Reaching out to Patients with Long COVID to Better Understand Their Life Experiences and How to Support Their Recovery: A Patient-Oriented Knowledge Sharing Session.

This article reports on participants' experiences with long COVID-19 (LC) (symptoms, impact, healthcare use, and perceived needs) and satisfaction with a patient-oriented knowledge-sharing session organized by a multidisciplinary team of healthcare professionals, researchers, and a patient partner. Twenty-six participants completed a pre-session survey. On average, they were 21 months post-COVID-19 infection (SD 10.9); 81% of them were female, and 84% were 40+ years old. The main symptoms reported included fatigue (96%), cognitive problems (92%), and general pain or discomfort (40%). More than half of the participants reported that LC has had a significant impact on their health-related quality of life. Eighty-one percent of the participants reported seeking medical help for their LC symptoms and found the services provided by physical therapists, primary care providers, and acupuncturists to be helpful in managing their condition. Participants would like to have access to healthcare providers and clinics specializing in LC. They liked the session and found the information presented useful. This information helps to better understand the experiences of people living with LC and how to support their recovery.

Understanding the influence of medical education on physician geographic disposition: A qualitative study of family physician perspectives in Canada.

RATIONALE: Primary care access challenges are experienced by many communities. In several jurisdictions, including Canada, family physicians (FP) have the professional autonomy to organize their practice in alignment with professional and personal interests. Although system-level interventions are tremendously important, investment in upstream interventions associated with the medical education of graduating FPs is a promising strategy for ameliorating primary healthcare access challenges. AIMS AND OBJECTIVES: This study investigates the medical education experiences that influence FP's decisions about practice locations in Canada. METHODS: We conducted semistructured interviews with FPs who completed undergraduate and postgraduate medical training in Canada and now have a practice in Ontario, Canada. Interview data were coded and analysed using an unconstrained descriptive approach. RESULTS: FPs preferred practice locations are intimately tied to their desired practice scope. Practice preferences were shaped through training experiences with patient populations, heightened clinical responsibilities, practice models and locations, professional mentorships and networks. Proximity to family, partner and lifestyle preferences, cultural connections and the available practice opportunities also shaped practice location decisions. CONCLUSION: Medical education influences the identification and refinement of professional family practice preferences. Health workforce policies and interventions should leverage medical education to promote more equitable primary healthcare access.

Associations between education policies and the geographic disposition of family physicians: a retrospective observational study of McMaster University education data.

The maldistribution of family physicians challenges equitable primary care access in Canada. The Theory of Social Attachment suggests that preferential selection and distributed training interventions have potential in influencing physician disposition. However, evaluations of these approaches have focused predominantly on rural underservedness, with little research considering physician disposition in other underserved communities. Accordingly, this study investigated the association between the locations from which medical graduates apply to medical school, their undergraduate preclerkship, clerkship, residency experiences, and practice as indexed across an array of markers of underservedness. We built association models concerning the practice location of 347 family physicians who graduated from McMaster University's MD Program between 2010 and 2015. Postal code data of medical graduates' residence during secondary school, pre-clerkship, clerkship, residency and eventual practice locations were coded according to five Statistics Canada indices related to primary care underservedness: relative rurality, employment rate, proportion of visible minorities, proportion of Indigenous peoples, and neighbourhood socioeconomic status. Univariate and multivariable logistic regression models were then developed for each dependent variable (i.e., practice location expressed in terms of each index). Residency training locations were significantly associated with practice locations across all indices. The place of secondary school education also yielded significant relationships to practice location when indexed by employment rate and relative rurality. Education interventions that leverage residency training locations may be particularly influential in promoting family physician practice location. The findings are interpreted with respect to how investment in education policies can promote physician practice in underserved communities.

Examining the effect of the COVID-19 pandemic on community virus prevalence and healthcare utilisation reveals that peaks in asthma, COPD and respiratory tract infection occur with the re-emergence of rhino/enterovirus.

INTRODUCTION: Airway disease exacerbations are cyclical related to respiratory virus prevalence. The COVID-19 pandemic has been associated with reduced exacerbations possibly related to public health measures and their impact on non-COVID-19 respiratory viruses. We aimed to investigate the prevalence of non-COVID-19 respiratory viruses during the pandemic compared with prior in Ontario, Canada and healthcare utilisation related to asthma, chronic obstructive pulmonary disease (COPD) and respiratory tract infection. METHODS: This is a population-based retrospective analysis of respiratory virus tests, emergency department (ED) visits and hospitalisations between 2015 and 2021 in Ontario. Weekly virus testing data were used to estimate viral prevalence for all non-COVID-19 respiratory viruses. We plotted the %positivity and observed and expected counts of each virus to visualise the impact of the pandemic. We used Poisson and binomial logistic regression models to estimate the change in %positivity, count of positive viral cases and count of healthcare utilisation during the pandemic. RESULTS: The prevalence of all non-COVID-19 respiratory viruses decreased dramatically during the pandemic compared with prior. Comparing periods, the incidence rate ratio (IRR) for positive cases corresponded to a >90% reduction for non-COVID-19 respiratory viruses except adenovirus and rhino/enterovirus. Asthma-related ED visits and hospital admissions fell by 57% (IRR 0.43 (95% CI 0.37 to 0.48)) and 61% (IRR 0.39 (95% CI 0.33 to 0.46)). COPD-related ED visits and admissions fell by 63% (IRR 0.37 (95% CI 0.30 to 0.45)) and 45% (IRR 0.55 (95% CI 0.48 to 0.62)). Respiratory tract infection ED visits and admissions fell by 85% (IRR 0.15 (95% CI 0.10 to 0.22)), and 85% (IRR 0.15 (95% CI 0.09 to 0.24)). Rather than the usual peaks in disease condition, during the pandemic, healthcare utilisation peaked in October when rhino/enterovirus peaked. CONCLUSIONS: The prevalence of nearly all non-COVID-19 respiratory viruses decreased during the pandemic and was associated with marked reductions in ED visits and hospitalisations. The re-emergence of rhino/enterovirus was associated with increased healthcare utilisation.

Acetylcysteine has No Mechanistic Effect in Patients at Risk of Contrast-Induced Nephropathy: A Failure of Academic Clinical Science.

Contrast-induced nephropathy (CIN) is a major complication of imaging in patients with chronic kidney disease (CKD). The publication of an academic randomized controlled trial (RCT; n = 83) reporting oral (N)-acetylcysteine (NAC) to reduce CIN led to > 70 clinical trials, 23 systematic reviews, and 2 large RCTs showing no benefit. However, no mechanistic studies were conducted to determine how NAC might work; proposed mechanisms included renal artery vasodilatation and antioxidant boosting. We evaluated the proposed mechanisms of NAC action in participants with healthy and diseased kidneys. Four substudies were performed. Two randomized, double-blind, placebo-controlled, three-period crossover studies (n = 8) assessed the effect of oral and intravenous (i.v.) NAC in healthy kidneys in the presence/absence of iso-osmolar contrast (iodixanol). A third crossover study in patients with CKD stage III (CKD3) (n = 8) assessed the effect of oral and i.v. NAC without contrast. A three-arm randomized, double-blind, placebo-controlled parallel-group study, recruiting patients with CKD3 (n = 66) undergoing coronary angiography, assessed the effect of oral and i.v. NAC in the presence of contrast. We recorded systemic (blood pressure and heart rate) and renal (renal blood flow (RBF) and glomerular filtration rate (GFR)) hemodynamics, and antioxidant status, plus biomarkers of renal injury in patients with CKD3 undergoing angiography. Primary outcome for all studies was RBF over 8 hours after the start of i.v. NAC/placebo. NAC at doses used in previous trials of renal prophylaxis was essentially undetectable in plasma after oral administration. In healthy volunteers, i.v. NAC, but not oral NAC, increased blood pressure (mean area under the curve (AUC) mean arterial pressure (MAP): mean difference 29 h⋅mmHg, P = 0.019 vs. placebo), heart rate (28 h⋅bpm, P < 0.001), and RBF (714 h⋅mL/min, 8.0% increase, P = 0.006). Renal vasodilatation also occurred in the presence of contrast (RBF 917 h⋅mL/min, 12% increase, P = 0.005). In patients with CKD3 without contrast, only a rise in heart rate (34 h⋅bpm, P = 0.010) and RBF (288 h⋅mL/min, 6.0% increase, P = 0.001) occurred with i.v. NAC, with no significant effect on blood pressure (MAP rise 26 h⋅mmHg, P = 0.156). Oral NAC showed no effect. In patients with CKD3 receiving contrast, i.v. NAC increased blood pressure (MAP rise 52 h⋅mmHg, P = 0.008) but had no effect on RBF (151 h⋅mL/min, 3.0% increase, P = 0.470), GFR (29 h⋅mL/min/1.73m², P = 0.122), or markers of renal injury. Neither i.v. nor oral NAC affected plasma antioxidant status. We found oral NAC to be poorly absorbed and have no reno-protective effects. Intravenous, not oral, NAC caused renal artery vasodilatation in healthy volunteers but offered no protection to patients with CKD3 at risk of CIN. These findings emphasize the importance of mechanistic clinical studies before progressing to RCTs for novel interventions. Thousands were recruited to academic clinical trials without the necessary mechanistic studies being performed to confirm the approach had any chance of working.

Influence of age, sex and respiratory viruses on the rates of emergency department visits and hospitalisations with respiratory tract infections, asthma and COPD.

BACKGROUND: The importance of age, sex and respiratory virus prevalence in emergency department (ED) visits and hospitalisations for respiratory tract infections (RTIs), asthma and COPD in a whole population over time is not well established. METHODS: This study retrospectively analysed data for daily ED visits and hospitalisations from 2003 to 2013 in Ontario, Canada and the daily number of virus positive tests. Daily numbers of ED visits and hospitalisations with RTIs, asthma and COPD listed as a primary diagnosis were collected from the Canadian Institute for Health Information. Virus data were obtained from the Respiratory Virus Detection Surveillance System. Multiple linear regression was used to assess the association of individual viruses with the daily rates. RESULTS: There were 4 365 578 ED visits and 321 719 (7.4%) admissions for RTIs, 817 141 ED visits and 260 665 (31.9%) admissions for COPD and 649 666 ED visits and 68 626 (10.6%) admissions for asthma. Respiratory syncytial virus and influenza A were associated with male ED visits, whereas human rhinovirus was associated with female ED visits for RTIs in preschool children. 19.2% of males, but only 7.2% of females were admitted. The correlation between the prevalence of each virus and ED visits and hospitalisations for asthma was weak, irrespective of age group and sex. Influenza A was most strongly associated with COPD ED visits and hospitalisations in males and females. CONCLUSIONS: There are significant age and sex differences in the contribution of respiratory viruses to the number of ED visits and hospitalisations for RTIs, asthma and COPD.

Emergency department visits and hospitalisations for asthma, COPD and respiratory tract infections: what is the role of respiratory viruses, and return to school in September, January and March?

BACKGROUND: Asthma exacerbations increase in September coinciding with children returning to school. The aim of this study was to investigate whether this occurs 1) for COPD and respiratory tract infections (RTIs); 2) after school resumes in January and March; and 3) identify which viruses may be responsible. METHODS: Emergency department (ED) visits and admissions for asthma, COPD and RTIs and the prevalence of viruses in Ontario, Canada were analysed daily between 2003 and 2013. ED visits and admissions were provided by the Canadian Institute for Health Information. Viral prevalence was obtained from the Centre for Immunisation and Respiratory Infectious Diseases. RESULTS: ED visits and admissions rates demonstrated a biphasic pattern. Lowest rates occurred in July and August and the highest rates in September for asthma, and after December for COPD and RTI. The increase in rates for 30 days before and after school return in September was greatest for children with asthma <15 years (2.4-2.6×). Event rates fell after school return in January for all three conditions ranging from 10-25%, and no change followed March break for asthma and COPD. Human rhinovirus was prevalent in summer with a modest relationship to asthma rates in September. The prevalence of respiratory syncytial virus, influenza A and coronavirus was associated with sustained event rates for COPD and RTIs. CONCLUSIONS: Asthma, COPD and RTIs increase in September but do not occur after return to school in January and March. Human rhinovirus is associated with ED visits and admissions only in September.

Prevalence and contribution of respiratory viruses in the community to rates of emergency department visits and hospitalizations with respiratory tract infections, chronic obstructive pulmonary disease and asthma.

BACKGROUND: The individual and combined contribution of viral prevalence in the community to Emergency Department (ED) visits and hospitalizations with respiratory tract infections (RTIs), chronic obstructive pulmonary disease (COPD) and asthma is unclear. METHODS: A retrospective analysis on daily viral positive tests and daily ED visits and hospitalizations between 01/01/2003 to 31/12/2013 in Ontario, Canada. Viral data was collected from the Centre for Immunization and Respiratory Infectious Diseases (CIRID). The Canadian Institute for Health Information reports daily ED visits and hospitalizations for RTIs, COPD and asthma as a primary diagnosis. RESULTS: There were 4,365,578 ED visits with RTIs of which 321,719 (7.4%) were admitted to hospital; 817,141 ED visits for COPD of which 260,665 (31.9%) were admitted and 649,666 ED visits with asthma of which 68,626 (10.6%) were admitted. The percentage of positive tests to influenza A and B, respiratory syncytial virus (RSV), parainfluenza and adenovirus prevalence explained 57.4% of ED visits and 63.8% of hospitalizations for RTI, 41.4% of ED visits and 39.2% of hospitalizations with COPD but only 1.5% of ED visits and 2.7% of hospitalizations for asthma. The further addition of human metapneumovirus, rhinovirus and coronavirus over the final 3 years accounted for 66.7% of ED visits and 74.4% of hospitalizations for RTI, 52.5% of visits and 48.2% of hospitalizations for COPD, and only 13.3% of visits and 10.4% of hospitalizations for asthma. CONCLUSIONS: Community respiratory viral epidemics are major drivers of ED visits and hospitalizations with RTIs and COPD but only a modest contributor to asthma.

Relation between socioeconomic variables and surgical, systemic and radiation treatment in a cohort of patients with breast cancer in an urban Canadian centre

Background: Studies have shown an association between socioeconomic status and breast cancer treatment. We examined the relation between socioeconomic status and the treatment of breast cancer (surgical, systemic and radiation) in a universal health care system. Methods: Data from a single urban Canadian centre were collected for consecutive patients who received a diagnosis of breast cancer from January 2010 to December 2011. Variables included patient and disease factors, surgery type, systemic and radiation treatment, and breast reconstruction. Socioeconomic variables were obtained from 2006 Canadian census data. We used multivariable logistic regression to identify predictors of breast cancer treatment. Results: A total of 721 patients were treated for breast cancer during the study period. Socioeconomic variables were not related to type of breast surgery for breast cancer. Age less than 50 years, having a first-degree relative with breast cancer and income status were predictors of breast reconstruction. Employment status was a consistent predictor of systemic and radiation treatment. Conclusion: Employment consistently predicted systemic and radiation treatment, and age and income were predictors of breast reconstruction in a universal health care system. Further research is required to determine precisely how socioeconomic factors affect care and to minimize possible disparities in delivery of health care services.

Contexte: Des études ont montré un lien entre la situation socio-économique et le traitement du cancer du sein. Nous avons analysé ce lien entre la situation socioéconomique et le traitement (chirurgie, chimiothérapie, radiothérapie) du cancer du sein dans un système de santé universel. Méthodes: Les données d'un seul centre urbain canadien ont été compilées pour les patientes consécutives ayant reçu un diagnostic de cancer du sein entre janvier 2010 et décembre 2011. Les variables incluaient des facteurs propres aux patientes et à la maladie, le type de chirurgie, la chimiothérapie, la radiothérapie et la reconstruction mammaire. Les variables socio-économiques proviennent des données du recensement canadien de 2006. Nous avons utilisé la régression logistique multivariée pour identifier les prédicteurs du traitement du cancer du sein. Résultats: En tout, 721 patientes ont été traitées pour un cancer du sein durant la période de l'étude. Les variables socio-économiques n'ont pas influé sur le type de chirurgie mammaire pour cancer du sein. L'âge inférieur à 50 ans, un cancer du sein chez une parente au premier degré et le revenu ont été des prédicteurs de la reconstruction mammaire. La situation professionnelle a été un prédicteur fiable du traitement systémique et de la radiothérapie. Conclusion: L'emploi a été un prédicteur fiable du traitement systémique et de la radiothérapie, et l'âge et le revenu ont été des prédicteurs de la reconstruction mammaire, dans un système de santé universel. Il faudra approfondir la recherche pour déterminer plus précisément l'influence des facteurs socio-économiques sur les soins et pour réduire les possibles disparités dans leur prestation.

Confirmation of ovulation from urinary progesterone analysis: assessment of two automated assay platforms.

Urinary concentrations of the major progesterone (P4) metabolite pregnanediol-3-glucuronide (PDG) are used to confirm ovulation. We aimed to determine whether automated immunoassay of urinary P4 was as efficacious as PDG to confirm ovulation. Daily urine samples from 20 cycles in 14 healthy women in whom ovulation was dated by ultrasound, and serial weekly samples from 21 women in whom ovulation was unknown were analysed. Daily samples were assayed by two automated P4 immunoassays (Roche Cobas and Abbott Architect) and PDG ELISA. Serial samples were assayed for P4 by Architect and PDG by ELISA. In women with detailed monitoring of ovulation, median (95% CI) luteal phase increase was greatest for PDG, 427% (261-661), 278% (187-354) for P4 Architect and least for P4 Cobas, 146% (130-191), p < 0.0001. Cobas P4 also showed marked inaccuracy in serial dilution. Similar ROC AUCs were observed for individual threshold values and two-sample percent rise analyses for P4 Architect and PDG (both >0.92). In serial samples classified as (an)ovulatory by PDG, P4 Architect gave ROC AUC 0.95 (95% CI 0.89 to 1.01), with sensitivity and specificity for confirmation of ovulation of 0.90 and 0.91 at a cutoff of 1.67 µmol/mol. Automated P4 may potentially be as efficacious as PDG ELISA but research from a range of clinical settings is required.

Colds as predictors of the onset and severity of COPD exacerbations.

RATIONALE: Common colds are associated with acute respiratory symptom exacerbations in COPD patients. OBJECTIVE: To determine exacerbation risk and severity in COPD patients with/without coincident self-reported colds. METHODS: Global initiative for chronic Obstructive Lung Disease stage I-IV COPD patients electronically transmitted respiratory symptom diaries to research staff daily between December 2006 and April 2009. Respiratory symptom worsening prompted contact by a study nurse and patient assessment to determine if a cold was present or an exacerbation underway. A composite daily symptom score was derived for each subject from diarized symptom data. The exacerbation/cold/virus relation was examined using a Poisson regression model, the relation of colds to respiratory symptom severity using generalized estimating equation models. RESULTS: Daily diary transmission compliance of >97% enabled detection of all possible exacerbations. Among 262 exacerbations meeting Anthonisen criteria, 218 (83%) had cold-like symptoms present at their inception, but respiratory viruses were detected in only 106 (40%). Within-subject exacerbation risk was 30 times (95% confidence interval [CI]: 20, 47; P<0.001) greater with colds present. Compared to cold- and virus-negative exacerbations (n=57), the mean increase in composite symptom score in those cold and virus positive (n=79) was 0.93 (95% CI: 0.61, 1.25; P<0.001), cold-positive and virus-negative exacerbations (n=100) 0.51 (95% CI: 0.21, 0.81; P<0.001), cold-negative and virus-positive exacerbations (n=26) 0.58 (95% CI: 0.23, 0.94; P<0.001). CONCLUSION: This study emphasizes the importance of colds in COPD exacerbation risk and severity, even in the absence of virus detection. COPD patients should act promptly when cold symptoms appear to facilitate early intervention for exacerbation prevention or management.

Seasonal and geographic variations in the incidence of asthma exacerbations in the United States.

BACKGROUND: Exacerbations drive the burden of asthma and lead to significant morbidity and consumption of health care resources. Many prior studies of the epidemiology of asthma exacerbations have relied upon data from hospital care. OBJECTIVE: The objective of this study was to determine US patterns of geographic and seasonal variations of asthma exacerbations being defined as asthma episodes requiring hospital care and/or a prescription for oral steroid. METHODS: The study was a retrospective observational cohort study using administrative claims data for insured individuals from the HealthCore Integrated Research Database, including around 43 million members in the United States. Analyses examined 3 age groups, 6-17, 18-64, and ≥65 years and four US regions, Northeast, Southeast, Central, and Western. RESULTS: Monthly rates of asthma exacerbations showed the greatest variation over the year in children, less so in adults and in the elderly. Clinically important differences in rates of asthma exacerbation were observed between regions with the Western Region having the lowest in all three age groups followed by the Northeast, Central, and Southeast regions. Peaks in children occurred in the early fall following troughs in the summer months, and peaks at year-end occurred in adults, particularly in those over 65 years. CONCLUSIONS: There is a striking seasonal variation in asthma exacerbations in the United States. Substantial differences between regions of the United States in asthma exacerbation rates cannot readily be explained and invite further investigation.

Effect of polyphenol-rich grape seed extract on ambulatory blood pressure in subjects with pre- and stage I hypertension.

Dietary polyphenols, such as those from grape products, may exert beneficial effects on cardiovascular health, including anti-hypertensive effects. We investigated the effect of a specific grape seed extract (GSE) rich in low-molecular-weight polyphenolic compounds on ambulatory blood pressure (ABP) in untreated subjects with pre- and stage I hypertension. In addition, potential mechanisms that could underlie the hypothesised effect of GSE on blood pressure (BP), and platelet aggregation, were explored. The study was designed as a double-blind, placebo-controlled, randomised, parallel-group intervention study including seventy healthy subjects with systolic BP between 120 and 159 mmHg. A 1-week run-in period was followed by an 8-week intervention period, during which subjects consumed capsules containing either 300 mg/d of GSE or a placebo (microcrystalline cellulose). Before and after the intervention, daytime ABP readings, 24 h urine samples and fasting and non-fasting blood samples were taken. The mean baseline systolic BP was 135.8 (SE 1.3) mmHg and diastolic BP was 81.5 (SE 0.9) mmHg. BP values were modestly, but not significantly, affected by the polyphenol-rich GSE treatment v. placebo with an effect of - 3.0 mmHg for systolic BP (95% CI - 6.5, 0.5) and - 1.4 mmHg for diastolic BP (95% CI - 3.5, 0.6). Vasoactive markers including endothelin-1, NO metabolites and asymmetric dimethylarginine, plasma renin activity and platelet aggregation were not affected by the GSE intervention. Our findings show that consumption of polyphenol-rich GSE does not significantly lower ABP in untreated subjects with pre- and stage I hypertension.

Detection of COPD Exacerbations and compliance with patient-reported daily symptom diaries using a smart phone-based information system [corrected].

BACKGROUND: Paper-based diaries and self-report of symptom worsening in COPD may lead to underdetection of exacerbations. Epidemiologically, COPD exacerbations exhibit seasonal patterns peaking at year-end. We examined whether the use of a BlackBerry-based daily symptom diary would detect 95% or more of exacerbations and enable characterization of seasonal differences among them. METHODS: Fifty participants with GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage I to IV COPD began a community-based study in December 2007. Another 30 began in December 2008. Participants transmitted daily symptom diaries using a BlackBerry. Alerts were triggered when symptom changes, missed diary transmissions, or medical care for a respiratory problem occurred. Participant encounters were initiated if COPD exacerbations were suspected. Participants used their BlackBerrys to report returns to normal breathing. RESULTS: Participants transmitted 99.9% of 28,514 possible daily diaries. All 191 (2.5/participant-year) COPD exacerbations meeting Anthonisen criteria were detected. During 148 of the 191 exacerbations (78%, 1.97/participant-year), patients were hospitalized and/or ordered prednisone, an antibiotic, or both. Respiratory viruses were detected in 78 of the 191 exacerbations (41%). Those coinciding with a respiratory viral infection averaged 12.0 days, and those without averaged 8.9 days (P < .04), with no difference in Anthonisen score. Respiratory symptom scores before exacerbations and after normal breathing return showed no differences. Exacerbations were more frequent during the Christmas period than the rest of the year but were not more frequent than in the rest of winter alone. CONCLUSIONS: Smartphone-based collection of COPD symptom diaries enables near-complete identification of exacerbations at inception. Exacerbation rates in the Christmas season do not reach levels that necessitate changes in disease management.

Histamine-induced vasodilatation in the human forearm vasculature.

AIM: To investigate the mechanism of action of intra-arterial histamine in the human forearm vasculature. METHODS: Three studies were conducted to assess changes in forearm blood flow (FBF) using venous occlusion plethysmography in response to intra-brachial histamine. First, the dose-response was investigated by assessing FBF throughout a dose-escalating histamine infusion. Next, histamine was infused at a constant dose to assess acute tolerance. Finally, a four way, double-blind, randomized, placebo-controlled crossover study was conducted to assess FBF response to histamine in the presence of H1 - and H2 -receptor antagonists. Flare and itch were assessed in all studies. RESULTS: Histamine caused a dose-dependent increase in FBF, greatest with the highest dose (30 nmol min(-1) ) infused [mean (SEM) infused arm vs. control: 26.8 (5.3) vs. 2.6 ml min(-1) 100 ml(-1) ; P < 0.0001]. Dose-dependent flare and itch were demonstrated. Acute tolerance was not observed, with an increased FBF persisting throughout the infusion period. H2 -receptor antagonism significantly reduced FBF (mean (95% CI) difference from placebo at 30 nmol min(-1) histamine: -11.9 ml min(-1) 100 ml(-1) (-4.0, -19.8), P < 0.0001) and flare (mean (95% CI) difference from placebo: -403.7 cm(2) (-231.4, 576.0), P < 0.0001). No reduction in FBF or flare was observed in response to the H1 -receptor antagonist. Itch was unaffected by the treatments. Histamine did not stimulate vascular release of tissue plasminogen activator or von Willebrand factor. CONCLUSION: Histamine causes dose-dependent vasodilatation, flare and itch in the human forearm. H2 -receptors are important in this process. Our results support further exploration of combined H1 - and H2 -receptor antagonist therapy in acute allergic syndromes.

Endothelin-A receptor antagonism modifies cardiovascular risk factors in CKD.

Arterial stiffness and impaired nitric oxide (NO) bioavailability contribute to the high risk for cardiovascular disease in CKD. Both asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO production, and endothelin-1 (ET-1) oppose the actions of NO, suggesting that ET-1 receptor antagonists may have a role in cardiovascular protection in CKD. We conducted a randomized, double-blind, three-way crossover study in 27 patients with proteinuric CKD to compare the effects of the ET(A) receptor antagonist sitaxentan, nifedipine, and placebo on proteinuria, BP, arterial stiffness, and various cardiovascular biomarkers. After 6 weeks of treatment, placebo and nifedipine did not affect plasma urate, ADMA, or urine ET-1/creatinine, which reflects renal ET-1 production; in contrast, sitaxentan led to statistically significant reductions in all three of these biomarkers. No treatment affected plasma ET-1. Reductions in proteinuria and BP after sitaxentan treatment was associated with increases in urine ET-1/creatinine, whereas reduction in pulse-wave velocity, a measure of arterial stiffness, was associated with a decrease in ADMA. Taken together, these data suggest that ET(A) receptor antagonism may modify risk factors for cardiovascular disease in CKD.

Mechanisms for an effect of acetylcysteine on renal function after exposure to radio-graphic contrast material: study protocol.

BACKGROUND: Contrast-induced nephropathy is a common complication of contrast administration in patients with chronic kidney disease and diabetes. Its pathophysiology is not well understood; similarly the role of intravenous or oral acetylcysteine is unclear. Randomized controlled trials to date have been conducted without detailed knowledge of the effect of acetylcysteine on renal function. We are conducting a detailed mechanistic study of acetylcysteine on normal and impaired kidneys, both with and without contrast. This information would guide the choice of dose, route, and appropriate outcome measure for future clinical trials in patients with chronic kidney disease. METHODS/DESIGN: We designed a 4-part study. We have set up randomised controlled cross-over studies to assess the effect of intravenous (50 mg/kg/hr for 2 hrs before contrast exposure, then 20 mg/kg/hr for 5 hrs) or oral acetylcysteine (1200 mg twice daily for 2 days, starting the day before contrast exposure) on renal function in normal and diseased kidneys, and normal kidneys exposed to contrast. We have also set up a parallel-group randomized controlled trial to assess the effect of intravenous or oral acetylcysteine on patients with chronic kidney disease stage III undergoing elective coronary angiography. The primary outcome is change in renal blood flow; secondary outcomes include change in glomerular filtration rate, tubular function, urinary proteins, and oxidative balance. DISCUSSION: Contrast-induced nephropathy represents a significant source of hospital morbidity and mortality. Over the last ten years, acetylcysteine has been administered prior to contrast to reduce the risk of contrast-induced nephropathy. Randomized controlled trials, however, have not reliably demonstrated renoprotection; a recent large randomized controlled trial assessing a dose of oral acetylcysteine selected without mechanistic insight did not reduce the incidence of contrast-induced nephropathy. Our study should reveal the mechanism of effect of acetylcysteine on renal function and identify an appropriate route for future dose response studies and in time randomized controlled trials. TRIAL REGISTRATION: Clinical Trials.gov: NCT00558142; EudraCT: 2006-003509-18.

Selective endothelin-A receptor antagonism reduces proteinuria, blood pressure, and arterial stiffness in chronic proteinuric kidney disease.

Proteinuria is associated with adverse cardiovascular and renal outcomes that are not prevented by current treatments. Endothelin 1 promotes the development and progression of chronic kidney disease and associated cardiovascular disease. We, therefore, studied the effects of selective endothelin-A receptor antagonism in proteinuric chronic kidney disease patients, assessing proteinuria, blood pressure (BP), and arterial stiffness, key independent, surrogate markers of chronic kidney disease progression and cardiovascular disease risk. In a randomized, double-blind, 3-way crossover study, 27 subjects on recommended renoprotective treatment received 6 weeks of placebo, 100 mg once daily of sitaxsentan, and 30 mg once daily of nifedipine long acting. Twenty-four-hour proteinuria, protein:creatinine ratio, 24-hour ambulatory BP, and pulse wave velocity (as a measure of arterial stiffness) were measured at baseline and week 6 of each treatment. In 13 subjects, renal blood flow and glomerular filtration rate were assessed at baseline and week 6 of each period. Compared with placebo, sitaxsentan reduced 24-hour proteinuria (-0.56±0.20 g/d; P=0.0069), protein:creatinine ratio (-38±15 mg/mmol; P=0.0102), BP (-3.4±1.2 mm Hg; P=0.0069), and pulse wave velocity (-0.64±0.24 m/s; P=0.0052). Nifedipine matched the BP and pulse wave velocity reductions seen with sitaxsentan but did not reduce proteinuria. Sitaxsentan alone reduced both glomerular filtration rate and filtration fraction. It caused no clinically significant adverse effects. Endothelin-A receptor antagonism may provide additional cardiovascular and renal protection by reducing proteinuria, BP, and arterial stiffness in optimally treated chronic kidney disease subjects. The antiproteinuric effects of sitaxsentan likely relate to changes in BP and renal hemodynamics.