevant for hyperglycemia and hypertension. The phenolic content, antioxidant activity and phenolic extract-mediated inhibitory activities for α-glucosidase and α-amylase were evaluated by spectrophotometry. The content of individual phenolics and the angiotensin I-converting enzyme (ACE) inhibitory activity of the phenolic extracts were evaluated by LC/MS-MS and RP-HPLC methods, respectively. A higher percentage of free phenolic content was seen for all the selected plants of the Rutaceae family (85.43-92.82% of the total phenolic content) than of the bound form (7.18-14.57% of total phenolic content). The major predominant bound phenolic in lemon and red blood orange was hesperidin. The major predominant bound phenolic in pummelo, shamouti and clementine was ferulic acid. The highest ACE and α-glucosidase inhibitory activity of the extracted phenolics from lemon was associated with free phenolic extracts obtained at 30 °C with values of 100% inhibition. Red blood orange free phenolic extract (30 °C) elicited the highest α-amylase inhibition activity (32.3%). In contrast, extracted bound phenolics after acid and base hydrolysis from all selected plants from the Citrus species were shown to induce activation of the ACE and α-amylase enzymes.